EMA发布集中审批程序上市后程序建议文件修订痕迹版（EMEA-H-19984/03）

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13 5 July October 2026

EMEA-H-19984/03 Rev. 1198

Human Medicines Evaluation Division

European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

Important information regarding ending of Irish language derogation

As of 1st January 2022, a derogation expires concerning the status of Irish as a working language of

the EU Institutions.

This means that Irish will be the authentic language of Commission decisions on marketing

authorisations, including the product information they contain, addressed to any marketing

authorisation holder established in Ireland, unless they request a language waiver. This will also apply

to post-authorisation decisions of the European Commission addressed to EU Member States, including

the product information they contain, which will be translated into Irish together with the other official

EU languages, for the following procedures: Referrals , Periodic safety update reports (PSURs) , Post-

authorisation safety studies (PASS) .

Companies should be aware that at a certain point in the future a more extensive use of the Irish

language may be required.

Please see also: Irish language (EMA webpage) and Guidance on Irish language derogation ending on 1

January 2022

Important technical information

As of 1 st of November 2021, the registration of new sites and organisations for centrally-authorised

medicinal products in Organisation Management Service (OMS) will become mandatory prior to the

associated regulatory submissions to the Agency (e.g. transfer of the marketing authorisation, addition

of a manufacturing site).

The EMA would like to emphasise the importance of these site/organisation registrations in OMS prior

to pre- and post-authorisation submissions, in order to avoid any delay in the start of these

procedures, as this would constitute a validation blocking issue.

Please see also: SPOR Web UI (europa.eu) and Q&A on the mandatory use of OMS for CAPs

This integrated version has been created for printing purposes only. Please refer to the individual question & answers as published in the post-authorisation guidance for access to the hyperlinked information. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

EMEA-H-19984/03 Page 2/305

Questions and answers are being updated continuously and will be marked by “NEW” or “Rev.” with

the relevant date upon publication.

This guidance document addresses a number of questions which marketing authorisation holders (MAHs) may have on post-authorisation procedures. It provides an overview of the Agency’s position

on issues, which are typically addressed in discussions or meetings with MAHs in the post-authorisation phase.

It will be updated regularly to reflect new developments, to include guidance on further post-authorisation procedures and to reflect the implementation of the new European legislation. Revised

topics will be marked by “New” or “Rev” upon publication.

The Agency emphasises the importance of pre-submission meetings between MAHs and the EMA/(Co-) Rapporteur. The product team is available to address any questions MAHs may have regarding a particular upcoming post-authorisation applications. Where appropriate, a pre-submission meeting could be organised at the Agency in order to obtain further procedural and regulatory/legal advice.

This guidance information and fruitful pre-submission dialogue between MAHs and the Agency should enable MAHs to submit applications, which are in conformity with the legal and regulatory requirements and which can be validated and processed promptly.

In addition, MAHs are strongly recommended to inform the Agency and (Co-) Rapporteur of all upcoming post-authorisation submissions for the following 6-12 months, in order to allow optimal planning, identification of procedural issues and handling of overlapping applications.

Note:

It should be highlighted that this document has been produced for guidance only and should be read in conjunction with "The Rules governing Medicinal Products in the European Union, Volume 2, Notice to Applicants".

MAHs must in all cases comply with the requirements of EU Legislation. Provisions, which extend to Iceland, Liechtenstein and Norway by virtue of the EEA agreement, are outlined in the relevant sections of the text. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

EMEA-H-19984/03 Page 3/305

Table of Contents

1. Type IA Variations ................................................................................. 15

1.1. When shall I submit my Type IA/IA IN variation(s)? Rev. Oct 2026 ............................. 15

1.2. Can I (super-)group the submission of Type IA/IA IN variations? Can they be grouped with other types of variations? Rev. Nov 2025 .............................................................. 17

1.3. Is the (Co-) Rapporteur involved in the review of Type IA/IA IN variations? Rev. Mar 2025 ....................................................................................................................... 18

1.4. How shall I present and submit my Type IA/ IA IN Variation(s)? Rev. Jul 2026............. 19

1.5. How shall my Type IA/IA IN variation be handled (timetable)? Rev. Mar 2025 .............. 22

1.6. Can my Type IA/ IA IN be part of worksharing? Rev. Mar 2025 .................................. 23

1.7. What should I do in case of an unfavourable outcome for my Type IA/ IA IN variation(s)? Rev. Mar 2025 .......................................................................................................... 23

1.8. What fee do I have to pay for a Type IA/ IA IN variation? Rev. Dec 2024 .................... 24

1.9. Do I have to submit mock-ups and specimens? Rev. July 2013 ................................ 24

1.10. What changes will trigger new EU number(s) (additional presentation(s))? Rev. Mar 2025 ....................................................................................................................... 24

1.11. How to obtain new EU sub-numbers for Type IA IN variation concerning an additional presentation (e.g. new pack-size)? Rev. Mar 2025 ........................................................ 25

1.12. When do I have to submit revised product information? In all languages? Rev. Jul 2026 ....................................................................................................................... 25

1.13. How and when will the updated product information Annexes become part of the Marketing Authorisation? Rev. Mar 2025 ...................................................................... 27

1.14. What should be the date of revision of the text for Type IA Variations? Rev. Mar 2025 .............................................................................................................................. 28

1.15. Who should I contact if I have a question when preparing my application or during the procedure? Rev. Nov 2025 ......................................................................................... 28

2. Type IB variations ................................................................................. 29

2.1. What changes are considered Type IB variations? Rev. Nov 2025 ............................. 29

2.2. Is the (Co-) Rapporteur involved in Type IB Variations? Rev. Feb 2019 ..................... 29

2.3. Can I group the submission of Type IB variations? Can they be grouped with other types of variations? Rev. Mar 2025 ...................................................................................... 30

2.4. How shall I present and submit my Type IB Variation? Rev. Jul 2026 ........................ 30

2.5. When shall I submit my Type IB Variation? Rev. Feb 2025 ...................................... 33

2.6. When do I need a linguistic review for changes in the product information? Rev. Nov 2025 ....................................................................................................................... 34

2.7. How shall my Type IB variation be handled (timetable)? Rev. Nov 2025 .................... 35

2.8. What fee do I have to pay for a Type IB Variation? Rev. Dec 2024 ........................... 37

2.9. Do I have to submit mock-ups and specimens? Rev. Apr 2016 ................................. 37

2.10. How should I submit revised product information? In all languages? Rev. Nov 2025 . 38

2.11. What changes will trigger new EU number(s) (additional presentation(s))? Rev. Nov 2025 ....................................................................................................................... 39

2.12. How to obtain new EU sub-numbers for a Type IB variation concerning an additional presentation (e.g. new pack-size)? Rev. Jul 2023.......................................................... 40

2.13. How and when will the updated Annexes become part of the Marketing Authorisation? Rev. Oct 2012 .......................................................................................................... 41 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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2.14. Who should I contact if I have a question when preparing my application or during the procedure? Rev. Nov 2025 ......................................................................................... 42

3. Type II variations .................................................................................. 43

3.1. What changes considered Type II variations? Rev. Dec 2016 ................................... 43

3.2. Do I need to notify the Agency of my intention to submit a Type II variation application? Rev. Nov 2025.......................................................................................................... 43

3.3. Which Committee will take the lead in the assessment of a Type II variation? Rev. Nov 2025 ....................................................................................................................... 44

3.4. Is the Co-Rapporteur involved in Type II Variations? Rev. Nov 2025 ......................... 44

3.5. Is the PRAC Rapporteur involved in Type II variations? Rev. Nov 2025 ...................... 45

3.6. Can I group the submission of Type II variations? Can they be grouped with other types of variations? Rev. Mar 2025 ...................................................................................... 45

3.7. How shall I present my Type II Variation application? Rev. Jul 2026 ......................... 45

3.8. How shall I present my application for a new or modified therapeutic indication? Rev. Oct 2026 ................................................................................................................. 49

3.9. How and to whom shall I submit my Type II Variation application? Rev. Feb 2019 ...... 51

3.10. When shall I submit my Type II variation? Rev. Nov 2025 ..................................... 51

3.11. How shall my Type II application be handled (timetable)? Rev. Oct 2026 ................. 52

3.12. How should parallel Type II variations that affect the product information be handled? Rev. Nov 2025.......................................................................................................... 57

3.13. Which post-opinion steps apply to my Type II variation and when can I implement the approved changes? Rev. Oct 2026 .............................................................................. 58

3.14. What fee do I have to pay for a Type II variation? Rev. Dec 2024 ........................... 61

3.15. Do I have to submit mock-ups and specimens? Rev. July 2013 .............................. 62

3.16. When do I have to submit revised product information? In all languages? Rev. Feb 2025 ....................................................................................................................... 62

3.17. What changes will trigger new EU number(s) (additional presentation(s))? Rev. Nov 2025 ....................................................................................................................... 65

3.18. What is the procedure for assignment of new European Union sub-numbers for a Type II variation concerning additional presentation(s)? NEW Nov 2012 .................................. 65

3.19. Will there be any publication on the outcome of my Type II variation? Rev. Oct 2012 66

3.20. What aspects should I consider at time of submission of a Type II variation if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication? Rev. May 2020 ......................................................................... 66

3.21. Do I need to confirm the maintenance of my orphan designation when applying for a Type II variation? Rev. Mar 2026 ................................................................................ 67

3.22. Can a non-orphan therapeutic indication be added to an already authorised orphan medicinal product? Rev. Nov 2025 .............................................................................. 68

3.23. Can a new indication based on less comprehensive data be added to an already authorised medicinal product? Rev. Nov 2025 .............................................................. 69

3.24. Do I need to address any paediatric requirements in my Type II variation application? Rev. Mar 2026 .......................................................................................................... 70

3.25. When will I get a PIP compliance statement? Rev. Oct 2026 .................................. 72

3.26. How and when can I withdraw my Type II variation application? Rev. Nov 2025 ....... 73

3.27. Who is my contact at the European Medicines Agency during a Type II variation, including extension of indications? Rev. Mar 2024 ......................................................... 74

3.28. Whom should I contact if I have a pre-submission question when preparing my Type II variation application? Rev. Mar 2024 ........................................................................... 75 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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4. Extension of marketing authorisation .................................................... 76

4.1. When will my variation application be considered a Type II variation or an extension application? Rev. Mar 2026 ........................................................................................ 76

4.2. Extension applications – will my invented name changes? Rev. Aug 2014 .................. 77

4.3. Do I need to notify the Agency of my intention to submit an extension application? Rev. Jan 2021 ................................................................................................................. 77

4.4. Is the (Co-) Rapporteur involved in Extension Applications? Rev. March 2013 ............ 78

4.5. How shall I present my Extension Application? Rev. Jul 2026 ................................... 78

4.6. What aspects should I consider at time of submission of an extension application if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication? Rev. May 2020 ........................................................... 80

4.7. Do I need to confirm the maintenance of my orphan designation when applying for an extension application? Rev. Mar 2026 .......................................................................... 82

4.8. Can a non-orphan therapeutic indication be added to an already authorised orphan medicinal product? NEW Mar 2016 .............................................................................. 83

4.9. Can a new indication based on less comprehensive data be added to an already authorised medicinal product? NEW Nov 2016 .............................................................. 83

4.10. Can I group the submission of Extensions with other types of variations? Rev. Oct 2013 ....................................................................................................................... 83

4.11. How, when and to whom shall I submit my Extension Application? Rev. Feb 2019 .... 83

4.12. How shall my Extension Application be handled (timetable)? Rev. Oct 2026 ............. 84

4.13. What fee do I have to pay for an Extension Application? Rev. Dec 2024 .................. 88

4.14. Do I have to submit mock-ups and specimens? Rev. July 2013 .............................. 88

4.15. When do I have to submit revised product information? In all languages? Rev. Mar 2026 ....................................................................................................................... 88

4.16. What is the procedure for assignment of new European Union sub-numbers for an extension including additional presentation(s)? New Nov 2012 ....................................... 90

4.17. Will there be any publication on the outcome of my Extension application? Rev. Oct 2012 ....................................................................................................................... 90

4.18. Do I need to address any paediatric requirements in my extension application? Rev. Mar 2025 ................................................................................................................. 91

4.19. Who should I contact if I have a question when preparing my application and during the procedure? Rev. Feb 2019 .................................................................................... 93

4.20. How and when can I withdraw my extension application? NEW Jun 2023 ................. 93

5. Grouping of variations ........................................................................... 95

5.1. What types of variations can be grouped? Rev. Mar 2025 ........................................ 95

5.2. What groups of variations would be considered acceptable? Rev. Mar 2026 ............... 97

5.3. How shall I present a grouped variations application? Rev. Jul 2026 ....................... 101

5.4. What procedure number will be given to grouped variation applications? Rev. Jul 2026 ............................................................................................................................ 102

5.5. Shall grouped variations be subject to a worksharing procedure? Rev. Mar 2025 ...... 103

5.6. How will grouped variation applications be handled (timetable)? What will be the outcome of the evaluation of a grouped variation application? Rev. Jul 2025 .................. 103

5.7. How and when will the marketing authorisation be updated for grouped variations? Rev. Mar 2025 ............................................................................................................... 104

5.8. What fee do I have to pay for grouped variations? Rev. Dec 2024 .......................... 105 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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6. Worksharing of variations ................................................................... 106

6.1. What is worksharing and what types of variations can be subject to worksharing? Rev. Nov 2025 ............................................................................................................... 106

6.2. Which variation(s) should be submitted under mandatory worksharing? Rev. Mar 2025 ............................................................................................................................ 107

6.3. What pre-submission steps will apply to a worksharing procedure? Rev. Mar 2025 ... 108

6.4. How shall I present a variation application under worksharing? Rev. Jul 2026 .......... 109

6.5. How and to whom shall I submit my variation application under worksharing? Rev. Mar 2026 ..................................................................................................................... 110

6.6. What procedure number will be given to variation applications under worksharing? Rev. Oct 2020 ............................................................................................................... 112

6.7. How will variation applications under worksharing be handled (timetable)? What will be the outcome of the evaluation of a variation application under worksharing? Rev. Nov 2025 ............................................................................................................................ 113

6.8. How and when will the marketing authorisations be updated following a worksharing procedure? When can I implement the approved changes? Rev. Jul 2026....................... 114

6.9. What fee do I have to pay for variation applications under worksharing? Rev. Dec 2024 ............................................................................................................................ 117

6.10. When do I have to submit revised product information? In all languages? Rev. Mar 2026 ..................................................................................................................... 118

7. Classification of changes ..................................................................... 121

7.1. Administrative changes Rev. Nov 2025 ............................................................... 121

7.2. Quality changes Rev. Nov 2025 .......................................................................... 122

7.3. (Non-) Clinical changes Rev. Nov 2025 ............................................................... 129

7.4. Editorial changes Rev. Mar 2026 ........................................................................ 138

8. Pre-submission queries service ........................................................... 142

8.1. What is the pre-submission queries service? Rev. Jul 2025 .................................... 142

8.2. How should I send queries to the pre-submission queries service? Rev. Jul 2023 ...... 142

8.3. How will my query be handled by the pre-submission queries service? .................... 143

8.4. When can I expect to receive a response to my query? Rev. May 2020 ................... 143

9. Changing the (Invented) Name of a Centrally Authorised Medicinal Product.................................................................................................... 144

9.1. Can I change the (Invented) Name of my CAP? Rev. Nov 2025 .............................. 144

9.2. Is the Invented Name (IN) checking procedure mandatory for the new proposed IN? Rev. Oct 2013 ........................................................................................................ 144

9.3. How shall I present my IN change application? Rev. Nov 2025 ............................... 145

9.4. Do I need to submit amended mock-ups/specimens with my variation? Rev. Oct 2013 ............................................................................................................................ 145

10. Annual Re-assessment ...................................................................... 146

10.1. What is the annual re-assessment? Rev. Dec 2015 ............................................. 146

10.2. Are the CHMP Co-Rapporteur and the PRAC involved in the assessment? Rev. Apr 2021 ............................................................................................................................ 146

10.3. How shall I present my annual re-assessment application? Rev. May 2020 ............ 147

10.4. Can I submit a PSUR with my annual re-assessment application? Rev. Dec 2015 .... 149

10.5. Can I submit an RMP with my annual re-assessment application? Rev. Aug 2017 ... 149 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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10.6. When, how and to whom shall I submit my annual re-assessment application? Rev. Jun 2022 ............................................................................................................... 149

10.7. How shall my annual re-assessment be handled (timetable)? Rev. Apr 2021 .......... 150

10.8. What could be the outcome of my annual re-assessment? Rev. Dec 2015 .............. 150

10.9. Can I submit my annual re-assessment within the renewal? Rev. Dec 2015 ........... 151

10.10. Do I have to pay fees for an annual re-assessment? Rev. Dec 2024 .................... 152

10.11. What impact do ongoing Variation(s) (Type IA/IB or Type II) have on the annual re-assessment? Rev. Dec 2015 ..................................................................................... 152

10.12. Do I have to submit mock-ups and specimens? Rev. Dec 2015 ........................... 152

10.13. When do I have to submit (revised) product information? In all languages? Rev. Apr 2021 ..................................................................................................................... 152

10.14. Will there be any publication on the outcome of my annual re-assessment? Rev. Dec 2015 ..................................................................................................................... 154

10.15. Who should I contact if I have a question when preparing my application and during the procedure? Rev. Feb 2019 .................................................................................. 155

11. Renewal ............................................................................................ 156

11.1. How long is my marketing authorisation valid for? Rev. Feb 2019 ......................... 156

11.2. When shall I submit my renewal application? Rev. May 2020 ............................... 156

11.3. How shall I present my renewal application? Rev. May 2020 ................................ 157

11.4. How and to whom shall I submit my renewal application? Rev. Feb 2019 ............... 162

11.5. How shall my renewal application be handled (timetable)? Rev. Aug 2016 ............. 162

11.6. What fee do I have to pay for a renewal? Rev. Dec 2024 ..................................... 163

11.7. Can other non-renewal specific changes be included in the renewal application? Rev. Dec 2015 ............................................................................................................... 163

11.8. How to handle other ongoing variation applications during the renewal procedure and what impact may ongoing procedures have on the renewal procedure? Rev. Dec 2015 .... 164

11.9. Do I have to submit mock-ups and specimens? Rev. Aug 2017 ............................ 164

11.10. When do I have to submit revised product information? In all languages? Rev. Apr 2021 ..................................................................................................................... 165

11.11. When will the linguistic checking of the product information take place? Rev. Apr 2021 ..................................................................................................................... 166

11.12. What do I need to do if I do not want to renew the Marketing Authorisation of certain product presentations or the entire product? Rev. Feb 2019 ......................................... 168

11.13. Will there be any publication on the outcome of my renewal application? Rev. Dec 2015 ..................................................................................................................... 168

11.14. Who should I contact if I have a question when preparing my application and during the procedure? Rev. Feb 2019 .................................................................................. 168

12. Annual renewal of conditional marketing authorisations ................... 169

12.1. How long is my conditional marketing authorisation valid? Rev. Feb 2019 .............. 169

12.2. When shall I submit my annual renewal application? Rev. Jun 2022 ...................... 169

12.3. How shall I present my annual renewal application? Rev. May 2020 ...................... 170

12.4. How and to whom shall I submit my annual renewal application? Rev. Feb 2019 .... 173

12.5. How shall my annual renewal application be handled (timetable)? Rev. Mar 2016 ... 173

12.6. What fee do I have to pay for a renewal? NEW Mar 2013 ..................................... 174

12.7. Can other non-renewal specific changes be included in the annual renewal application? Rev. Mar 2016 ........................................................................................................ 174 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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12.8. How to handle other ongoing variation applications during the renewal procedure and what impact may ongoing procedures have on the renewal procedure? Rev. Mar 2016 .... 174

12.9. Do I have to submit mock-ups and specimens? Rev. Mar 2016 ............................. 175

12.10. When do I have to submit revised product information? In all languages? Rev. Apr 2021 ..................................................................................................................... 175

12.11. When will the linguistic checking of the product information take place? Rev. Apr 2021 ..................................................................................................................... 176

12.12. What do I need to do if I do not want to renew the Marketing authorisation of certain product presentations or the entire product? Rev. Mar 2016 ......................................... 178

12.13. What do I need to do if all Specific Obligations have been completed? Rev. Feb 2019 ............................................................................................................................ 178

12.14. Will there be any publication on the outcome of my annual renewal application? Rev. Mar 2016 ............................................................................................................... 179

12.15. Who should I contact if I have a question when preparing my application? Rev. Feb 2019 ..................................................................................................................... 179

13. Post Authorisation Safety Study (PASS) ............................................ 180

13.1. What is a non-interventional imposed PASS? NEW Jul 2017 ................................. 180

13.2. Under which procedure should I submit my non-interventional imposed PASS? Rev. Nov 2025 ............................................................................................................... 180

13.3. What if the results of a non-interventional imposed PASS make a variation necessary? NEW Jul 2017 ......................................................................................................... 182

13.4. How shall I present my non-interventional imposed PASS and in which format? Rev. May 2020 .............................................................................................................. 182

13.5. To whom should I submit my imposed non-interventional PASS? Rev. May 2020 .... 183

13.6. How do I submit a joint PASS? Rev. May 2020 ................................................... 184

13.7. How will my non-interventional imposed PASS protocol be handled? Rev. Mar 2024 185

13.8. How will my imposed non-interventional PASS final study report be handled? Rev. Mar 2025 ..................................................................................................................... 187

13.9. How is the CHMP opinion / CMDh position structured and which annexes need to be translated? ............................................................................................................. 190

13.10. How shall I implement the outcome of a non-interventional imposed PASS final study report procedure? Rev. Mar 2026 .............................................................................. 195

13.11. When should I register my studies in the HMA-EMA Catalogue of real-world data studies (previously EU PAS Register)? Rev. Jul 2026 ................................................... 196

13.12. Are outcomes of non-interventional imposed PASS published? Rev. Jul 2026 ........ 197

13.13. What fee do I have to pay? Rev. Mar 2025 ....................................................... 197

13.14. Who should I contact if I have questions regarding my submission? Rev. Mar 2025

............................................................................................................................ 198

13.15. Scientific advice for safety studies Rev. Mar 2025 ............................................. 198

13.16. When and how should study progress reports and interim results be submitted? Rev. Apr 2021 ............................................................................................................... 203

14. Post-authorisation efficacy study (PAES) .......................................... 204

14.1. What is a PAES imposed in accordance with the Commission Delegated Regulation? 204

14.2. How and where the PAES imposed in accordance with the Commission Delegated Regulation will be reflected in the marketing authorisation? Rev. Mar 2026 .................... 204

14.3. Following which procedure will my imposed PAES protocol be assessed?................ 205

14.4. When should I submit my imposed PAES protocol? Rev. Mar 2026 ........................ 205 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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14.5. In which timeframe will my imposed PAES protocol be evaluated (timetable)? ....... 206

14.6. What are the possible outcomes of the evaluation of an imposed PAES protocol? .... 206

14.7. Do I have to submit interim results? ................................................................. 206

14.8. Do I have to submit the final results of my imposed PAES? Rev. Jun 2016 ............. 207

14.9. Do I have to pay fees for the protocol and final study results submission? ............. 207

14.10. How is a PAES enforced? ............................................................................... 207

14.11. Will there be any publication on the outcome of my PAES protocol and final study results assessment? ................................................................................................ 208

14.12. Who should I contact if I have a question when preparing my application and during the procedure? Rev. Feb 2019 .................................................................................. 208

15. Post-Authorisation Measures (PAMs) ................................................ 209

15.1. What are PAMs? Rev. Apr 2015 ........................................................................ 209

15.2. What is a specific obligation [‘SOB’]? Rev. Dec 2017 ........................................... 210

15.3. What is an annex-II condition [‘ANX’]? Rev. Jun 2016 ......................................... 211

15.4. What is an additional pharmacovigilance activity in the risk-management plan [‘MEA’]?

Rev. Aug 2020........................................................................................................ 212

15.5. What is a legally binding measure [‘LEG’]? Rev. May 2020 ................................... 213

15.6. What is a recommendation [‘REC’]? Rev. Apr 2015 ............................................. 214

15.7. Can the classification of my PAM change during its lifecycle? Rev. Apr 2015 ........... 214

15.8. When shall I submit my PAM? Rev. Mar 2026 ..................................................... 214

15.9. Under which procedure should I submit my PAM? Rev. Mar 2026 .......................... 215

15.10. How shall I structure my PAM submission dossier? Rev. May 2020 ...................... 218

15.11. How and to whom shall I submit my PAM data? Rev. Feb 2019 ........................... 219

15.12. How shall my submission of PAM be handled (timetable), and what could be the outcome of the evaluation? Rev. Jul 2021 .................................................................. 219

15.13. Do I have to pay fees for the PAM data submission? Rev. Apr 2015 ..................... 220

15.14. How are PAMs enforced? Rev. Mar 2026 .......................................................... 220

15.15. Will there be any publication on the outcome of my PAM? Rev. Apr 2015 ............. 221

15.16. Who should I contact if I have a question when preparing my application? Rev. Apr 2019 ..................................................................................................................... 221

15.17. Who is my contact at the European Medicines Agency during post-authorisation procedures? Rev. Feb 2019 ...................................................................................... 221

16. Risk Management Plan ...................................................................... 222

16.1. When should I submit a new/updated RMP? Rev. Dec 2017 ................................. 222

16.2. When is my RMP a stand-alone variation? Rev. Dec 2017 .................................... 223

16.3. What if my application does not include an updated RMP? Rev. Dec 2017 .............. 223

16.4. Which variation classification will apply for my RMP updates? Rev. Mar 2026 ......... 224

16.5. Which changes can be included in an RMP update without the need for an additional variation? Rev. Dec 2017 ......................................................................................... 225

16.6. Can I group my RMP updates? Rev. Mar 2026 .................................................... 226

16.7. How should I handle parallel RMP submissions? Rev. Dec 2017 ............................ 227

16.8. How shall I present my RMP update? Rev. Oct 2019 ........................................... 230

16.9. Can I submit a version of the RMP after the Opinion to reflect the last-minute changes made during the CHMP? Rev. Mar 2026 ..................................................................... 231

16.10. Is the PRAC Rapporteur involved in the assessment of RMP updates? .................. 231 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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16.11. How long after the European Commission decision should Annex 1 of the RMP be submitted to EudraVigilance? Rev. Jun 2023 .............................................................. 232

16.12. How and to whom shall I submit my RMP application? Rev. May 2020 ................. 232

16.13. What templates should I use for the RMP submission? NEW Dec 2017 ................. 232

16.14. When and how will the RMP Summary be published on the EMA website? Rev. Dec 2023 ..................................................................................................................... 233

16.15. How should I compile the list of safety concerns in the RMP for generic products when the originator products have an RMP? NEW Apr 2019 .................................................. 233

17. Periodic Safety Update Reports (PSURs) ........................................... 235

17.1. How shall I present my PSUR and in which format? Rev. Mar 2025 ....................... 235

17.2. What is the European Union reference dates list (EURD list) and frequency of submission of PSURs? Rev. Mar 2025 ........................................................................ 236

17.3. When do changes to the EURD list become legally binding? Rev. Mar 2025 ............ 237

17.4. How can I request to amend the EURD? Rev. Mar 2025 ....................................... 238

17.5. Do I have to submit a PSUR if the active substance/combination of active substances of my medicinal product is not in the EURD list? Rev. Mar 2025 .................................... 238

17.6. Do I have to submit a PSUR if the combination of active substances of my product is not in the EURD list, but one or more individual components are listed? Rev. Mar 2025 ... 239

17.7. Do I have to submit a PSUR if my medicinal product is not marketed? Rev. Mar 2025 ............................................................................................................................ 239

17.8. Do I have to submit a PSUR if the marketing authorization for my product has been granted on or after the data lock point (DLP) in the EURD list? ..................................... 239

17.9. My company holds a Parallel Import Authorisation; do we have to submit PSUR for these product(s)? If a PSUR is submitted, will it be assessed? Rev. Mar 2025 ................. 239

17.10. Do I have to submit a PSUR for my medicinal product if it is a generic, a product containing a well-established substance, a homeopathic or herbal medicinal product? Rev. Mar 2025 ............................................................................................................... 240

17.11. Do I have to submit a PSUR for my hybrid medicinal product? Rev. Sep 2014 ...... 240

17.12. Do I have to submit a PSUR if my medicinal product is authorised in accordance with Article 126(a) of Directive 2001/83/EC? Rev. Mar 2025 ............................................... 240

17.13. Do I have to submit a PSUR if my medicinal product is authorised in accordance with Article 58 of Regulation EC No. 726/2004 (EU-M4all)? Rev. Mar 2026 ............................ 240

17.14. Will the withdrawal/non-renewal/revocation of the marketing authorisation of my product impact on the ongoing EU single PSUR assessment? NEW Aug 2017 .................. 241

17.15. Will I have to submit PSUR after withdrawal/non-renewal/revocation/suspension of the marketing authorisation of my product? Rev. Mar 2025 .......................................... 241

17.16. Do PSURs need to contain case narratives and line listings? Rev. Mar 2025 .......... 242

17.17. How can I submit the proposed changes to the product information within the PSUR for the procedures which are part of an EU single assessment? Rev. Mar 2025 ............... 242

17.18. Can I submit a RMP update together with my PSUR? Rev. Mar 2025 ................... 243

17.19. Can I submit a clinical study report together with my PSUR? Rev. Mar 2025......... 243

17.20. What are the general timelines for the submission of PSURs? Rev. Mar 2025 ........ 244

17.21. What are the timelines for the submission of PSURs after a positive opinion of a centrally approved product? NEW Mar 2025 ............................................................... 244

17.22. What happens if I missed the PSUR submission deadline? Rev. Mar 2025 ............ 245

17.23. To whom should I submit my PSUR? Rev. Mar 2025 .......................................... 245

17.24. How to identify the official contact person for the PSUR? NEW Mar 2017 .............. 245

17.25. How will my PSUR submission be handled? Rev. Mar 2025 ................................. 246 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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17.26. How shall I submit the response to a request for supplementary information during a PSUSA procedure? Rev. Mar 2025 ............................................................................. 250

17.27. How is the CHMP opinion/CMDh position structured? How does the translation process work, and which annexes need to be translated? Rev. Mar 2025 ................................... 251

17.28. To whom should I submit follow-up data requested as part of the conclusion of a PSUSA procedure? Rev. Mar 2025 ............................................................................. 256

17.29. How can I know about the outcome of a PSUSA procedure? Rev. Mar 2025 .......... 257

17.30. How shall I implement the outcome of a PSUSA procedure? Rev. Oct 2026 .......... 257

17.31. Can I extrapolate the PRAC recommendation on a PSUSA to medicinal products not included in the procedure? NEW Mar 2026 ................................................................. 259

17.32. Who should I contact if I have a question regarding the preparation of a PSUR submission and during the procedure? Rev. Mar 2025 ................................................. 259

17.33. Who should I contact if I have a technical issue with the submission of the PSUR? Rev. Mar 2025 ........................................................................................................ 260

17.34. Who should I contact if I have an issue related to the EURD list? Rev. Mar 2025 ... 260

17.35. What fee should I pay and whom to contact if I have an issue related to the payment of fee and QPPV advice notes? Rev. Oct 2026 ............................................................. 260

18. Article 46 paediatric study submission .............................................. 262

18.1. What is the “Article 46 paediatric study submission”? Rev. Oct 2023 ..................... 262

18.2. When shall I submit my article 46 paediatric study application? Rev. Dec 2014 ...... 262

18.3. How shall I present my article 46 paediatric study application at submission? Rev. Mar 2026 ..................................................................................................................... 262

18.4. How and to whom shall I present my article 46 paediatric study application? Rev. Feb 2019 ..................................................................................................................... 263

18.5. How shall the evaluation of my article 46 paediatric study application be handled (timetable), and what could be the outcome of the evaluation? NEW Feb 2014 ............... 263

18.6. Do I have to pay fees for the article 46 paediatric study submission? NEW Feb 2014 ............................................................................................................................ 264

18.7. Will there be any publication on the outcome of my article 46 paediatric study? Rev. Feb 2014 ............................................................................................................... 264

19. Transfer of Marketing Authorisation .................................................. 265

19.1. What is a Transfer of Marketing Authorisation? Rev. Mar 2026 ............................. 265

19.2. How shall I present my application for the Transfer of Marketing Authorisation? Rev. Jul 2026 ................................................................................................................ 265

19.3. How and to whom shall I submit my Transfer of Marketing Authorisation application? Rev. Feb 2019 ........................................................................................................ 268

19.4. How shall my Transfer of Marketing Authorisation application be handled (timetable)? Rev. Jul 2021 ......................................................................................................... 268

19.5. How to choose the implementation date? Rev. Jun 2024...................................... 269

19.6. What fee do I have to pay for my Transfer of Marketing Authorisation application? Rev. Dec 2024 ............................................................................................................... 270

19.7. How to handle planned/ongoing variations procedures during the Transfer of Marketing Authorisation? Rev. Mar 2026 ................................................................................... 271

19.8. How to handle remaining Post-authorisation Measures and recommendations when transferring a Marketing Authorisation? Rev. Mar 2024 ............................................... 271

19.9. Do I have to submit mock-ups and specimens? Rev. Mar 2026 ............................. 271

19.10. Do I also have to transfer the Orphan designation when my medicinal product has been granted such a designation? Rev. Dec 2007........................................................ 272 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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19.11. Can I include changes to manufacturing sites in my Transfer of Marketing Authorisation application? Rev. Jul 2021 .................................................................... 273

19.12. Can I change the Qualified Person for Pharmacovigilance and what information on the

summary of the transferee’s pharmacovigilance system should I submit as part of my

Transfer of Marketing Authorisation application? Rev. May 2018 ................................... 273

19.13. Can I change the name of a medicinal product as part of a transfer application? Rev. Mar 2026 ............................................................................................................... 274

19.14. Will there be any publication on the Transfer of Marketing Authorisation? Rev. Mar 2024 ..................................................................................................................... 275

19.15. Who should I contact if I have a question when preparing my application or during the procedure? Rev. Mar 2024 .................................................................................. 275

20. Transparency ..................................................................................... 276

20.1. Which EMA transparency measures apply for on-going marketing authorization application procedures? Rev. Aug 2016 ...................................................................... 276

20.2. Which transparency measure applies for the publication of assessment reports? Rev. Aug 2016 ............................................................................................................... 276

20.3. Which transparency measures apply with regard to the clinical data submitted by applicants/MAHs to support their regulatory applications? NEW May 2017 ...................... 276

20.4. Which transparency measures apply with regard to EMA’s scientific committees? NEW

Aug 2016 ............................................................................................................... 277

20.5. Which specialised databases are publicly available? Rev. Aug 2016 ....................... 277

20.6. Does EMA provide monthly figures on centralised procedures for human medicines? Rev. Aug 2016........................................................................................................ 278

21. Pharmacovigilance system summary ................................................. 279

21.1. Requirements regarding the summary of the pharmacovigilance system Rev. Jan 2016 ............................................................................................................................ 279

21.2. Requirements regarding the pharmacovigilance system and pharmacovigilance system master file NEW March 2013 .................................................................................... 280

21.3. Subcontracting pharmacovigilance activities NEW March 2013 .............................. 280

21.4. How to inform the authorities of a change in the summary of the pharmacovigilance system? Rev. Jan 2016 ............................................................................................ 281

21.5. Is it mandatory to enter and maintain the location of the Pharmacovigilance System Master File in the XEVMPD? If so, how do we enter this information in the XEVMPD? NEW Jan 2016 ..................................................................................................................... 281

21.6. Is the information on the Deputy QPPV required as part of the summary of the pharmacovigilance system? Rev. Jan 2016 ................................................................. 282

21.7. Is there a PSMF template? NEW Jan 2016 .......................................................... 282

21.8. Pharmacovigilance System Master File location: can the server of the Pharmacovigilance System Master File be physically located and administered outside EU if it is validated and operational/accessible 24/7 for EU markets and EU QPPV? New Jan 2016 282

21.9. What information will be made public on the EU web-portal regarding pharmacovigilance contact details and PSMF locations? Will details of the QPPV be made public? New Jan 2016 .............................................................................................. 282

22. Article 61(3) Notifications ................................................................. 283

22.1. What is an Article 61(3) Notification? Rev. Oct 2026 ........................................... 283

22.2. Is the Rapporteur involved in 61(3) Notifications? Rev. Jul 2026........................... 284

22.3. When can I submit my 61(3) Notification? Rev. Oct 2026 .................................... 285

22.4. How shall I present my 61(3) Notification? Rev. Jul 2026 .................................... 285 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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22.5. How and to whom shall I submit my 61(3) Notification? Rev. Feb 2019 ................. 286

22.6. How shall my 61(3) Notification be handled (timetable), and what could be the outcome? Rev. Jul 2026 ........................................................................................... 287

22.7. What fee do I have to pay for a 61(3) Notification? ............................................. 288

22.8. Do I have to submit mock-ups and specimens? Rev. Mar 2026 ............................. 288

22.9. How and when will the updated Annexes become part of the Marketing Authorisation? Rev. Aug 2014........................................................................................................ 289

22.10. Will there be any publication on the outcome of my 61(3) Notification? Rev. Apr 2012 ............................................................................................................................ 289

22.11. Who is my contact at the European Medicines Agency during post-authorisation procedures? Rev. Feb 2019 ...................................................................................... 290

22.12. How to present mobile scanning and other technologies in the labelling and/or package leaflet of centrally authorized medicinal products submitted via a 61(3) Notification? NEW Mar 2026 ....................................................................................................... 290

23. Marketing status updates and withdrawals ....................................... 291

23.1. What is the meaning of “actual marketing” / “placing on the market”? Rev. Jul 2021

............................................................................................................................ 291

23.2. What is the meaning of “cessation of placing on the market”? Rev. Jul 2021 .......... 291

23.3. What is the aim of monitoring the marketing status of medicinal products? Rev. Jul 2021 ..................................................................................................................... 292

23.4. What information should be reported to the Agency on the marketing status of CAPs? Rev. Dec 2022 ........................................................................................................ 292

23.5. When to report the marketing status overview of centrally authorised products to the Agency? Rev. Jul 2021............................................................................................. 293

23.6. How to report marketing status updates to the Agency for CAPs? Rev. Feb 2022 .... 294

23.7. When and how to notify marketing cessations for nationally authorised products to the Agency? NEW Jul 2021 ............................................................................................ 297

23.8. How will the Agency inform the Member States? Rev. Jul 2021 ............................. 298

23.9. How should I request the withdrawal of my central marketing authorisation? Rev. Oct 2023 ..................................................................................................................... 299

23.10. When and how to report to the Agency actions taken in 3 rd countries? NEW Feb 2022 ............................................................................................................................ 300

23.11. Which information does the Agency publish about the marketing status of EU medicinal products? Rev. Dec 2022 ........................................................................... 300

23.12. Is there an obligation to market a medicine which is authorised for a paediatric indication, following completion of an agreed paediatric investigation plan, and the product has already been marketed with other indications? Rev. Mar 2025 ................................ 301

24. Sunset clause monitoring .................................................................. 302

24.1. What is the sunset clause? Rev. Jul 2021 ........................................................... 302

24.2. Does the sunset clause apply to existing medicinal products? Rev. Jul 2021 ........... 302

24.3. What are the requirements to maintain a marketing authorisation for a centrally authorised medicinal product? Rev. Jul 2021 .............................................................. 303

24.4. How the sunset clause is monitored by the EMA? Rev. Jul 2021 ............................ 303

24.5. When is the sunset timer ON/OFF? Rev. Jul 2021 ............................................... 303

24.6. In case of a protection period to be respected before placing the medicinal product on the market, when will the sunset clause period start? Rev. Jul 2021 .............................. 304

24.7. How to request an exemption to sunset clause provision for centrally authorised products? Rev. Dec 2022 ......................................................................................... 305 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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1. Type IA Variations

1.1. When shall I submit my Type IA/IA IN variation(s)? Rev. Jul Oct 2026

Commission Regulation (EC) No 1234/2008, as amended (‘the Variations Regulation’) and the “Commission guidelines on the details of the various categories of variations, on the operation of the

procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 and on the documen tation to be submitted pursuant to those procedures” (‘the Classification Variations Guidelines’) set -out a list of changes to be considered as Type IA variations. Such minor variations have only a minimal impact or no impact at all, on the quality, safety or efficacy of the medicinal

product, and do not require prior approval before implementation (“Do and Tell” procedure). The

Classification Guideline clarifies the conditions which must be met in order for a change to be considered a Type IA variation.

Such minor variations are classified in two subcategories, which impact on their submission:

Type IA variations requiring immediate notification (‘IA IN ’)

The Classification Guideline specifies which Type IA variations must be notified (submitted)

immediately to the National Competent Authorities/European Medicines Agency (‘the Agency’)

following implementation, in order to ensure the continuous supervision of the medicinal product.

Type IA variations NOT requiring immediate notification (‘IA’)

Type IA variations which do not require immediate notification should be collected and submitted by the marketing authorisation holder (MAH) as a ‘Type IA annual update’, within 12 months after the oldest variation IA implementation date. The submission should be done as a single submission covering all minor variations of Type IA implemented during the period. The application should be submitted no earlier than 9 months and no later than 12 months after the first implementation date of the Type IA variation included in the ’Type IA annual update’ . An annual update is usually a Type IA grouping. However, it may also be a Type IA single variation if only one variation has been implemented within the period.

To facilitate the implementation of the revised EC Variations Guideline (2025), the first type IA variation implemented as of 15 January 2026 will start a new cycle for the annual update, unless one of the listed annual update exemptions applies to that variation. For further information please refer to the EMA’s Guidance on the application of the revised variations framework .

As an example, if an applicant has three Type IA variations to the same marketing authorisation implemented on 1 February 2026, 7 March 2026 and 21 April 2026 respectively, an annual update of Type IA variation grouping the three variations would be expected between 1st November 2026 (9 months after 1st February 2026) and 31 st January 2027, unless one of the exceptions below applies.

A submission outside the Type IA annual update is possible in the following cases:

• as part of an acceptable grouping together with variations of other types (IAIN, IB or II).

• as part of a super-grouping (one or more Type IA variations for multiple marketing authorisations from the same MAH). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• when a single Type IA variation in an annual update was refused and the company needs to resubmit to comply with the 12 months reporting period.

• exceptionally, an individual submission immediately after implementation when duly justified. This encompasses the following cases listed below:

– When the Type IA variation is needed to mitigate a shortage, and regulatory flexibilities have been agreed with the MSSG (Executive Steering Group on Shortages and Safety of Medicinal Products).

– When the Agency deems the immediate update of the marketing authorisation dossier in relation to a public health concern necessary (e.g. an emerging or declared public health emergency).

– When the Type IA variation is needed to update the marketing authorisation dossier prior to a routine site inspection or a MAH transfer.

– When a third country is requesting proof of acceptance in EU (e.g. by the means of a Certificate of Pharmaceutical Product (CPP) or EU authorisation letter) for a particular change intended to mitigate a shortage or a critical need in the third country or the medicinal product is part of an international reliance program that has been accepted by the Agency.

– Type IA variation(s) implemented before 15 January 2026 that have not been included in an annual update before this date.

In those exceptional cases, a justification is required in the application form.

The Type IA annual update must fulfil the conditions for grouping or super-grouping, if it concerns more than one Type IA variation and/or more than one marketing authorisation:

• all Type IA variations affect the same marketing authorisation approved via centralised procedure, or

• the Type IA variation(s) affect several marketing authorisations approved via centralised procedure owned by the same holder, provided that the variation(s) notified is/are identical for all marketing

authorisations concerned (“super -grouping”).

Please note that currently it is not operationally possible to have super-grouping of Type IA variations including simultaneously marketing authorisations approved via the centralised procedure and non-centralised procedure. Additional cases taking into account the experience acquired may be identified in the future and appropriate operational guidance will be provided on Agency and CMDh websites accordingly.

In line with the objective of a single review and to ensure its effectiveness, it is expected that the individual supporting data for the variation(s) applying to the several marketing authorisations are identical.

It is also not acceptable to combine a grouping with a super-grouping in the same application (i.e. having variations not applicable to all marketing authorisations concerned). Separate submissions should be done in such case.

Most Type IA variations do not impact the product information. However, in case of an upcoming submission of a variation, extension or other regulatory procedure which will affect the product information as part of a grouping application, the MAH should also include any Type IA change(s) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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affecting the product information, in order to keep the product information up-to-date and to facilitate document management.

Meaning of “implementation” for Type IA variations

For quality changes, implementation is when the Company makes the change in its own Quality System.

This interpretation allows companies to manufacture conformance batches and generate any needed stability studies to support a Type IA IN variation before making an immediate notification because the change will not be made in their own Quality System until these data are available.

For product information, it is when the Company internally approves the revised product information. The revised product information will then be used in the next packaging run.

1.2. Can I (super-)group the submission of Type IA/IA IN variations? Can they be grouped with other types of variations? Rev. Nov 2025

Groups of Type IA variations:

Article 7(2)(a) of the Variations Regulation, as amended sets out the possibility for a MAH to group several Type IA/IA IN variations to the terms of the same marketing authorisation under a single notification to the same relevant authority.

Possible grouping of Type IA/IA IN changes only:

• Several Type IA and or Type IA IN affecting one medicinal product.

When the grouping includes only Type IA variations that do not require immediate notification, the submission should be done as part of the Type IA annual update, unless otherwise permitted by the Agency (see question When shall I submit my Type IA/IAIN variation(s)?).

This means for instance that Type IA variations, which are normally not subject to immediate notification, can be included in the submission of a Type IA IN variation, if they are related.

Supergroups of Type IA variations:

Article 7(a) of the Variations Regulation sets out the possibility for a MAH to super-group one or several Type IA/IA IN variations to the terms of more than one marketing authorisations under a single notification to the same relevant authority.

Possible super-grouping of Type IA/IA IN changes only:

• one Type IA or IA IN affecting several medicinal products from the same MAH authorised through the centralised procedure, provided that the variation is the same for all medicinal products .

MAH 1 Prod. 1 IA (1) IA (2) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure EMEA-H-19984/03 Page 18/305

• several Type IA and/or Type IA IN affecting several medicinal products from the same MAH authorised through the centralised procedure, provided that those variations are the same for all medicinal products

When the grouping includes only Type IA variations that do not require immediate notification, the submission should be done as part of the Type IA annual update, unless otherwise permitted by the Agency (see question When shall I submit my Type IA/IA IN variation(s) ?).

Possible grouping of Type IA/IA IN with other types of variations :

• Type IA/IA IN can also be grouped with other variations (e.g. Type IB, Type II, Extension, as listed in Annex III of Commission Regulation 1234/2008, as amended. Groupings not included in the aforesaid Annex should be discussed and agreed with the Agency prior to submission.

• Such grouped submissions will follow the review procedure of the highest variation in the group.

Please also refer to “What type of variations can be grouped?”.

It must be noted however, that when submitting Type IA/ IA IN variations as part of a group, the legal deadlines for submission of each variation should be respected i.e. a Type IA IN should always be submitted immediately, whether or not it is grouped with other variations.

1.3. Is the (Co-) Rapporteur involved in the review of Type IA/IA IN

variations? Rev. Mar 2025

The Agency will review the notification within 30 days following receipt, without involvement of the Rapporteur or Co-Rapporteur.

The same principle applies whether a single or a (super-)group of Type IA/ IA IN variations is being submitted.

MAH 1 Prod. 1 IA (1) Prod. 2 IA (1) MAH 1 Prod. 1 Prod. 2 IA (1) IA (2) IA (1) IA (2) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure EMEA-H-19984/03 Page 19/305

However, if the Type IA/ IA IN Variations are grouped with other variations (Type IB, Type II, Extension), the grouped submission will follow the review procedure and timelines of the highest variation in the group and the Rapporteur will provide an assessment report for the group. Although the Rapporteur is not expected to assess the Type IA/IA IN variations in the group the Rapporteur will confirm in the assessment report whether non-acceptance of (part of) the change(s) in the group leads to non-acceptance of the Type IA/ IA IN changes in the group.

1.4. How shall I present and submit my Type IA/ IA IN Variation(s)? Rev. Jul 2026

A Type IA/IA IN variation notification should contain the elements listed in Annex IV of the Variations Regulation and should be presented in accordance with the appropriate headings and numbering of the EU-CTD format. The Commission “Variations Guidelines” further speci fies which elements should be included in a Type IA/ IAIN variation notification.

In order to help MAHs ensuring that their Type IA/IA IN variations are complete and correct before submitting them to the Agency, it is strongly recommended to use the pre-notification checklist before submission of any Type IA or Type IA IN variation. Also, in order to facilitate the completion of the application form, MAHs are advised to consult the EMA/CMDh Explanatory Notes on Variation Application Form, the Guidance for applicants for the preparation of the precise scope section of the variation application form and the EMA Practical Guidance on the Application Form for Centralised Type IA and IB variations.

Type IA variations are intended to provide for a simple, rapid and efficient procedure for minor changes. The MAH should be aware that the submission of redundant information or a confusing dossier presentation will not facilitate such procedures. Similarly, deficient and missing documentation can lead to rejection of the variation. However, in exceptional cases the Agency may issue a single request for supplementary information, for which a response should be provided within 4 working days in the mandatory eCTD format for electronic submissions. Failure to provide the requested information, or submission of incomplete and/or unsatisfactory responses within 4 working days may lead to an unfavourable outcome.

The following elements should be included in a Type IA/ IA IN variation notification, as specified in the Variations Guidelines:

eSubmission delivery file

• In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file UI .

Cover letter (optional)

• For notifications including only Type IA or Type IA IN changes, super-groupings and annual updates, the submission of a cover letter is not necessary.

• A tracking table is required. A missing tracking table will lead to a technical invalidation.

Procedure/case number

• Several Type IA/IA IN variations affecting one medicinal product:

The procedure/case number will be assigned by the EMA only upon receipt of an eCTD application. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• One or more Type IA/IAIN variations affecting several medicinal products:

The EMA will allocate a ‘high -level’ cross -products procedure/case number shortly before

submission. To submit your request, raise a ticket via EMA Service Desk. Please click on “Finance Services”, then the Type of question to be selected is “Request for high -level procedure or ASMF

number” followed by sub -option “Super Grouping (Type IA grouping)”.

EU variation application form

• The completed electronic EU variation application form (eAF) should include the details of the marketing authorisation(s) concerned, as well as the precise description of all variations submitted together with their date of implementation Information on the electronic Application Form for variations can be found in the eSubmissions eAF webpage.

• MAH should pay particular attention when preparing the eAF for (super-)groupings and ensure that all variations included are listed with its corresponding classification code according to the Annex to the Variation Guideline, or Article 5 of the Variation Regulation, and a description of the proposed precise scope is provided for each one.

• Applicable conditions and documentation should be clearly ticked. Explanations on the conditions and required documentation can be added as applicable or a reference on where the information can be found.

• A detailed presentation and proposed section should also be included for all proposed changes, including editorial changes if applicable - please note that extensive editorial changes are not allowed as part of a IA submission.

• Any change not clearly covered by any scope of a variation included (except editorial), and that is not clearly described in the precise scope section of the application form and included in the present and proposed section should not be considered as accepted.

• For a super-grouping affecting several medicinal products, MAHs are reminded to confirm in the

application form under “Declaration of the applicant” that the MAs concerned belong to the same

MAH and that the main signatory confirms authorisation to sign on behalf of the designated contacts.

Supporting documentation

• Relevant documentation in support of the proposed variation, including all documentation as specified in the Annex should be included in the application .

• If applicable, the revised summary of product characteristics (SmPC or Annex I), annex II, labelling (Annex IIIA) and/or package leaflet (Annex IIIB) should be provided as a full set of annexes. If the change applied for affects Annex A, this should be provided as a separate set of one document per EU language. (See also question on ‘When do I have to submit revised product information? In all languages? ’) Additional information on how to comply with this in a required technical format can be found in the Harmonised eCTD Guidance.

• Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version as well as to all the other languages translation versions. The annotated product information files must include the statement containing the procedure number(s) and may be published on the EMA website as part of the product EPAR page. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA, the publication on the EMA website and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

• Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected, the need for the provision of mock-ups or specimens should be discussed with the EMA ([email protected]) on a case-by-case basis.

• For super-grouping , the supportive documentation for all variations concerned should be submitted as one integrated package with a common application form referring to all medicinal products and variations concerned as stated above. The present-proposed section of the application form should clearly identify the relevant CTD sections in support of each variation and indicate the precise present and proposed wording for each change, including editorial changes if applicable.

• In addition, for each medicinal product the relevant supportive documentation and revised product information (if applicable) should be provided in one sequence per medicinal product, in order to allow the Agency to update the dossier of each marketing authorisation with the relevant updated/new information. Cross-references to any documentation submitted for another

medicinal product can therefore not be accepted. For further details, please refer to “How shall I present a grouped variations application?” and to the Ha rmonised technical eCTD Guidance.

It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH and is crucial to the overall process. The MAH is responsible for ensuring that the Type IA variation complies fully with the conditions and documentation requirements as specified in the Variations guidelines.

Submission of Type IA annual update

The submission of an annual update should be done as a Type IA variation procedure covering a grouping of Type IA variations or a single Type IA variation, as relevant for the period covered. It should contain all the elements as specified above.

In section one of the application form ‘type of application’, the boxes ‘Grouping of variations’ or ‘Single variation’, as relevant, should be ticked, as well as the box ‘Type IA’. ‘Annual update’ tick box should

be ticked as applicable. Implementation date of the earliest Type IA/IA IN will be auto filled with information from section 3 of the application form.

In the ‘precise scope and background’ section of the application form, the applicant should specify that

the Type IA variation procedure concerns an annual update.

Type IA IN notifications should be submitted immediately after implementation in order to ensure continuous supervision of the product. They may only be included in an annual update if the update is submitted immediately after the implementation of the Type IA IN variation.

Submission of Type IA/ IA IN Variation Notifications

Information is available on ‘Submitting a post -authorisation application’. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• Electronic Variation application form

• Variation application form, The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2C

• EMA/CMDh Explanatory Notes on Variation Application Form (CMDh/EMA/133/2010)

• EMA Practical Guidance on the Application Form for Centralised Type IA and IB Variations (EMA/233564/2014)

• Pre-notification checklist for Type IA variations

• Improving quality of submissions

• Article 5 Recommendation

• Classification of changes: questions and answers

1.5. How shall my Type IA/IA IN variation be handled (timetable)? Rev. Mar 2025

The Agency will review the ((super-)grouped) Type IA/ IA IN variation(s) within 30 calendar days following receipt. The Agency will check the correctness of the application form, the presence of the required documentation and compliance with the required conditions, in accordance with the Classification guideline.

Receipt of Type IA/ IA IN variation notification Day 0

Start of Agency check Day 1

Favourable/Unfavourable review outcome by Day 30

By day 30, the Agency will inform the MAH about the outcome of the review.

Where the outcome of the procedure is favourable and the Commission Decision granting the Marketing Authorisation requires amendments, the Agency will inform the Commission accordingly.

Where one or several Type IA/ IA IN variations are submitted as part of one notification, the outcome will clearly indicate which scope(s)/change(s) have been accepted or rejected following its review.

Type IA/ IA IN changes should be implemented prior to submission of the notification. However, in case of unfavourable outcome, the Variations Regulation requires the MAH to immediately cease applying

the rejected variation(s). Please refer to “What should I do in case of an unfavourab le review outcome for my Type IA/ IA IN variation?” for further details. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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It is still possible for MAHs to submit Type IA notifications prior to its implementation, when the proposed changes are related to other notifications/variations requiring prior approval. The expected implementation date should be clearly stated in the application form.

1.6. Can my Type IA/ IA IN be part of worksharing? Rev. Mar 2025

In accordance with the provisions of Article 20 of the Variations Regulation, the worksharing procedure does not apply to Type IA/ IA IN variations.

However, the submission of one or several Type IA/ IA IN variations affecting more than one marketing authorisation of the same MAH, in one notification to the same relevant authority (similar to worksharing) is possible under Article 7a of the Regulation – see also “Can I (super-)group the submission of Type IA/ IA IN variations? Can they be grouped with other types of variations?”

In addition, it is also possible to group a Type IA/ IA IN variation(s) with a Type IB or Type II variation, which is submitted for a worksharing procedure. In such case, the Rapporteur will be asked to confirm whether the non-acceptance of (part of) the change(s) leads to non-acceptance of the Type IA/IA IN

variation(s). In this case, the 'high level' cross-products procedure number for the worksharing should be requested to the Agency. For further information see also Worksharing: questions and answers

‘What procedure number will be given to variation applications under worksharing?’

1.7. What should I do in case of an unfavourable outcome for my Type IA/ IA IN variation(s)? Rev. Mar 2025

A Type IA/ IA IN variation will be fully or partially rejected when:

• The classification of the proposed change(s) is incorrect

• not all of the conditions for the Type IA/ IA IN variation are met

• the submitted documentation as required by the Variations Guideline is deficient or inaccurate, including provision of the product information Annexes and Annex A, if affected by the change(s) applied for.

In such case, the MAH shall immediately cease to apply the rejected changes.

In case of a negative outcome of a Type IA application because the conditions for the Type IA variation(s) are not met and consequently a resubmission (as a Type IB, Type II variation or Extension or additional Type IA variations)is needed or because documentation is deficient, the MAH should revert the impacted sections of the regulatory dossier back to the latest approved version by means of a consolidating eCTD sequence within 15 working days. The MAH is also responsibleto judge whether the rejected Type IA variation has an impact on the quality, safety or efficacy of the medicinal product. If this is the case, the MAH has to take appropriate action.

The Agency may ask the MAH to complete a suspected quality defect notification form and provide a Risk Assessment report on the impact of the product on the market via e-mail to [email protected] within 7 calendar days from the date of the rejection letter. Such requests are expected to be very exceptional. The MAH has to follow the instructions under Notifying Quality Defects or Product Recalls. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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1.8. What fee do I have to pay for a Type IA/ IA IN variation? Rev. Dec 2024

There is no fee payable for Type IA/IA IN variations.

References

• New Fee Regulation (from 1 January 2025)

1.9. Do I have to submit mock-ups and specimens? Rev. July 2013

For information concerning submission of mock-ups and specimens in the framework of post-

authorisation procedures, please refer to the document ‘Checking process of mock -ups and specimens of outer/immediate labelling and package leaflet of human medicinal products in the centralised procedure, 3.4 Other post-authorisation procedures.

References

• Checking Process of Mock-Ups and Specimens of outer/immediate labelling and package leaflets of human medicinal products in the Centralised Procedure (EMEA/305821/2006)

1.10. What changes will trigger new EU number(s) (additional presentation(s))? Rev. Mar 2025

Any changes in the number of units of medicinal product or medical device being an integral part of the medicinal product (e.g. prefilled syringes) will trigger a different EU number.

Differentiation should be made between the addition of a presentation where the two presentations will co-exist on the market on a long-term basis versus a replacement of a presentation where the new presentation will replace the previous one (it is expected that for a certain period of time, the two presentations will co-exist on the market until the stock of the previous presentation runs out).

In principle, a replacement of one presentation by another presentation does not trigger a new EU number, unless the number of units of medicinal product or medical device being an integral part of

the medicinal product (e.g. prefilled syringes) is changed.

Examples of changes in presentations for replacement, not triggering a new EU number (this is not an exhaustive list):

• Replacement of the primary or secondary packaging,

• Changes in the number of medical devices not being integral part of the medicinal product,

• Change in composition (e.g. change in excipients),

• Change in units per blisters (without change to the total number of units per pack).

Examples of changes in presentations for replacement, triggering a new EU number (this is not an exhaustive list):

• 30 to 60 tablets, European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• 2 prefilled syringes containing the medicinal product instead of one prefilled syringe.

In case of addition , as the presentations will co-exist on the market, two packs with different contents cannot be covered by the same EU number and will be considered as different presentations.

Changes in the number of any unit (not restricted to the medicinal product) or changes in the specifications of any unit (not restricted to the medicinal product) contained in the pack will trigger a new EU number.

Examples of changes that will trigger new EU numbers (this is not an exhaustive list):

• Introduction of an alternative injection kit with a different number of syringes or swabs,

• Introduction of an alternative syringe of different volume or an alternative syringe with a needle guard,

• Introduction of an alternative immediate (primary) packaging made from a different material,

• Introduction of an alternative shape/dimension of a pharmaceutical form (pre-rolled sealant matrix versus flat, change in size of patch).

1.11. How to obtain new EU sub-numbers for Type IA IN variation concerning an additional presentation (e.g. new pack-size)? Rev. Mar 2025

In the specific case of a Type IA IN Variation for an additional presentation, the new EU marketing authorisation sub-number should be requested from the Agency before implementation.

The request should be sent together with a Checklist for requesting new EU sub-numbers (Type IA IN

and Type IB lead procedures only) and a draft Annex A (in English only) through the EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post -authorisation - Human”, followed by the sub -option: “New EU number request”. The request should be made at least 5 working days in advance of the intended submission of the variation. Once a number has been allocated, this number should subsequently be included in the Annex A and product information annexes submitted together with the Variation notification.

1.12. When do I have to submit revised product information? In all languages? Rev. Jul 2026

In case the Type IA/ IA IN notification affects any of the annexes, i.e. annex A, SPC, annex II, labelling and/or package leaflet, the affected revised product information Annexes must be submitted as follows:

• All EU language versions: complete set of Annexes electronically only in Word format (highlighted) and in PDF (clean)

The ‘complete set of Annexes’ includes Annex A (if applicable), I, II, IIIA and IIIB i.e. all authorised

presentations (if applicable), SmPC, labelling and PL texts for all strengths and pharmaceutical forms of the product concerned, as well as Annex II. The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU language. Page European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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numbering should start with "1" (bottom, centre) on the title page of Annex I. If annex A is affected,

the document should also be provided in all EU official languages as a separate set. The ‘QRD Convention’ published on the Agency website should be follo wed. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed formatting checklist. A user guide on how to generate PDF versions of the product information and annexes is also available.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version and as well as all the other languages translation versions. The annotated product information files must include the statement containing the procedure number(s) and may be published on the EMA website as part of the product EPAR page . Please submit annotated product information in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA, the publication on the EMA website and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

The electronic copy of all languages should be provided as part of the variation application. Highlighted

changes should be indicated via ‘Tools – Track Changes’. Clean versions should have all changes ‘accepted’.

Icelandic and Norwegian language versions must always be included.

The Annexes provided should only reflect the changes introduced by the Variation(s) concerned. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic or typographical corrections in the texts this should be clearly mentioned in the scope section of the application form.

In addition, the section “present/proposed” in the application form should clearly list the minor

linguistic or typographical corrections introduced for each language. Alternatively, such listing may be provided as a separate document attached to the application form. Any changes not listed, will not be considered as part of the variation application.

In such cases and in cases where any other on-going procedure(s) may affect the product information Annexes, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedure(s) concerned.

When the Type IA/ IA IN Notification concerns several medicinal products, the relevant complete set of product information Annexes should be included in the eCTD sequence for each product concerned.

For Type IA/ IA IN variations affecting Annex A (e.g. introduction of a new presentation), translations of the revised Annex A in all EU languages should be provided as separate documents in PDF format and EN tracked Word, together with the variation application. Where the variation introduces (a) new EU sub-number(s), this/these should be included in the Annex A and in the product information texts

as part of the variation application (see also “How to obtain new EU sub -numbers for a Type IA IN

variation concerning an additional presentation (e.g. new pack-size)”?).

Similarly, in case of a deletion of a pharmaceutical form/strength/pack-size(s), the amended Annex A and product information Annexes should be provided as part of the Variation application. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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1.13. How and when will the updated product information Annexes become part of the Marketing Authorisation? Rev. Mar 2025

For Type IA/ IA IN variations affecting the product information Annexes to the Commission Decision, the Commission Decision will be updated within one year.

By the end of this period, the Agency will send the complete set of Annexes, based on the latest (previously) approved Annexes and reflecting the Type IA/ IA IN change(s) agreed during the past year together with a line-listing of those Type IA/ IA IN notification(s). The Commission will subsequently issue a Commission Decision on the Type IA/ IA IN notification(s) concerned.

However, where an Opinion affecting the Annexes which is followed by an immediate Commission Decision, e.g. listed in the Article 23.1a(a), is transmitted to the Commission within this yearly period the changes of the Type IA/ IA IN notification(s) concerned will already be included in the Annexes to that Opinion and will consequently be reflected in the resulting Commission Decision. This Commission Decision will therefore replace the yearly updating of the MA for the Type IA/ IA IN notification(s) concerned.

At the occasion of the next Type IA/ IA IN variation affecting the Annexes, the procedure outlined above

will be repeated based on the new ‘Reference point’ of the next Type IA/ IA IN concerned.

(See also diagram below, which illustrates the updating process.)

In addition, it is important that in case of an upcoming submission of a variation, extension or other regulatory procedure which will affect the product information, the MAH should also include as a grouping application any Type IA change(s) affecting the product information that have not been previously notified, in order to keep the product information up-to-date and to facilitate document management.

Where a Type IA/ IA IN notification concerns several marketing authorisations, the Commission will update the marketing authorisation with one Decision per marketing authorisation concerned.

Next

Type IA 1 year Type IA IN 1 year

Reference Send all Annexes =

Point to EC New

• line-listing reference point

Type II Next

Type IA

CXMP opinion

Art. 23.1a(a) Type IA 1 year

Reference Send all Annexes =

Point to EC New

• line listing reference point European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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1.14. What should be the date of revision of the text for Type IA Variations? Rev. Mar 2025

Type IA/IA IN variations do not require prior approval before implementation (“Do and Tell” procedure),

i.e. they can be implemented and notified to the Agency either immediately for Type IA variations

requiring immediate notification (‘IA IN ’) or within 12 months for Type IA variations not requiring immediate notification (‘IA’) as an annual update, or outside the annual update if one of the exceptions applies.

For Type IA variations affecting the product information, the date of revision of the text to be included in section 10 of the summary of product characteristics and in the corresponding section of the package leaflet at the time of printing should be the date of implementation of the change by the Marketing Authorisation Holder.

The meaning of “implementation” is explained in ‘ When shall I submit my Type IA/IA IN variation(s)? ’

1.15. Who should I contact if I have a question when preparing my application or during the procedure? Rev. Nov 2025

If you cannot find the answer to your question in the Q&A when preparing your application, please contact us by raising a ticket via EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post -authorisation - Human”, followed by the

sub-option: “Variation IA queries”.

The Agency aims to respond to your query within 10 working days. To help us deal with your enquiry, please provide as much information as possible including the name of the product in your correspondence.

You should submit your query once (please avoid opening multiple tickets with the same question, tickets can always be reopened in case of follow-up) and it is important that you submit it using the applicable type of question and sub-option. If you are uncertain on a classification of a variation as Type IA or Type IB please use only one of the sub-option “Variation IA queries ” or “Variation IB A&B

scopes queries ” or “Variation IB C scopes queries ”. Your query will be channelled internally to the relevant service(s) that will respond to you.

If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".

Type IA variations will be handled by a dedicated team of Procedure Managers (PM). A PM will be nominated upon receipt of the variation. You will be able to contact this PM throughout the procedure via the IRIS case. If you have any comments or questions once the procedure has started, please send them to the IRIS case rather than through ServiceDesk, so that they can be replied to directly by the PM allocated to the procedure. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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2. Type IB variations

2.1. What changes are considered Type IB variations? Rev. Nov 2025

Commission Regulation (EC) No 1234/2008 (‘the Variations Regulation’) defines a minor variation of

Type IB as a variation which is neither a Type IA variation nor a Type II variation nor an Extension. Such minor variations must be notified to the relevant authority(ies) (competent authority of each Member State that granted a marketing authorisation /European Medicines Agency (‘the Agency’) ) by the Marketing Authorisation Holder (MAH) before implementation, but do not require a formal approval. Upon acknowledgement of receipt of a valid notification and the notification of the start of the procedure, the MAH must wait a period of 30 days to ensure that the notification is deemed acceptable by the relevant authority(ies) before implementing the change (“Tell, Wait and Do”

procedure).

The “Commission guidelines on the details of the various categories of variations, on the operation of

the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 and on the documentation to be submitted pursuant to those procedures” (‘the Variations Guidelines’),

contains examples of changes which are considered as Type IB variations. In addition, any change which is not an Extension and whose classification is not determined taking into account the Commission Guideline and the recommendations delivered pursuant to Article 5 of the Variations Regulation is considered a Type IB variation by default.

When one or more of the conditions established in the Classification Guideline for a Type IA variation are not met, the concerned change may be submitted as a Type IB variation unless the change is specifically classified as a major variation of Type II.

For changes which are submitted as default Type IB variations, the Agency will determine during validation whether the proposed classification as Type IB variation is appropriate before the start of the

evaluation procedure (see also “How shall my Type IB variation be handled?”)

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• CMDh recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) 1234/2008

2.2. Is the (Co-) Rapporteur involved in Type IB Variations? Rev. Feb 2019

Upon validation of the notification by the Agency, the Rapporteur will be involved in the evaluation of

Type IB variations “How shall my Type IB variation be handled (timetable)”?

The Co-Rapporteur is not involved in the assessment of Type IB variations. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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2.3. Can I group the submission of Type IB variations? Can they be grouped with other types of variations? Rev. Mar 2025

MAHs may choose to group the submission of several Type IB variations for the same product into one notification. It is also possible for a MAH to group a Type IB variation with other variation(s) for the same product (e.g. Type IA, Type II, Extension), where applicable.

Allowed groupings are listed in Annex III of the Variations Regulation. Other groupings have to be agreed in advance with the Agency. Any proposal to group clinical and quality variations should be adequately justified.

Such grouped submissions will follow the review procedure of the highest variation in the group. Please

also refer to “What type of variations can be grouped?”.

Where the same minor Type IB variation(s) affect more than one marketing authorisations from the same holder, the MAH shall submit these variations as one application for ‘worksharing’. Please also refer to ”What is worksharing and what type of variations can be subject to worksharing?”.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

2.4. How shall I present and submit my Type IB Variation? Rev. Jul 2026

A Type IB variation notification should contain the elements listed in Annex IV of the Variations Regulation and should be presented in accordance with the appropriate headings and numbering of the EU-CTD format.

In order to help MAHs ensuring that their Type IB variations are complete and correct before submitting them to the Agency, it is strongly recommended to use the pre-notification checklist before submission of any Type IB variation.

MAH 1

Prod. 1

IB (1)

IB (2)

MAH 1

Prod. 1

II

IB

IA European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In order to facilitate the completion of a correct application form before submission to the Agency, MAHs are advised to consult the EMA/CMDh Explanatory Notes on the Variation Application Form and the EMA Practical Guidance on the Application Form for Centralised Type IA and IB variations.

The Commission ‘Variations Guidelines’ further specifies which elements should be included in a Type

IB variation notification:

• Cover letter (for groupings, include a short overview of the nature of the changes and indicate whether it is submitted under Article 7.2(b), i.e. it falls within one of the cases listed in Annex III of the variations regulation or it is submitted under Article 7.2(c), i.e. the grouping has been agreed with the Agency). The MAH should indicate when the exact same change is submitted for different products in separate IBs.

• In order to facilitate the registration of the submission, applicants are required to fill in all the submission attributes through the eSubmission delivery file UI.

• Procedure number – The procedure number will be assigned by the EMA only upon receipt of an eCTD application. For further details please refer to EMA pre-submission guidance “How is an EMA application/procedure number attributed?”

• The completed electronic EU variation application form (eAF), including the details of the marketing authorisation concerned. Where a variation is considered a Type IB by default, a detailed justification for its submission as a Type IB notification must be included. MAHs are reminded that the variation application form should be signed by the official contact person as specified in section 2.4.3 of Module 1. Should the official contact person not be available, an official letter of authorisation confirming the delegation of signature to a different person should be enclosed.

• Reference to the variation code as laid down in the Annex to the Variations Guidelines, or reference to the published Article 5 Recommendation, if applicable, used for the relevant application. Applicable documentation should be clearly ticked in the application form or marked as n/a if the is the case. If documentation is not applicable, a justification for its absence should be provided.

• Any change not clearly covered by any scope of a variation included (except editorial), and that is not clearly described in the precise scope section of the application form and included in the present and proposed section should not be considered accepted.

• Relevant documentation in support of the proposed variation including all documentation as specified in the Annex of the Commission Variations Guidelines.

• For procedures affecting the product information (with or without linguistic review), the revised summary of product characteristics (SmPC or Annex I), annex II, labelling (Annex IIIA) and package leaflet (Annex IIIB) should be provided as a full set of annexes in all EEA languages (in word highlighted electronically and in PDF clean version). (See specific requirements for

procedures with and without linguistic review in section “When do I need a linguistic review for changes in the product information?” and “How should I submit revised product information? In all languages?”).

• Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version as well as all the other translation versions. The annotated product information files must include the statement containing the procedure number(s) and may be published on the EMA website as part of the product EPAR page. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA, the publication on the EMA website and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

• If the change also affects Annex A (irrespective of the need for a linguistic review), the Annex A should be provided as a separate set of documents (in word highlighted electronically and in PDF clean version) in each EU language (See section “How should I submit revised product information? In all languages?”).

• Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected, the need for the provision of mock-ups or specimens should be discussed with the EMA ([email protected]) on a case-by-case basis.

Note : For additional guidance on the elements that should be included in a Type IB variation notification please refer to section 2 and the Annex of the EC Variations Guidelines.

Grouped variations

For grouped variations concerning one marketing authorisation, all variations must be declared in the variation application form. The documentation requirements for each type of variation in the group must be adhered to. However, the supportive documentation for all variations concerned should be submitted as one integrated package (i.e. there is no need to submit a separate documentation package for each variation). The present-proposed section of the application form should clearly identify the relevant eCTD sections in support of each variation. For grouped variations please refer to

“Can I group the submission of Type IB variations? Can they be grouped with other types of variations?”. For grouped variations concerning more than one marketing authorisat ion please refer to

”What is worksharing and what types of variations can be subject to worksharing?".

It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH and is crucial to the overall process. The MAH is responsible for ensuring that the Type IB variation complies fully with the data and documentation requirements as specified in the Variations Guidelines. The MAH should pay particular attention to grouping of variations, for which each change should be clearly identified as well as the related supportive documentation. A confusing dossier presentation may delay the procedure.

For queries on technical matters please contact the EMA Service Desk. For procedural matters related to a Type IB notification for a specific product and in order to avoid rejection, please see Question 12.

“Who should I contact if I have a question when preparing my application?”) .

Variations to implement changes for generic/hybrid/biosimilar products

The Product Information (PI) for generic/hybrid/biosimilar medicinal products requires update following changes to the reference product via a post-authorisation regulatory procedure (e.g. safety update).

The EMA will no longer actively contact the MAHs of generic/hybrid/biosimilar medicinal products.

Instead, for centrally authorised medicinal products, the EMA will publish the reference medicinal product track changes PI in all EU languages on the reference medicinal product EPAR page. MAHs of generic/hybrid/biosimilar medicinal products of centrally authorised medicinal products are requested European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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to monitor to EPAR updates of the reference medicinal product, download the track changes PI in all languages from the EPAR page following its publication and submit the appropriate variation(s) as soon as possible but no later than 2 months from the implementation of the changes in the PI as adopted for the reference product.

Should the relevant published track changes PI be superseded by a more recent EPAR update, the MAH of the generic/hybrid/biosimilar medicinal product should contact the Product Lead (PL) or Product Assistant (PA) of their product to request a copy of the track changes PI version which has not been downloaded on time. There is no need to file an Access to Documents (AtD) request.

For centrally authorised generic/hybrid/biosimilar medicinal products of nationally authorised reference medicinal products, the MAHs of generic/hybrid/biosimilar medicinal products are requested to follow the updates of the nationally authorised products PI and submit the relevant variation(s) to update the PI of the generic/hybrid/biosimilar medicinal product accordingly.

A submission of a Type IB variation to implement changes for a generic/hybrid/biosimilar medicinal product, should include a detailed precise scope for the change(s) implemented, including relevant PI sections affected. In addition, for generic/hybrid/biosimilar medicinal product of a centrally authorised reference medicinal product, a copy of the relevant English track changes PI(s) of the centrally authorised medicinal product should be included in the application, as well as a confirmation that the translations have been implemented in line with the translations of the reference medicinal product.

Submission of Type IB Notifications

Information is available on ‘Submitting a post -authorisation application’.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• Electronic Variation application form, The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2C

• EMA/CMDh Explanatory Notes on Variation Application Form (CMDh/EMA/133/2010)

• EMA Practical Guidance on the Application Form for Centralised Type I variations (EMA/233564/2014)

• Article 5 Recommendation

2.5. When shall I submit my Type IB Variation? Rev. Feb 2025

There are no recommended submission dates for Type IB variations with no changes to the product information or IB variations with changes to the product information which do not require linguistic European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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review. The Agency has published recommended submission dates for Type IB variations requiring linguistic review. The timetable for IB variations with linguistic review does not apply to:

• Type IB variations included in a worksharing (WS) submission (as they follow WS timetable)

• Type IB variations submitted as part of a group including Type II variations and/or extensions (as they follow Type II or extensions timetable).

(See specific requirements for procedures with and without linguistic review in section “When do I need a linguistic review for changes in the product information?” and “How should I submit revised product information? In all languages?”)

For generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product, MAHs must submit the corresponding variation application at the latest within 2 months following the adoption of the relevant assessment conclusion.

Variation applications reflecting the outcome of an Urgent Safety Restriction (USR) shall be submitted immediately and in any case no later than 15 days after the initiation of the USR to the Agency. This applies to USRs initiated by the MAH or imposed by the European Commission.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• The Linguistic Review Process of Product Information in the Centralised Procedure - Human

2.6. When do I need a linguistic review for changes in the product information? Rev. Nov 2025

The linguistic review for IB variations will take place in parallel to the 30-day scientific assessment.

A linguistic review will, in general, be required for Type IB variations with changes affecting the product information where the changes in wording have not previously undergone linguistic review.

Some examples of Type IB variations where a linguistic review will be performed include safety and efficacy Type IB variations affecting the product information, where the wording has not been provided by the Agency in all languages prior to the start of the procedure.

Some examples of Type IB variations where, in principle, a linguistic review will not be performed are:

• Quality variations:

− change in the shelf life of the finished product

− change to the storage conditions of the finished product

− change in the name and/or address of the marketing authorisation holder and batch release site

− change in the name of the medicinal product

− addition of new presentations or changes to the existing ones European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Change in the Summary of Product Characteristics, Labelling or Package Leaflet of a generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product

• Deletion of information from the product information

• Change to a new version of QRD template (a linguistic review could be exceptionally deemed necessary if the change encompasses several QRD versions)

• Implementation of safety signals following a recommendation from the PRAC where the translations have been provided to the applicant.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• The Linguistic Review Process of Product Information in the Centralised Procedure – Human

2.7. How shall my Type IB variation be handled (timetable)? Rev. Nov 2025

Upon receipt of a Type IB notification, the Agency will handle the notification as follows:

a) Handling of Type IB variations included (‘foreseen’) in the Classification Guideline or

covered by an Article 5 Recommendation :

Submission and validation

The Agency will check within 7 calendar days whether the variation is correct and complete

(‘validation’) before the start of the evaluation procedure.

Day Action

Day x Receipt of Type IB variation

Day x+1 Start of Agency validation

Day x+7

(in case of missing or incorrect information, this period will be extended to accommodate a Validation Supplementary Information to the MAH)

Agency validation

Issues identified during validation will be notified to the MAH via e-mail. The MAH will be requested to provide responses to the issues raised within 5 working days. Delayed or insufficient responses will lead to complete or partial invalidation (in case of groupings) of the application as only one request for supplementary information will be issued during the validation phase.

The Agency will send to the MAH a confirmation of the positive outcome of the validation and the start date of the procedure.

Evaluation European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Day Action

Day 1 Start of evaluation

by Day 20 Internal circulation of Assessment Report*

by Day 30 (Non-)acceptance of the variation

*Assessment Report will be sent to the applicant only at the end of the procedure not at Day 20 together with the IB notification.

Within 30 calendar days following the acknowledgement of receipt of a valid notification and the notification of the start of the procedure, the Agency will notify the MAH of the outcome of the

procedure. The message will contain “Notification of a Type IB variation to the terms of the Marketing Authorisation” and the Assessment Report. If the Agency has not sent the holder its opinion on the

notification within 30 calendar days, the notification shall be deemed acceptable.

Submission of amended notification (responses to Request for Supplementary Information (RSI))

Day Action

by Day 30 Non-acceptance of the variation (RSI)

by Day 60 Submission of an amended Notification (submission of responses to RSI by MAH)

In case of an unfavourable outcome the MAH may, within 30 calendar days, amend the notification to take due account of the grounds for the non-acceptance of the variation. Clock-stops are not foreseen ina Type IB procedure. If the MAH does not amend the notification as requested, the notification shall be rejected.

Evaluation (assessment of responses to RSI)

Day Action

Day 60 Receipt of an amended Notification

by Day 80 Internal circulation of Assessment Report

by Day 90 Final (non-)acceptance of the variation

Within 30 calendar days of receipt of the amended notification, the Agency will inform the MAH of its final (non-)acceptance of the variation and whether the Commission Decision granting the Marketing Authorisation requires any amendments.

Where the outcome of the procedure is favourable and the Commission Decision granting the Marketing Authorisation requires amendments, the Agency will inform the Commission accordingly.

Where Type IB Variations affect the Annexes to the Marketing Authorisation, such changes can be implemented without awaiting the update of the Commission Decision and the agreed change(s) should be included in the Annexes of any subsequent Regulatory Procedure.

b) Handling of Type IB variations claimed by the MAH to be IB variations by default

The Agency will check within 7 calendar days whether the proposed change can be considered a minor

variation of Type IB, and whether the notification is correct and complete (‘validation’) before the start European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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of the evaluation procedure. In exceptional cases, the Agency may have to consult with the Rapporteur on the appropriate classification of the variation, which may lead to a slightly longer validation period (up to 10 working days).

When the Agency is of the opinion that the proposed variation may have a significant impact on the quality, safety or efficacy of the medicinal product, the MAH will be notified that the applied change cannot be handled as a Type IB and that the variation will have to be reclassified as a Type II variation. As a consequence, the MAH will be requested to revise and supplement its variation application so that the requirements for a Type II variation application are met.

Following receipt of the valid revised variation application, a Type II assessment procedure will be initiated according to the Agency procedural timetables for Type II variation.

When the Agency is of the opinion that the proposed variation can be considered a Type IB variation, the MAH will be informed of the outcome of the validation and of the start date of the procedure. The Type IB notification will be handled as set-out in section a) above.

c) Handling of Groupings of Minor Variations (Type IB/Type IA)

For grouping of minor variations, where not all of the changes applied for can be positively validated, all valid and not valid variations will be clearly listed in the validation outcome correspondence.

Where a Type IB by default variation, within a group of variations, has to be reclassified as a Type II variation, the MAH will be requested to confirm whether this variation should remain in the group. If confirmed, the whole group will be handled as a Type II variation, as set out in b) above.

Where several Type IB variations are submitted as part of one notification, it will be clearly specified in the final Agency notification which variation(s) have been accepted or rejected following assessment, unless some of the variations have been withdrawn by the MAH during the procedure (see grouping Q&A).

2.8. What fee do I have to pay for a Type IB Variation? Rev. Dec 2024

There is no fee payable for Type IB variations.

References

• Fees payable to the European Medicines Agency

2.9. Do I have to submit mock-ups and specimens? Rev. Apr 2016

For information concerning submission of mock-ups and specimens in the framework of post-authorisation procedures, please refer to section 3.4 Other post-authorisation procedures in the

document ‘Checking process of mock -ups and specimens of outer/immediate labelling and package leaflet of human medicinal products in the centralised procedure ’.

References

• The Checking Process of Mock-Ups and Specimens of outer/immediate labelling and package leaflets of human medicinal products in the Centralised Procedure (EMEA/305821/2006) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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2.10. How should I submit revised product information? In all languages? Rev. Nov 2025

In case the Type IB notification affects any of the Annexes, i.e. Annex A, SmPC, Annex II, labelling and/or package leaflet, the affected revised product information Annexes must be submitted as follows:

a) For Type IB procedures without linguistic review of product information:

At submission, the MAH should provide:

• within the eCTD sequence: complete set of annexes of the product information in all EEA languages in PDF (clean)

• electronically: complete set of annexes of the product information in all EEA languages in word (highlighted)

If Annex A is affected, please submit all EEA language versions in word (highlighted) electronically and in PDF (clean) in eCTD.

b) For Type IB procedures with linguistic review of product information:

At submission, the MAH should provide:

• within the eCTD sequence: complete set of Annexes of the product information in EN (only) in PDF (clean)

• electronically: complete set of Annexes of the product information in all EEA languages in word (highlighted)

If Annex A is affected, please submit all EEA language versions in word (highlighted) electronically and in PDF (clean) in eCTD.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version as well as all the other translation versions. The annotated product information files must include the statement containing the procedure number(s) and may be published on the EMA website as part of the product EPAR page. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA, the publication on the EMA website and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

Upon validation of the procedure the MAH will receive the timetable for the submission of the translations of the product information for linguistic review.

In all cases the ‘complete set of Annexes’ includes Annex A (if applicable), I, II, IIIA and IIIB i.e. all

authorised presentations (if applicable), SmPC, labelling and PL texts for all strengths and pharmaceutical forms of the product concerned, as well as Annex II. The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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language. Page numbering should start with "1" (bottom, centre) on the title page of Annex I. The

‘QRD Convention’ published on the Agency website should be followed. When submitting the full set of

Annexes in PDF format, this should be accompanied by the completed formatting checklist which provides guidance on how to correctly prepare the PDF versions.

The electronic copy of all languages should be provided as part of the variation application. Highlighted

changes should be indicated via ‘Tools – Track Changes’. Clean versions should have all changes ‘accepted’.

Icelandic and Norwegian language versions must always be included.

The Annexes provided should only reflect the changes introduced by the Variation(s) concerned. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments in the texts this should be clearly mentioned in the cover letter and in the scope section

of the application form (see also “What can be considered an editorial change and how can it be

submitted as part of a T ype IA/IB/II variation?”).

In addition, the section “present/proposed” in the application form should clearly list the minor

linguistic amendments introduced for each language. Alternatively, such listing may be provided as a separate document attached to the application form. Any changes not listed, will not be considered as part of the variation application.

In such cases and in cases where any other on-going procedure(s) may affect the product information Annexes, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedure(s) concerned.

For Type IB variations affecting Annex A where the variation introduces a new EU sub-number, the sub-number should be included in the Annex A and in the product information texts as part of the

variation application (see also “How to obtain new EU sub -numbers for a Type IB variation concerning an additional presentation? (e.g. new pack-size)?”).

Similarly, in case of a deletion of a pharmaceutical form/strength(s), the amended Annex A and product information Annexes should be provided as part of the Variation application.

2.11. What changes will trigger new EU number(s) (additional presentation(s))? Rev. Nov 2025

Any changes in the number of units of medicinal product or medical device being an integral part of the medicinal product (e.g. prefilled syringes) will trigger a different EU number.

Differentiation should be made between the addition of a presentation where the two presentations will co-exist on the market on a long-term basis versus a replacement of a presentation where the new presentation will replace the previous one (it is expected that for a limited period of time, the two presentations may co-exist on the market until the stock of the previous presentation runs out).

In principle, a replacement of one presentation by another presentation does not trigger a new EU number, unless the number of units of medicinal product or medical device being an integral part of the medicinal product (e.g. prefilled syringes) is changed.

Examples of changes in presentations for replacement, not triggering a new EU number (this is not an exhaustive list): European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Replacement of the primary or secondary packaging,

• Changes in the number of medical devices not being integral part of the medicinal product,

• Change in composition (e.g. change in excipients),

• Change in units per blisters (without change to the total number of units per pack).

Examples of changes in presentations for replacement, triggering a new EU number (this is not an exhaustive list):

• 30 to 60 tablets,

• 2 prefilled syringes containing the medicinal product instead of one prefilled syringe.

In case of addition , as the presentations will co-exist on the market, two packs with different contents cannot be covered by the same EU number and will be considered as different presentations.

Changes in the number of any unit (not restricted to the medicinal product) or changes in the specifications of any unit (not restricted to the medicinal product) contained in the pack will trigger a new EU number.

Examples of changes that will trigger new EU numbers (this is not an exhaustive list):

• Introduction of an alternative injection kit with a different number of syringes or swabs,

• Introduction of an alternative syringe of different volume or an alternative syringe with a needle guard,

• Introduction of an alternative immediate (primary) packaging made from a different material,

• Introduction of an alternative shape/dimension of a pharmaceutical form (pre-rolled sealant matrix versus flat, change in size of patch).

2.12. How to obtain new EU sub-numbers for a Type IB variation concerning an additional presentation (e.g. new pack-size)? Rev. Jul 2023

In the specific case of a Type IB Variation for an additional presentation, the new EU marketing authorisation sub-number should be requested from the Agency before submission.

The request should be sent together with a checklist and a draft Annex A (in English only) through the EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post -authorisation - Human”, followed by the sub -option: “New EU number request”. The request should be made at least 5 working days in advance of the intended submission of the variation. Once a number has been allocated, this number should subsequently be included in the Annex A and Product Information Annexes submitted together with the Variation notification. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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2.13. How and when will the updated Annexes become part of the Marketing Authorisation? Rev. Oct 2012

For Type IB variations affecting the annexes to the Commission Decision, the Commission Decision will generally be updated within one year, unless the Type IB variation concerns any of the changes listed in Article 23.1a(a) whereby the Commission Decision will be updated within two months. This would include variations related to the addition of a new therapeutic indication or modification of an existing one, addition of a new contraindication or change in posology. It is expected that such variations would be processed as Type IB variations mainly in the framework of generics/hybrids following changes to the product information of the reference medicinal product.

However, all Type IB variations affecting the annexes can be implemented without awaiting the update of the marketing authorisation and the agreed Type IB changes should be included in the Annexes of any subsequent Regulatory Procedure.

For Type IB variations subject to yearly update of the respective Commission decision, at the end of this yearly period, the Agency will send the complete set of Annexes, based on the latest approved Annexes and reflecting the Type IB change(s) introduced during the past year as well as a line-listing of those variations pending update of the Commission decision.

Where a notification contained several Type IB variations concerning one marketing authorisation, the Commission will update the marketing authorisation with one single decision to cover all the approved minor variations.

However, where a notification/opinion affecting the Annexes which is followed by an immediate Commission decision, is transmitted to the Commission within this yearly period, the changes of the Type IB notification(s) concerned will already be included in the Annexes to the notification/opinion and will consequently be reflected in the resulting Commission Decision. This Commission Decision will therefore replace the yearly updating of the MA for the Type IB notification(s) concerned.

At the occasion of a next Type IB variation affecting the Annexes, the procedure outlined above will be

repeated based on the new ‘Reference point’ of the next Type IB concerned.

(see also diagram below)

Next

Type IB 1 year Type IB

Type IB

Art 23.1a(a)

Reference

Send all Annexes

to EC

• line-listing =

Send all Annexes

to EC

• line-listing

Point New

reference point

Type II Next

Type IB

CXMP opinion

Art.23.1a(a) Type IB 1 year European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Reference Send all Annexes =

Point to EC New

• line listing reference point

2.14. Who should I contact if I have a question when preparing my application or during the procedure? Rev. Nov 2025

If you cannot find the answer to your question in the Q&A when preparing your application, please raise a ticket via the EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post -authorisation - Human”, followed by the sub -

option: “Variation IB A&B scopes queries” or “Variation IB C scopes queries” .

The Agency aims to respond to your query within 10 working days. To help us deal with your enquiry, please provide as much information as possible including the name of the product in your correspondence.

You should submit your query once (please avoid opening multiple tickets with the same question, tickets can always be reopened in case of follow-up) and it is important that you submit it using the applicable type of question and sub-option. If you are uncertain of a classification of a variation as Type IB or Type IA please use only one of the sub-option “Variation IA queries ” or “Variation IB A&B

scopes queries ” or “Variation IB C scopes queries ”. If you seek advice on the classification of change(s), please include your proposal for classification. Your query will be channelled internally to the relevant service(s) that will respond to you.

If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".

Type IB variations will be handled by a dedicated team of Procedure Managers (PM). A PM will be nominated upon receipt of the variation. You will be able to contact this PM throughout the procedure via the IRIS case. If you have any comments or questions once the procedure has started, please send them to the IRIS case rather than through ServiceDesk, so that they can be replied directly by the PM allocated to the procedure. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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3. Type II variations

3.1. What changes considered Type II variations? Rev. Dec 2016

Commission Regulation (EC) No 1234/2008 (‘the Variations Regulation’) defines a major variation of

Type II as a variation that is not an extension of the marketing authorisation (line extension) and that may have a significant impact on the quality, safety or efficacy of a medicinal product.

The Variations Regulation and the Variations Guidelines set out a list of changes to be considered as Type II variations. In addition, any other change that may have a significant impact on the quality, safety or efficacy of the medicinal product must be submitted as a Type II variation. Please refer also

to “When will my variation application be considered a Type II variation or an extension application?”.

During validation of an ‘unforeseen’ variation, submitted by the MAH as a Type IB variation, the

Agency may consider that the proposed variation may have a significant impact on the quality, safety or efficacy of the medicinal product. In such case, the MAH will be requested to revise and supplement

its variation application so that the requirements for a Type II variation application are met (see ”How shall my Type IB variations be handled (timetable)?”.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• CMDh recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) 1234/2008

3.2. Do I need to notify the Agency of my intention to submit a Type II variation application? Rev. Nov 2025

There is generally no requirement to notify the Agency in advance of an upcoming submission of a Type II variation. For Type II variations entailing additions of new therapeutic indication(s) or modification of already approved one(s), due to the substantial amount of data expected, the assessment timeframe is typically longer (see also q uestion “How shall my Type II application be handled (timetable)”) and significant assessment resources need to be committed by the Rapporteur

and usually also from the Co-Rapporteur (see also q uestion “Is the Co -Rapporteur involved in Type II

Variations”). For this reason, MAHs are requested to give an advance notice of their intention to submit

an extension of indication or other changes to the authorised therapeutic indication ideally 6 months in advance of the planned submission. This can be achieved by means of an email to the Product Lead, the Rapporteur, Co-Rapporteur and, if applicable, PRAC Rapporteur, summarising the scope of the intended application and specifying the target submission date. The information will be used for

planning purposes by the Agency and the Rapporteurs’ assessme nt teams. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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3.3. Which Committee will take the lead in the assessment of a Type II variation? Rev. Nov 2025

The CHMP leads the assessment of most Type II variations and always adopts the final Opinion for Type II variations.

However, in case of Type II variations concerning clinical safety to update the product information and/or the Risk Management Plan upon request by the PRAC, as a follow-up to a previous PSUR procedure or following a previous PRAC assessment of a signal, the PRAC will take the lead in the assessment of the variation.

It should be noted that the CHMP will lead the assessment of a post-PSUR variation where the scope is related to other aspects of the dossier e.g. non-clinical data, clinical pharmacology and/or clinical efficacy. In addition, the PRAC will lead in the assessment of Type II variations:

• Specifically intended to update the RMP;

• Or providing final results of non-interventional post-authorisation safety studies (PASS).

The latter refers to both imposed (PASS category 1 and 2 in the RMP) and requested non-interventional studies (PASS category 3 in the RMP), and regardless of whether or not consequential changes to the product information are proposed.

It should be noted that final results of imposed non-interventional studies are expected to be submitted under the Art 107q of Directive 2001/83/EC procedure (please also refer to guidance on post-authorisation safety studies). Please also refer to “ Under which procedure should I submit my PAM? ” for further guidance on the submission of PASS results.

Whether the CHMP or the PRAC will take the lead in the assessment of the variation will be decided at the time of the validation and communicated to the applicant through the assessment timetable.

It should be noted that the CAT, instead of the CHMP, will take the lead in the assessment of Type II variations for advanced therapy medicinal products (ATMPs), unless these are PRAC-led. The CAT will adopt a draft Opinion for all Type II variations for ATMPs, including for PRAC-led ones, with the CHMP adopting the final Opinion.

3.4. Is the Co-Rapporteur involved in Type II Variations? Rev. Nov 2025

The CHMP (or CAT for ATMPs) Co-Rapporteur is normally not involved in the assessment of a Type II variation application concerning quality, non-clinical and clinical including product information changes and RMP updates.

However, the involvement of the CHMP Co-Rapporteur is in most cases deemed necessary for the assessment of a new therapeutic indication or modification of an approved indication.

The MAH should therefore inform the Agency (Product Lead) of an upcoming Type II application for a new indication ideally 6 months before submission, so that the CHMP is informed of the future submission and can agree on the Co-Rapporteur’s involvement.

At the time of validation, the Agency will inform the MAH of the involvement of the CHMP Co-Rapporteur through the assessment timetable which will refer to the relevant assessment reports expected from the Co-Rapporteur as appropriate. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Regarding the submission of a Type II variation application to the (Co-) Rapporteurs, please see also

question “How and to whom shall I submit my Type II Variation application” below.

3.5. Is the PRAC Rapporteur involved in Type II variations? Rev. Nov 2025

As explained in the question “Which Committee will take the lead in the assessment of a Type II

variation?” above, the PRAC Rapporteur is involved in and performs the primary assessment of PRAC -led variations.

In addition, the PRAC Rapporteur will systematically be involved in the assessment of all CHMP-led Type II variations that include an updated RMP for the purposes of assessing the proposed RMP changes.

The CHMP may also on a case-by-case basis involve the PRAC Rapporteur in the assessment of other Type II variations during the assessment procedure, e.g. variations involving a ‘Direct Healthcare Professional Communication ’.

3.6. Can I group the submission of Type II variations? Can they be grouped with other types of variations? Rev. Mar 2025

Marketing authorisation holders may choose to group the submission of several Type II variations for the same product into one application, provided that this corresponds to one of the cases listed in Annex III of the Variations Regulation or when this has been agreed upfront with the Agency.

It is also possible for a marketing authorisation holder to group a Type II variation with other variation(s) (e.g. Type IB or IA variations) or extension applications. Such grouped submissions will follow the assessment timetable of the highest variation in the group. Please also refer to ”What types of variations can be grouped?”.

Where the same Type II variation(s) affect(s) one or more marketing authorisations from the same holder, the marketing authorisation holder shall submit these variations as one application for

‘worksharing’. Please also refer to ”What is worksharing and what types of variations can be subject to worksharing?”.

References

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

3.7. How shall I present my Type II Variation application? Rev. Jul 2026

A Type II variation application should contain the elements listed in Annex IV of the Variations Regulation and should be presented in accordance with the appropriate headings and numbering of the EU-CTD format. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In addition, the MAHs are expected to complete the relevant validation checklist (Clinical/Non-clinical or Quality) and submit it as a word document (as part of the working documents) in Module 1 as an Annex. The checklist will help MAHs to ensure that their Type II variations are complete and in compliance with legal and regulatory requirements, leading to streamline the validation.

The Commission ‘Variations Guidelines’ further specifies which elements should be included in a Type II

variation application. More specifically, a Type II variation application should contain the following elements:

Module 1

• Cover letter (for groupings, include a short overview of the nature of the changes and indicate whether it is submitted under Article 7.2(b), i.e. it falls within one of the cases listed in Annex III of the variations regulation or it is submitted under Article 7.2.(c), i.e. the grouping has been agreed with the Agency).

• In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file UI .

• If the variation addresses a specific post-authorisation measure (PAM), the applicant should refer to the PAM reference number in the cover letter, application form and clinical and/or non-clinical overview, as appropriate. In case the reference number for the PAM has not been confirmed by the Agency, a description of the commitment/measure is sufficient at time of submission.

• The applicant may provide relevant documents as attachments to the cover letter, e.g. Agency requests for variations implementing changes for generic/hybrid/biosimilar medicinal products, CHMP PAM assessment reports, PRAC PSUSA assessment reports and Scientific Advice letters etc.

• Procedure number – The procedure number will be assigned by the EMA only upon receipt of an eCTD application and does not need to be included by the applicant at the time of submission. For further details refer to EMA pre-submission guidance “How is an EMA application/pr ocedure

number attributed?”

• The completed electronic EU variation application form (eAF) including the details of the marketing authorisation(s) concerned. Where a variation leads to or is the consequence of other variations, a description of the relation between these variations should be provided in the

appropriate section of the application form. All proposed changes should be declared in the ‘ Type of changes ’ section of the form and clearly described in the ‘ scope’ section of the form.

• Any change not clearly covered by any scope of a variation included (except editorial), and that is not clearly described in the precise scope section of the application form and included in the present and proposed section should not be considered as accepted.

• The ‘present/proposed ’ section in the application form should reflect all proposed changes to the English Product Information (SmPC, Annex II, labelling and package leaflet) as current and proposed text. Alternatively, if the proposed changes are extensive the applicant may instead

provide the ‘present/proposed’ comparison as part of a separate annex to the application form. In this case, the applicant should include in the ‘present/proposed’ section of the application form a

cross-reference to this annex.

• Presenting all changes in a ‘present/proposed’ format is a mandatory requirement in addition to

the updated Product Information provided in module 1.3.1 (see below). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• For T ype II variations concerning quality changes, the ‘present/proposed’ table (or attachment)

should reflect all changes applied for. Dossier section numbers should be provided to the lowest level possible and, where feasible, include the precise current and proposed wording as reflected in the relevant sections of the dossier. Where this is not feasible, a summary of the change(s) applied for should be included in the section.

• Reference to the variation scope laid down in the ‘Variations Guidelines’ or reference to the

published Article 5 recommendation, if applicable, should be made. The extract(s) of the

‘Variations Guidelines’ should preferably be submitted as a separate annex in module 1.2. In case

of groupings the corresponding classification scopes should be indicated as many times as needed taking into account that one classification scope is to be indicated per variation.

• Module 1.3.1 – In case changes to the Product Information are proposed, a revised full set of annexes (SmPC, Annex II, labelling and package leaflet) should be provided in English. The application must include clean and highlighted versions of the annexes, clearly showing all proposed amendments in track changes. The clean version should be provided as a PDF document in module 1.3.1 and the highlighted version preferably as a word document as part of

the ‘working documents’ outside the eCTD structure. In a ddition, the proposed Product Information should always be included in the eCTD submission as a pdf version with track changes, as a comparison of the present and proposed wording in the application form and/or as an attachment to the application form. Ple ase also refer to Question “When do I have to submit revised product information? In all languages?” below.

• Module 1.4.1 – Information about the quality expert (signed and dated expert statement + CV) is mandatory for all Type II variations including or referring to quality data in module 3. The quality expert is accountable for the quality overview/addendum (see below in section on Module 2).

• Module 1.4.2 – Information about the non-clinical expert (signed and dated expert statement + CV) is mandatory for all Type II variations including or referring to non-clinical data. The non-clinical expert is accountable for the non-clinical overview/addendum (see below in section on Module 2).

• Module 1.4.3 - Information about the clinical expert (signed and dated expert statement + CV) is mandatory for all Type II variations including or referring to clinical data and/or applications including an updated version of the Risk Management Plan (RMP). The clinical expert is accountable for the clinical overview/addendum (see below in section on Module 2).

• Module 1.5.3 – When the applicant requests consideration of an additional year of market protection in accordance with Article 14(11) of Regulation (EC) No 726/2004 or an additional year of data protection in accordance with Article 10(5) of Directive 2001/83/EC, a report should be provided in this module. For further details on the content of the report, reference should be

made to Eudralex Volume 2B for the Commission ‘Guidance on elements required to support the

significant benefit in comparison with existing therapies of a new therapeutic indication in order

to benefit from an extended (11 years) marketing protection period’ or ‘Guidance on a new

therapeutic indication for a well-established substance’.

• Module 1.8.2 - updated RMP (with revision date and version number) if applicable. When an updated RMP is proposed, the application should include both a clean and highlighted version of the revised RMP, clearly showing all proposed changes in track changes. All parts and modules of the clean RMP should be submitted in one single PDF-file. The highlighted version should also be European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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provided as a word document in the ‘working documents’ outside the eCTD structure (see below). Please also refer to “Risk Management Plan (RMP): questions and answers”.

• Module 1.9 – if applicable - Statement indicating that clinical trials conducted outside the EU meet the ethical requirements of Directive (EC) No 2001/20/EC, together with a listing of all trials (protocol numbers), and third countries involved. This is relevant when clinical trial reports are submitted.

Module 2

• Module 2.3 – Update or addendum to the quality summary . A quality summary is mandatory for all quality Type II variations. The document should discuss the data provided and address the impact on the Product Information (if any) and on the overall benefit/risk balance.

• Module 2.4 - Update or addendum to the non-clinical overview . A non-clinical overview /addendum is mandatory for all non-clinical Type II variations regardless of the impact on the Product Information. The document should discuss the data provided, address the impact on the Product Information and/or the RMP (if any), and conclude on the impact on the overall benefit/risk balance.

• Module 2.5 – Update or addendum to the clinical overview . A clinical overview/addendum is mandatory for all clinical Type II variations regardless of the impact on the Product Information. The document should discuss the data provided, address the impact on the Product Information and/or the RMP (if any), and conclude on the impact on the overall benefit/risk balance. It should be noted that a clinical overview/addendum is mandatory also for Type II variations that only concern an update of the RMP.

• Module 2.6 – Non-clinical summary(ies) . Whenever non-clinical study reports are provided, even if only one, relevant non-clinical summary(ies) are mandatory.

• Module 2.7 – Clinical Summary(ies) . Whenever clinical study reports for interventional studies are submitted, even if only one, relevant clinical summary(ies) are mandatory. However, it should be noted that summaries are not required for non-interventional studies.

In order to facilitate the assessment, the relevant Module 2 update(s) or addendum(s) should also be

provided as Word document in the ‘working documents’ outside the eCTD structure (see below).

Modules 3, 4 and 5

• Supporting quality, non-clinical and/or clinical data/study reports relating to the proposed variation(s), including literature references, should be provided.

The applicant can cross refer to information already included in the same dossier by using hyperlinks in modules 3, 4 and/or 5 rather than re-submitting the data again.

Working documents outside the eCTD structure:

Additional Word formats of certain documents are required to facilitate the assessment i.e. ‘tracked changes’ versions for SmPCs, RMPs or other documents specified by the Agency such as relevant

Module 2 update(s) or addendum(s). These should be provided i n the separate folder ‘XXXX -working

documents’. Further details can be found in the Harmonised Technical Guidance for eCTD Submissions in the EU . It is generally not necessary to include the RMP annexes in the ‘working document’ version

(unless annexes are being revised). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The above requirements also apply to the submission of the validation checklist (see above) and the responses to Request(s) for Supplementary Information.

See also “How should I present a grouped -variation application?” and “How should I present a variation application under worksharing?”

It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH and is crucial to the overall process.

For queries relating to the presentation of the application, please see ‘Who is my contact at the European Medicines Agency during a Type II variation, including extension of indications’ .

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• Electronic Variation application form

• Harmonised Technical Guidance for eCTD Submissions in the EU

3.8. How shall I present my application for a new or modified therapeutic indication? Rev. Nov Oct 20265

The MAHs are expected to complete the relevant validation checklist (Clinical/Non-clinical or quality)

and submit it as a word document (as part of the working documents) in Module 1 as an Annex. The checklist will help MAHs to ensure that their Type II variations are complete and in compliance with legal and regulatory requirements, leading to a smoother validation.

In addition to the requirements foreseen in the question above, the following considerations specifically

apply to applications concerning a new or a modified indication (please refer to question ‘What is

considered a new or modified therapeutic indication ?’):

• The sections in the application form on orphan medicinal products and paediatric requirements should be completed for all Type II variation applications that concern a new indication. In case of doubt, advice can be requested from the Agency in advance of the submission.

Please also refer to Q&As on ‘What aspects should I consider at time of submission of a Type II variation if there are orphan medicinal products designated or authorised for a condition related to

my proposed therapeutic indication?’, ‘Do I need to confirm the maintenance of my orphan

designation when applying for a T ype II variation?’, ‘Can a non -orphan therapeutic indication be

added to an already authorised orphan medicinal product?’ and ‘Do I need to address any

paediatric requirements in my T ype II variation application?’.

• Module 1.3.4 - Consultation with target patient groups (user testing results) or a justification why this was not considered necessary should be provided. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Module 1.6 – Environmental Risk Assessment (ERA) , where applicable. Expert assessment with or without study report(s) or justification why not considered necessary and the CV and signature of the expert should be provided.

• Module 1.7.1 – Similarity assessment , as applicable. See above and also refer to Q&A ‘What

aspects should I consider at time of submission of a Type-II variation if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic

indication?’.

• Module 1.8.2 - Updated RMP (with revision date and version number) or justification where not considered necessary should be provided. The justification, where applicable, should be included in module 1.8.2 or alternatively in the cover letter and/or the clinical overview.

• Module 1.10 – Paediatric information , as applicable. In case of doubt, advice can be requested from the Agency in advance of the submission.

Working documents outside the eCTD structure:

Additional word formats of certain documents are required to facilitate the scientific assessment by the

relevant scientific bodies i.e. ‘tracked changes’ versions for SmPCs, RMPs or other documents specified

by the Agency such as relevant Module 2 update(s) or addendum(s) and the summary of the main

efficacy results. These should be provided in the separate folder ‘XXXX -working documents’. Further

details can be found in the Harmonised Technical Guidance for eCTD Submissions in the EU. It is

generally not necessary to include the RMP annexes in the ‘working document’ version (unless annexes

are being revised).

The above requirements also apply to the submission of the validation checklist (see above) and the responses to Request(s) for Supplementary Information

Please also refer to the following questions which address paediatric related aspects ‘Do I need to

address any paediatric requirements in my T ype II variation application?’ and ‘What is considered a new or modified therapeutic indication?’.

Submission of responses to request(s) for supplementary information

The MAH should use the ‘Template for response to list of questions/list of outstanding issues/request

for supplementary information: Quality / Non-clinical / Clinical’ to respond to any request for

supplementary information. The MAH is expected to respond to all the questions directly in this

response template document and submit both pdf version (in Modul 1) and word version (in the

Working Documents folder) with their official responses in eCTD.

References

• Harmonised Technical Guidance for eCTD Submissions in the EU

• Table of summary of the main efficacy results template

• Template for response to list of questions/list of outstanding issues/request for supplementary

information: Quality / Non-clinical / Clinical European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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3.9. How and to whom shall I submit my Type II Variation application? Rev. Feb 2019

Information is available on ‘Submitting a post -authorisation application’.

3.10. When shall I submit my Type II variation? Rev. Nov 2025

The assessment timetable and hence the submission deadline applicable to a Type II variation application depends on the committees involved in the assessment, the amount of assessment needed and whether the CHMP Opinion will be followed by an amendment of the Commission Decision granting the Marketing Authorisation within two months.

There are three types of submission deadlines and consequently procedure start dates: monthly, alternative monthly and weekly.

Weekly starts are applicable to Type II variation applications received by the Agency not involving the PRAC. Alternative monthly start dates apply for variations involving the PRAC. The following Type II variations applications follow a monthly start date:

• extensions of indications and other variations requiring amendment of the Commission Decision granting the Marketing Authorisation within two months from CHMP Opinion. Please refer to

Question ‘Which post -opinion steps apply to my Type II variation and when can I implement the approved changes?’ below.

• variations involving multiple committees, i.e. PRAC, CAT in addition to the CHMP (e.g. variations including an RMP update or variations for ATMPs).

Opinions for monthly start variations requiring Commission Decision within two months from CHMP Opinion (including extensions of indication) are adopted during the week of the CHMP plenary meeting. Opinions for alternative monthly start variations involving the PRAC and not requiring Commission Decision within two months are adopted during the week of the PRAC plenary meeting. Opinions for weekly start variations are adopted independently of the committee plenary meetings.

For variations following the weekly start, the Agency may need to amend the timetable if during the procedure the need for discussion at plenary / involvement of other committees (e.g. PRAC), working parties (i.e. BWP) or for immediate EC decision arise.

In case there is uncertainty before submission as to which timetables and submission deadlines are to be followed, MAHs can request the advice of the Agency (please refer to ‘Who is my contact at the European Medicines Agency during a Type II variation, including extension of indications?’ ). The Agency will inform the MAH of the applicable timetable in the validation confirmation e-mail. For more information see also q uestion ‘How shall my Type II application be handled (timetable)?’ .

For each of the assessment timetables, the MAH should submit their application at the latest by the

recommended submission dates published on the Agency’s website (Please refer to “Human Medicines – Procedural Timetables / Submission dates”).

MAHs are reminded of their obligation to submit forthwith any information that becomes available which might entail the variation of the MA. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Where the CHMP requests the submission of a variation following the assessment of a post-authorisation measure (PAM), Specific Obligation (SOB) or signal, MAHs must submit the corresponding variation application within the requested timeframe.

Variation applications reflecting the outcome of an Urgent Safety Restriction (USR) shall be submitted immediately and in any case no later than 15 days after the initiation of the USR to the Agency. This applies to USRs initiated by the MAH or imposed by the European Commission.

Implementation of agreed wording changes following the above-mentioned procedures for which no additional data are submitted by the MAH will follow a Type IB variation procedure.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

3.11. How shall my Type II application be handled (timetable)? Rev. Mar Oct 2026

Upon receipt of a technically valid application, the Validation Team (Non-clinical, Clinical/RMP variations) or Quality Specialist (Quality variations) will perform the validation of the application content. Supplementary information may be requested in order for the validation to be finalised and the procedure will commence at the next available start date after resolution of issues identified during validation. The Agency will inform the MAH of the outcome of the validation and timetable (TT).

Assessment of Type II variations following a 60-day TT may either follow a weekly or a monthly start date, depending on the need or not for the variation to be aligned with the CHMP plenary meeting

periodicity (See also question “ When shall I submit my application?” above ).

Extensions of indication on a 90-day TT always follow the monthly start TT. They are discussed during the CHMP plenary meeting and require a Commission Decision (CD) to be adopted within two months from CHMP Opinion.

Type II variation procedures following a 30-day TT (e.g. urgent safety issues) will in principle follow the monthly start TT. They are likely to be discussed during the CHMP plenary meeting and require the adoption of a Commission Decision (CD) within two months from CHMP Opinion.

For variations following a weekly-start TT, the opinion or request for supplementary information (RSI) will be adopted by the CHMP independently of the plenary meetings. The MAH can also provide their responses to an RSI during the procedure in line with the weekly re-start dates.

Variations following a 60-day TT (= standard TT)

Condition:

• All Type II variations not qualifying for a 30 or 90-day TT (see below) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Variations assessed by the CHMP only or variations involving the PRAC (refer to question ‘Is the PRAC Rapporteur involved in Type II Variations?’) not requiring CD within two months from CHMP Opinion:

Day Action

Day 1 Start of evaluation

Day 36 Receipt of CHMP # Rapporteur’s Assessment Report

Day 43^ Receipt of PRAC Rapporteur’s Assessment Report

Day 47^ Comments by other PRAC members

Day 50 Comments by other CHMP members

Day 51^ Receipt of PRAC Rapporteur’s updated Assessment

Report*

Day 53 Receipt of CHMP # Rapporteur’s updated

Assessment Report*

Day 58^ PRAC outcome

Day 60 Adoption of the CHMP Opinion

[or Request for supplementary information]

*Updated assessment reports are optional, depending on comments received by other committee members.

There is(are) no CHMP Rapporteur’s assessment report(s) in case of PRAC -led variations.

^Steps not applicable for CHMP-only variations.

Variations assessed by PRAC (refer to question ‘Is the PRAC Rapporteur involved in Type II Variations?’) and CHMP requiring CD within two months from CHMP Opinion:

Day Action

Day 1 Start of evaluation

Day 30 Receipt of CHMP Rapporteur’s Assessment Report

Day 33 Receipt of PRAC Rapporteur’s Assessment Report

Day 38 Comments by other PRAC members

Day 39 Receipt of PRAC Rapporteur’s updated Assessment

Report*

Day 46 PRAC outcome

Day 50 Comments by other CHMP members

Day 53 Receipt of CHMP Rapporteur’s updated

Assessment Report*

Day 60 Adoption of the CHMP Opinion European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Day Action

[or Request for supplementary information]

• Updated assessment reports are optional, depending on comments received by other committee members.

Variations following a 30-day TT

Condition:

• Changes which, in the opinion of the Agency, would benefit from a shortened assessment having regard to the urgency of the matter in particular for safety issues

Variations assessed by the CHMP only or variations involving the PRAC (refer to question ‘Is the PRAC Rapporteur involved in Type II Variations?’) not requiring CD within two months from CHMP Opinion:

Day Action

Day 1 Start of evaluation

Day 15 Receipt of CHMP # Rapporteur’s Assessment

Report +

Day 17^ Receipt of PRAC Rapporteur’s Assessment Report

Day 20^ Comments by other PRAC members +

Day 20 Comments by other CHMP Members

Day 21^ Receipt of PRAC Rapporteur’s updated

Assessment Report*

Day 23 Receipt of CHMP # and PRAC Rapporteur’s updated

Assessment Report* +

Day 28^ PRAC outcome

Day 30 Adoption of the CHMP Opinion

[or Request for supplementary information]

*Updated assessment reports are optional, depending on comments received by other committee members.

There is(are) no CHMP Rapporteur’s assessment report(s) in case of PRAC -led variations.

^ Steps not applicable for CHMP-only variations.

For the initial submission assessment of CHMP-only variations following a weekly start 30-day TT. the CHMP assessment report, CHMP members comments and CHMP updated assessment report is foreseen at Day 20, 22 and 24 respectively.

Variations assessed by PRAC (refer to question ‘Is the PRAC Rapporteur involved in Type II Variations?’) and CHMP requiring Commission Decision within two months from CHMP Opinion: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Day Action

Day 1 Start of evaluation

Day 6 Receipt of PRAC Rapporteur’s Assessment Report

Day 8 Comments by other PRAC Members

Day 9 Receipt of PRAC Rapporteur’s updated

Assessment Report*

Day 15 Receipt of CHMP Rapporteur’s Assessment Report

Day 16 PRAC outcome

Day 20 Comments by other CHMP Members

Day 23 Receipt of CHMP Rapporteur’s updated

Assessment Report*

Day 30 Adoption of the CHMP Opinion

[or Request for supplementary information]

• Updated assessment reports are optional, depending on comments received by other committee members.

In exceptional cases, this timetable could be further shortened.

Variations following a 90-day TT

Condition:

• For variations concerning changes to or addition of therapeutic indications or for grouped variation agreed with the Agency:

Day Action

Day 1 Start of evaluation

Day 56 Receipt of and CHMP (Co-) Rapporteur’s

Assessment Report

Day 63^ Receipt of PRAC Rapporteur’s Assessment Report

Day 68 Comments by other PRAC members^

Day 69^ Receipt of PRAC Rapporteur’s updated

Assessment Report

Day 76^ PRAC outcome

Day 80 Comments by other CHMP members

Day 83 Receipt of CHMP Rapporteurs’ Joint Assessment

Report

Day 90 Adoption of the CHMP Opinion European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Day Action

[or Request for supplementary info]

^The PRAC is normally involved in the assessment of Type II variation applications following the 90-day TT as an (updated) RMP is expected to be submitted as part of the application. Absence of an RMP update should be justified at the time of submission.

In case issues which prevent the adoption of an Opinion are identified at D90, the CHMP will adopt an RSI together with a deadline for submission of the requested data by the MAH and a TT for the

assessment of the MAH’s responses. The MAH will receive the adopted TT embedded within the RSI. The clock will be stopped until the receipt of the MAH’s response to the RSI.

Responses to the RSI must be sent to the Agency, as per the instructions included in the “Submitting

post-authorisation application” section of the post-authorisation guidance .

For responses to request for supplementary information concerning variations to modify or add

therapeutic indications, please refer to the question on ‘How shall I present my application for a new or

modified therapeutic indication?’ above.

Clock-stop scenarios:

• By default, a one-month clock-stop will apply.

• For type II variations following the weekly-start TT, clock-stops in increments of weeks (i.e. shorter than one month) can apply.

• In certain cases and in agreement with the Rapporteur(s), for type II variations under a monthly (including extension of indications) or alternative monthly TT, when minor issues remain, and, if a PRAC plenary discussion is not needed, the MAH may be able to respond within a few days (usually 5 days) from the CHMP adoption of the RSI (i.e. 30-day immediate responses TT).

If the MAH intends to request a ‘clock-stop ’ period different from the default one-month ‘clock-stop ’

period (shorter or longer), it should contact the EMA product assistant (PA) and the EMA product lead

(PL) (or EMA Quality Specialist in case of quality type II variations).

For clock-stops longer than 1 month (clock-stop extension), the MAH should send a justified written request to the Agency for agreement by the Rapporteur(s) and the corresponding Committee(s):

• The clock-stop length should be discussed with the EMA product lead (PL) (or EMA Quality Specialist in case of quality type II variations) during the active time of the procedure before the adoption of the RSI. Upon receipt of a written justification sent to the EMA via the PL (or EMA Quality Specialist in case of quality type II variations), such clock-stop extension request will be shared with the Rapporteur(s) and the corresponding Committee(s) for agreement and will be discussed by the committee(s) as relevant. For extension of indications, the written justification

should be included in the ‘ Template for request of clock-stop extension ’ and submitted as per the

instructions included in this specific template.

• When the procedure is already in clock-stop, the MAH should send to the EMA PL (or EMA Quality Specialist in case of quality type II variations) a justified written request or for extension of

indications fill in the ‘ Template for request of clock-stop extension ’. Such clock -stop extension request is shared upon receipt for agreement with the Rapporteur(s) and the corresponding

Committee(s) prior to the previously agreed deadline to submit the MAH’s responses to the European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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adopted RSI. For extension of indications, clock-stop extension requests are to be discussed at

the CHMP plenary and hence should be submitted in writing using the ‘Template for request of

clock-stop extension’ by the MAH before the start of the next Commi ttee(s) plenary meeting.

Assessment of responses

The Committee assessment of the MAH’s responses will take up to 30 or 60 days depending on the

complexity and amount of data provided by the MAH. Upon receipt of the responses from the MAH, the procedure will be re-started following a weekly-start , alternative monthly or monthly-start timetable according to the same principles as the ones applied at the initial start of procedure.

Oral explanation

An oral explanation in front of the relevant Committee can be held at the request of the Committee or the MAH, where appropriate.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

3.12. How should parallel Type II variations that affect the product information be handled? Rev. Nov 2025

When two or several stand-alone Type II variation applications are being submitted and/or assessed in parallel the following general principles apply:

• Each variation should comprise only the supporting data and Product Information change(s) and/or RMP change(s) proposed in the context of the specific variation;

• The assessment of the different variations will be independent, and the procedures will be kept separate regardless of the anticipated timelines of the different procedures;

• The Product Information from one variation should not include the proposed Product Information changes from a different variation, neither as highlighted nor as clean text.

In order to simplify the handling of different versions of the Product Information, submissions affecting the Product Information should be whenever possible combined in a grouped variation application, if

allowed by grouping rules. Please also refer to “W hat groups of variations would be considered

acceptable?”.

Once a CHMP opinion has been adopted for a Type II variation, or a Commission Decision has been granted in case an immediate EC Decision is required, the approved Product Information can be used as baseline for the Product Information of any subsequent variation(s). The consolidation can be done

at the time of any procedural milestone of the subsequent variation(s) e.g. as part of the MAH’s European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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responses to a request for supplementary information, but in any case, at the latest before the adoption of the CHMP opinion.

Once included, the already approved changes related to a previous variation should appear as clean text in both the clean and highlighted versions of the Product Information for subsequent variation(s). It should be noted that only the new proposed changes related to the subsequent variation should continue to be highlighted in tracked changes during that procedure.

3.13. Which post-opinion steps apply to my Type II variation and when can I implement the approved changes? Rev. Jul Oct 2026

Upon adoption of the CHMP opinion, the Agency will inform the MAH within 15 days as to whether the CHMP opinion is favourable or unfavourable (including the grounds for the unfavourable outcome), as well as whether the Commission Decision granting the marketing authorisation requires any amendments.

Where the outcome of the procedure is favourable and the Commission Decision granting the Marketing Authorisation requires amendments, the Agency will inform the Commission accordingly.

Re-examination

Article 9(2) of Regulation (EC) No 726/2004, also applies to CHMP Opinions adopted for Type II variation applications. This means that the MAH may give written notice to the Agency/CHMP within 15 days of receipt of the opinion (after which the opinion shall be considered as final) that they wish to request a re-examination. The grounds for the re-examination request must be forwarded to the Agency within 60 days of receipt of the opinion.

In case the MAH requests that the committee consults a scientific advisory group (SAG or AHEG ) in connection with the re-examination, the MAH should inform the CHMP as soon as possible of this request and at the latest with the submission of the detailed grounds for re-examination. This is necessary to allow for the SAG/AHEG consultation to be organised, and the outcome of this consultation duly taken into account by the CHMP, within the timelines established for the re-examination procedure.

The CHMP will appoint different (Co-) Rapporteurs, to co-ordinate the re-examination procedure. In case a PRAC Rapporteur is deemed necessary, a different PRAC Rapporteur will be appointed. Within 60 days from the receipt of the grounds for re-examination, the CHMP will consider whether its opinion is to be revised. If considered necessary, an oral explanation can be held within this 60-day timeframe.

In case of withdrawal of the request for re-examination, the initial CHMP opinion will immediately become the final CHMP opinion.

EMA charges a fee for a re-examination of an opinion. For more information, please refer to the Fee Q&As in Annex IV, Section 4, on the Fees payable to the European Medicines Agency page.

Linguistic review

Where the product information is affected, a linguistic review of the Product Information changes will be performed. The linguistic review will start 5 days after the CHMP plenary meeting following the adoption of the CHMP opinion on the variation. The monthly linguistic review will cover all procedures European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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affecting the annexes concluded since the latest linguistic review i.e. all variations adopted in line with

the ‘weekly -start’ timetables as well as those following the ‘monthly’ timetables that have had an

opinion adopted at the CHMP plenary meeting in the same month will be included. The EPAR update will also consolidate all procedures concluded since the latest EPAR update.

In the event that the only change to the Product Information concerns deletion of text or a change to numerical characters e.g. shelf-life of a finished product, no post-opinion linguistic review would be necessary.

In all cases, the amended Product Information in all languages should be provided by the MAH by the date specified in the translation timetable which is provided with the CHMP opinion.

Decision-Making Process

Upon receipt of a favourable CHMP opinion which requires amendments to the decision granting the marketing authorisation, the Commission shall amend the marketing authorisation to reflect the variation within 2 months, for the variations listed under Article 23(1a)(a) and other specific cases, or

within one year for the other Type II variations.

Article 23(1a)(a) provides for a two-month timeframe for amending the Commission decision granting the marketing authorisation for the following variations:

• Variations related to the addition of a new therapeutic indication or to the modifications of an existing one;

• Variations related to the addition of a new contra-indication;

• Variations related to a change in posology;

• Variations related to changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against human influenza;

• Other Type II variations that are intended to implement changes to the decision granting the marketing authorisation due to a significant public health concern ( e.g. when a ‘Direct Healthcare

Professional Communication’ (DHPC) is agreedor a change of legal status or an Annex in

accordance with Article 127a of Directive 2001/83/EC is agreed. This would also encompass

variations following an Urgent Safety Restriction or variations concerning new safety warning

statements related to adventitious agents);

• Variations related to changes to the active substance of a human coronavirus vaccine, including replacement or addition of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences;

• Variations related to the replacement or addition of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences of a human vaccine that has the potential to address a public health emergency.

A two-month timeframe for amending the Commission decision is also expected for variations:

• of orphan medicinal products that include a compliance statement as per Article 28(3) of

Regulation (EC) No 1901/2006.

All the other Type II variations will follow a yearly timeframe for update of the respective Commission decision. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Where a group of variations to the terms of one marketing authorisation submitted as part of one variation have been approved, the Commission will update the marketing authorisation with one single decision to cover all the approved variations.

Where the variation leads to a switch of conditional MA to standard MA, the Commission will grant a

new marketing authorisation that is initially valid for five years. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Implementation

Type II variations listed in Article 23(1a)(a) may only be implemented once the Commission has amended the marketing authorisation and has notified the MAH accordingly. Variations related to safety issues, including urgent safety restrictions, must be implemented without delay and/or within a timeframe agreed by the MAH and the Agency.

Type II variations which do not require any amendment of the marketing authorisation or which follow a yearly update of the respective Commission Decision can be implemented once the MAH has been informed of the favourable outcome by the Agency. However, it is expected that where the variation includes changes to the product information, the MAH waits for the finalisation of the linguistic review process by the Agency before implementing the variation, as appropriately checked translations are considered essential for a correct implementation of the variation.

The agreed change(s) should be included in the product information annexes of any subsequent regulatory procedure.

See also question “How should parallel Type II variations that affect the Product Information (PI) be

handled?” above.

Date of revision of the text

The date of revision of the text to be included in section 10 of the SmPC and corresponding section of the package leaflet for variations affecting the product information should be as follows:

• For Type II variations listed in Article 23(1a)(a) this should be the date of the Commission Decision amending the marketing authorisation;

• For Type II variations not listed in Article 23(1a)(a), which follow a yearly timeframe for update of the respective Commission decision, this should be the date of the adoption of the positive CHMP opinion on the variation to the terms of the marketing authorisation.

This date corresponds to the date of EC decision or CHMP opinion when that specific annex was affected.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• The Linguistic Review Process of Product Information in the Centralised Procedure – Human

3.14. What fee do I have to pay for a Type II variation? Rev. Dec 2024

For information on fees to be paid, applicable fee reductions and payment process, please refer to the Fee Q&As in Annex I, Section 5, on the Fees payable to the European Medicines Agency page. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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References

• Fees payable to the European Medicines Agency

3.15. Do I have to submit mock-ups and specimens? Rev. July 2013

For information concerning submission of mock-ups and specimens in the framework of post-

authorisation procedures, please refer to the document ‘Checking process of mock -ups and specimens of outer/immediate labelling and package leaflet of human medicinal products in the centralised procedure, 3.4 Other post-authorisation procedures.

References

• The Checking Process of Mock-Ups and Specimens of outer/immediate labelling and package leaflets of human medicinal products in the Centralised Procedure (EMEA/305821/2006)

3.16. When do I have to submit revised product information? In all languages? Rev. Feb 2025

In case the Type II Variation affects the SmPC, Annex II, labelling and/or package leaflet, the revised product information Annexes must be submitted as follows:

At submission

• English language: Revised complete set of product information annexes (SmPC, Annex II, labelling and package leaflet). The application must include a clean and highlighted version of the annexes, clearly showing all proposed changes in track changes. The clean version should be provided in module 1.3.1 and the highlighted version should be provided as a word document as

part of the ‘working documents’ outside the eCTD structure. The provision of a highlighted word

version is mandatory as it facilitates the review of the application. The highlighted version should additionally be provided as a PDF document in module 1.3.1. Alternatively, proposed changes

should be documented in the ‘present/proposed table’ of the application form or in an annex to

the appli cation form (see also question “How shall I present my Type II Variation application?”

above).

During the procedure

• English language: The MAH should take into account the assessment feedback and provide revised versions of the highlighted product information as part of the responses to any requests for supplementary information during the procedure. The revised highlighted product information that is provided at these procedural milestones should be submitted in line with the requirements

outlined above ‘at submission’.

In addition, during the latter stages of the procedure there is often a need for fast informal exchanges between the MAH and the Rapporteur in preparation of the final CHMP opinion. During this process the MAH can provide any revised versions of the product information as well as comments/justifications by Eudralink/email in Word format. These product information versions are

considered ‘working documents’ only and there is consequently no need to submit these updated European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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product information proposals as part of a formal eCTD sequence (unless part of formal responses to a CHMP request for supplementary information).

See also question “How should parallel Type II variations that affect the PI be handled?” above.

At CHMP Opinion (Day 0)

• English language: complete set of finally agreed product information, annexes electronically only in Word format (highlighted and clean). It is sufficient to provide the final agreed annexes by Eudralink/email at this stage (i.e. before the CHMP opinion).

After CHMP Opinion (Day +5, for all variations with an opinion that month – both those on a weekly-start timetable and those on a monthly-start timetable, this is 5 days after the CHMP plenary meeting following the adoption of the CHMP opinion)

• All EU languages (incl. NO+IS): complete set of annexes electronically only in Word format (highlighted)

After Linguistic check (Day +25, for all variations that month – both those on a weekly-start timetable and those on a monthly-start timetable, this is 25 days after the CHMP plenary meeting following the adoption of the CHMP opinion)

• All EU languages (incl. NO+IS): complete set of annexes electronically only in Word format (highlighted) and in PDF (clean)

The final adopted annexes should always be provided post opinion as part of an eCTD closing sequence within 15 days of the Commission Decision (if there is one) or within 2 weeks after the finalisation of the linguistic review process (if this is not followed by a Commission Decision).

Overview

Day Lang.* Post-opinion linguistic review Timetable

0 EN Electronically

Word format (highlighted)

+5 All EEA Electronically

Word format (highlighted)

+25 All EEA Electronically

Word format (highlighted)

PDF format (clean)

• = complete set of Annexes i.e. Annex I, II, IIIA and IIIB submitted as one document per language

The ‘complete set of Annexes’ includes Annex, I, II, IIIA and IIIB i.e. all SmPC, labelling and package

leaflet texts for all strengths and pharmaceutical forms of the product concerned, as well as Annex II.

The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU language. Page numbering should start with "1" (bottom, centre) on the

title page of Annex I. The ‘QRD Convention’ published on the Agency’s website should be followed.

When submitting the full set of Annexes in PDF format, this should be accompanied by the completed formatting checklist which provides guidance on how to correctly prepare the PDF versions. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The electronic copy of all languages should be provided as part of the variation application on the

Gateway / Web Client package. Highlighted changes should be indicated via ‘Tools – Track changes’. Clean versions should have all changes ‘accepted’.

Icelandic and Norwegian language versions must always be included.

At the time of the submission and throughout the procedure, the annexes provided should only reflect as highlighted text the changes introduced by the specific variation concerned. However, following adoption of the CHMP opinion it may be necessary to consolidate the adopted annexes for separate variations running in parallel, i.e. when these conclude concurrently. In that case the linguistic review will be undertaken based on the consolidated version which should reflect as highlighted text all changes for the parallel variations adopted by the CHMP at that plenary meeting and include variations adopted earlier during the month in line with the weekly-start timetable.

The section “present/proposed” in the application form should clearly list all changes proposed to the

English annexes. Any minor linguistic amendments introduced for other languages should be provided as a separate document attached to the application form.

In such cases and in cases where any other ongoing procedures may affect the product information annexes, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedure(s) concerned.

For those variations which affect the Annex A (e.g. introduction of a new presentation), the following principles apply:

Upon adoption of the opinion, the Agency will prepare and send to the MAH the revised English Annex A reflecting the new/amended presentation.

After CHMP Opinion (Day +5, for variations on a weekly-start timetable, this is 5 days after the CHMP plenary meeting following the adoption of the CHMP opinion ) the MAH provides the Agency with the electronic versions of the complete set of annexes in all languages as well as the translations of the revised Annex A as a separate word document.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translation versions of the product information annexes in all the languages submitted at Day+5 as well as the final translations submitted at Day+25. The annotated product information files must include the statement containing the procedure number(s) and may be published on the EMA website as part of the product EPAR page. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA, the publication on the EMA website and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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3.17. What changes will trigger new EU number(s) (additional presentation(s))? Rev. Nov 2025

Any changes in the number of units of medicinal product or medical device being an integral part of the medicinal product (e.g. prefilled syringes) will trigger a different EU number.

Differentiation should be made between the addition of a presentation where the two presentations will co-exist on the market on a long-term basis versus a replacement of a presentation where the new presentation will replace the previous one (it is expected that for a limited period of time, the two presentations may co-exist on the market until the stock of the previous presentation runs out).

In principle, a replacement of one presentation by another presentation does not trigger a new EU number, unless the number of units of medicinal product or medical device being an integral part of the medicinal product (e.g. prefilled syringes) is changed.

Examples of changes in presentations for replacement, not triggering a new EU number (this is not an exhaustive list):

• Replacement of the primary or secondary packaging,

• Change in composition (e.g. change in excipients),

In case of addition , as the presentations will co-exist on the market, two packs with different contents cannot be covered by the same EU number and will be considered as different presentations.

Changes in the number of any unit (not restricted to the medicinal product) or changes in the specifications of any unit (not restricted to the medicinal product) contained in the pack will trigger a new EU number.

Examples of changes that will trigger new EU numbers (this is not an exhaustive list):

• Introduction of an alternative immediate (primary) packaging made from a different material,

• Introduction of an alternative shape/dimension of a pharmaceutical form (pre-rolled sealant matrix versus flat, change in size of patch).

If you have any questions on any upcoming submission, please contact the allocated Product Lead.

3.18. What is the procedure for assignment of new European Union sub-numbers for a Type II variation concerning additional presentation(s)? NEW Nov 2012

At the time of the adoption of a CHMP opinion for a Type II variation which includes additional presentation(s), the Agency will assign the new EU sub-numbers and include them in the revised Annex A of the medicinal product, which will be transmitted to the marketing authorisation holder together with the CHMP Opinion and respective annexes.

The marketing authorisation holder should include the newly assigned numbers in all language versions of the Annex A and in all applicable sections of the product information, which are submitted following the CHMP opinion for linguistic review. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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3.19. Will there be any publication on the outcome of my Type II variation? Rev. Oct 2012

The meeting highlights following each CHMP meeting give information on opinions in relation to new indications, changes to an existing indication and the addition, change or removal of a contraindication. This will include the name of the product, the name of the MAH, the indication(s). Where applicable, the CHMP gives also an update on safety information.

Please refer also to “What we publish on medicines and when?”.

References

• EMA website – What we publish on medicines and when

3.20. What aspects should I consider at time of submission of a Type II variation if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication? Rev. May 2020

Type II variations for a new indication, which is the same as the indication of an authorised Orphan Medicinal Product, should include relevant information in Module 1.7 of the application, based on the following considerations:

In accordance with Article 8.1 of Regulation (EC) No 141/2000, where a marketing authorisation in respect of an orphan medicinal product has been granted in all Members States, the Union and the Member States shall not, for a period of 10 years, accept another application for marketing authorisation, or grant a marketing authorisation or accept an application to extend an existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product.

Where a designated orphan medicinal product has been authorised for the condition which covers the proposed therapeutic indication being applied for, and a period of market exclusivity is in force, the MAH must submit a report in module 1.7.1 addressing th e possible “similarity” with the authorised

orphan medicinal product (even if the concerned product does not have orphan designation).

The assessment of similarity between two medicinal products takes into consideration the following criteria:

• Principal molecular structural features,

• Mechanism of action and

• Therapeutic indication.

The critical report provided in Module 1.7.1 should address the possible similarity between the proposed new medicinal product and the authorised orphan medicinal products for each of these criteria.

If significant differences exist within one or more of these criteria, the two products will not be considered as similar. These criteria are explained in the Guideline on aspects of the application of Article 8(1) and 8(3) of Regulation (EC) No 141/2000: Assessing similarity of If significant differences exist within one or more of these criteria, the two products will not be considered as similar. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Commission Regulation (EC) No 847/2000 provides additional specific considerations for the definition of similar active substance applicable to chemical, biological and advanced therapy medicinal products.

If the medicinal product is deemed to be “similar” to an authorised orphan medicinal product, the MAH

must furthermore provide justification in module 1.7.2 that one of the derogations laid down in Article 8.3, paragraphs (a) to (c) of the same Regulation applies, namely:

(a) the holder of the marketing authorisation for the original orphan medicinal product has given his consent to the second applicant, or

(b) the holder of the marketing authorisation for the original orphan medicinal product is unable to supply sufficient quantities of the medicinal product, or

(c) the second applicant can establish in the application that the second medicinal product, although similar to the orphan medicinal product already authorised, is safer, more effective or otherwise clinically superior.

The assessment of similarity is conducted in parallel to the evaluation of the variation application and follows the same timetable. The assessment includes the consultation of the Quality Working Party or the Biologicals Working Party for the aspects concerning the similarity of the molecular structures of the products.

Even if the variation does not concern an orphan designated product, all MAHs should still check whether their claimed new indication would potentially overlap with the indication of authorised orphan medicinal products, as listed on the Commission Website in the “Community register” of designated

orphan medicinal products and include the relevant documentation in their variation application as set-out above.

References

• Regulation (EC) No 141/2000

• Regulation (EC) No 847/2000 as amended by Regulation (EU) 2018/781

• Guideline on aspects of the application of Article 8(1) and (3) of Regulation (EC) No 141/2000: Assessing similarity of medicinal products versus authorised orphan medicinal products benefiting from market exclusivity and applying derogations from that market exclusivity

• Community Register - website of the European Commission

3.21. Do I need to confirm the maintenance of my orphan designation when applying for a Type II variation? Rev. Mar 2026

If the product has been designated as orphan and the application concerns a new therapeutic indication or a modification of an existing one, in order to ensure that the Marketing Authorisation only covers indications that fulfil the orphan designation criteria foreseen in Art 3 of Regulation (EC) No 141/2000, a COMP review may be required as following:

• for a new therapeutic indication falling within a new orphan designation , i.e. an orphan designation other than the one(s) related to the already approved indication(s), the COMP will have to confirm the maintenance of the orphan designation before authorisation of the new indication. In this case, the sponsor should provide at the time of submission a maintenance European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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report using the template provided on the EMA website. The maintenance report should be

submitted via the IRIS Platform.

• for a new therapeutic indication falling within an already authorised orphan designation , the COMP will have to consider if the specific scope of the variation raises justified and serious doubts in respect to the fulfilment of the orphan designation criteria and indicate if a formal review process of the maintenance of the orphan designation is needed.

To support this process, the MAH/sponsor is requested to provide at the time of submission of the variation either a justification that the variation does not raise doubts on the fulfilment of the orphan criteria or a maintenance report to justify that the orphan criteria are still met. The justification/ maintenance report should be submitted via the IRIS Platform.

Further to the COMP preliminary discussion based on the sponsor’s justification/ maintenance report, a

formal review process of the maintenance of the orphan designation for the applied indication will be triggered if justified and serious doubts are raised on the maintenance of the orphan designation. In this case, if previously only a justification was submitted, the MAH/sponsor will be requested to provide a maintenance report. The procedure for assessment will follow the usual procedure, as described in Orphan status management – BPD-H-008.

For the purpose of defining what is a new therapeutic indication or a modification of an existing one for the COMP review for post-authorisation extensions of indications, the Guideline on the elements required to support the significant clinical benefit in comparison to existing therapies of a new therapeutic indication in order to benefit from an extended (11-year) marketing protection should be followed.

In case of doubt, the Agency encourages applicants to contact the Orphan Medicines Office in advance of a planned submission in order to clarify orphan requirements. Please submit your message via EMA-info: Send a question to the European Medicines Agency.

Further information can be found on the dedicated EMA Website on Orphan designation.

References

• Regulation (EC) No 141/2000

• Commission Notice on the application of Articles 3,5 and 7 of Regulation (EC) No 141/2000 on orphan medicinal products

• Orphan status management – BPD-H008

3.22. Can a non-orphan therapeutic indication be added to an already authorised orphan medicinal product? Rev. Nov 2025

As provided for in Article 7(3) of the Regulation, it is not possible to combine within the same marketing authorisation orphan and non-orphan indications. In case the MAH wishes to extend the therapeutic indications of the orphan medicinal product to include additional non-orphan therapeutic indications, the following regulatory options should be considered:

• To apply for a separate application for marketing authorisation covering the therapeutic indications which are outside the scope of the Orphan Regulation European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• To request the withdrawal of the orphan designation from the Union register of Orphan Medicinal Products for your medicinal product.

If the orphan designation is not yet withdrawn at time of submission, the marketing authorisation holder should undertake in their cover letter to request the withdrawal the orphan designation from the Union register not later than 2 days after the receipt of the CHMP opinion.

Based on this commitment, the Agency will validate the variation / MA extension application pertaining to a non-orphan indication. If the MAH has not requested the withdrawal of the Orphan designation within the said deadline, nor requested re-examination in accordance with Article 16(4) of Commission Regulation (EC) No 1234/2008, the validation of application will become automatically null and void with retroactive effect.

Sponsors should use EMA’s IRIS system to submit the request to remove the orphan designation from

the Union Register. To request removal, the sponsor should:

• Prepare a letter requesting the removal of the orphan designation, signed by an authorised person.

• Create and submit the removal request in the IRIS portal, selecting as submission type ‘Removal of

an orphan designation from the EU register’. An electronic copy of the letter above should be

included with the submission.

Upon receiving the submission, EMA will forward the request to the European Commission, who will notify the removal to the sponsor and update the Union Register accordingly.

References

• Regulation (EC) No 141/2000 on orphan medicinal products

• Removing an orphan designation

3.23. Can a new indication based on less comprehensive data be added to an already authorised medicinal product? Rev. Nov 2025

According to Articles 14-a and 14(8) of the Regulation (EC) No 726/2004, a marketing authorisation can be granted in certain situations based on less comprehensive data than normally required, i.e. a conditional marketing authorisation or marketing authorisation under exceptional circumstances, respectively.

Granting these types of authorisation is only foreseen in the context of an application for an initial

marketing authorisation. Therefore, when a “standard”/“full” marketing authorisation has been already

granted, it is not possible to subsequently convert this authorisation into a conditional marketing authorisation or a marketing authorisation under exceptional circumstances. In such case, introduction of a new indication within the same marketing authorisation will have to comply with the standard data requirements and not be based on less comprehensive data than normally required. Alternatively, submission of a relevant separate marketing authorisation (either conditional of under exceptional circumstances) may be considered by the applicant, taking into account also provisions concerning multiple applications. For further details please refer to EMA pre-submission guidance ‘What should I do if I want to submit multiple/duplicate applications for the same medicinal product?’.

Nevertheless, if a product already has a conditional marketing authorisation, it is possible to modify (including extend) the indication and related specific obligations, provided that any modifications that European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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are based on less comprehensive data comply with the requirements for a conditional marketing authorisation. These requirements are set out in Article 14-a of Regulation (EC) No 726/2004 abd in

Commission Regulation (EC) No 507/2006 and further elaborated in the respective “CHMP guideline on conditional marketing authorisation”.

Similarly, if a product has a marketing authorisation under exceptional circumstances, it is possible to modify (including extend) the indication and related specific obligations, provided that any modifications based on less comprehensive data comply with the requirements for a marketing authorisation under exceptional circumstances. These requirements are set out in Article 14(8) of the Regulation (EC) No 726/2004 and in Part II of Annex I of Directive 2001/83/EC and further elaborated

in the respective “CHMP guideline on marketing authorisation under exceptional circumstances”.

References

• Regulation (EC) No 726/2004

• Directive 2001/83/EC

• Commission Regulation (EC) No 507/2006

• Pre-submission guidance question on “Is my medicinal product eligible for approval under

exceptional circumstances?

• Pre-submission guidance question on “Could my application qualify for a conditional marketing authorisation?”

3.24. Do I need to address any paediatric requirements in my Type II variation application? Rev. Mar 2026

Regulation (EC) No 1901/2006 (the ‘Paediatric Regulation’) lays down obligations, rewards and

incentives for the development and placing on the market of medicines for use in children. The Paediatric Regulation places some obligations for the applicant when developing a new medicinal product as well as new uses of an authorised product, in order to ensure that medicines to treat children are subject to ethical research of high quality and are appropriately authorised for use in children, and to improve collection of information on the use of medicines in the various subsets of the paediatric population. The paediatric population is defined as the population between birth and the age of 18 years (meaning up to but not including 18-years).

As set out in Article 8 of the Paediatric Regulation, applications for new indication(s), new pharmaceutical form(s) and/or new route(s) of administration concerning an authorised medicinal product protected either by a supplementary protection certificate or by a patent which qualifies for the granting of such a certificate must include one of the following documents/data in order to be

considered ‘valid’:

• The results of all studies performed and details of all information collected in compliance with an agreed Paediatric Investigation Plan (PIP).

This means that the application will have to include the PIP decision but also the results in accordance with the agreed PIP.

• A decision of the EMA on a PIP including the granting of a deferral European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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This means that the application will have to include the PIP decision including the deferral granted and if applicable, any completed studies.

• A decision of the EMA granting a product-specific waiver

• A decision of the EMA granting a class waiver (together with the Agency’s outcome document of applicability if requested by the MAH)

This requirement applies irrespective of the type of application submitted for such a change(s) i.e. variation or extension (or new marketing authorisation application) and irrespective of whether the change is related to adult or paediatric use.

To define what is a ‘new indication’ for the purpose of the application of Article 8, please visit the

webpage ‘Paediatric investigation plans: questions and answers’ under section ‘Articles 7 and 8: Definitions’.

Where results of PIP studies for an authorised medicinal product which do not support a paediatric indication, and the corresponding proposal for amending the SmPC and, if appropriate the Package Leaflet Product Information may be submitted as part of a variation C.4. Applicants are requested to mention in the application form of the variation including the paediatric results and in the cover letter the following statement in the section ‘Precise scope and background for change’: ‘ Submission of paediatric study results performed in compliance with a paediatric investigation plan which do not support a paediatric indication ’.

Applicants should include in the clinical overview a rationale supporting the proposed changes to the Product Information. In particular, if the PIP is completed and the results of all studies are available, the applicant should discuss whether the generated data support or not the intended paediatric indication(s) stated in the PIP.

Inclusion of the results of all studies performed in compliance with an agreed Paediatric Investigation Plan requirement in the Product Information is a prerequisite for benefiting from the paediatric reward (Article 36(1) of Regulation (EC) No 1901/2006).

As for all applications including results of studies performed in compliance with an agreed PIP, the applicant should also include in Module 1.10 an overview table of the PIP results, indicating in which application(s) they were/are going to be submitted, status of the application(s), as well as their location in the present application.

In addition, in accordance with Article 8, the PIP or Waiver application and the related decision should cover both the new and existing indications, routes of administration and pharmaceutical forms of the authorised medicinal product, taking into account the Global Marketing Authorisation (GMA) concept

together with the notion of ‘same marketing authorisation holder’. Further information can be found in

the Procedural advice on paediatric applications’ which is available on the Agency’s website under ‘Paediatric m edicines’.

Those required data/documents should be included in Module 1.10 of the EU-CTD dossier.

The following types of application are exempted from the application of Article 8:

• Generics medicinal products (Art 10(1) of Directive 2001/83/EC)

• Hybrid medicinal products (Art 10(3) of Directive 2001/83/EC)

• Similar biological medicinal products (Art 10(4) of Directive 2001/83/EC) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Medicinal products containing active substance(s) of well-established medicinal use (Art 10a of Directive 2001/83/EC)

Furthermore, when planning submission of their marketing authorisation application, the applicant has

to take into account also the need for a “PIP” compliance check to be done.

Such compliance check consists of verifying that the fulfilments of the measures as mentioned in the PIP decision including the timelines for the conduct of the studies or collection of the data are fulfilled. The compliance check procedure is explained in the document Questions and answers on the procedure of paediatric investigation plan compliance verification at the European Medicines Agency. Applicants are strongly recommended to apply for the compliance check before submission of the application to not delay the validation phase.

Further details on the format, timing and content of PIP or waiver applications as well as on the compliance check can be found in the Commission guideline. In addition, deadlines for submission of PIP or Waiver applications, application templates as well as Procedural Advice documents respectively regarding applications for PIPs, Waivers and Modifications and validation of new MAA, Variation/Extension applications and compliance check with an agreed PIP are available on the

Agency’s website in section “ Paediatric m edicines”.

References

• Regulation (EC) No 1901/2006

• Commission Guideline on “The format and content of applications for agreement or modification

of a paediatric investigation plan and request for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing signifi cant studies”

• Procedural advice on paediatric applications

• Questions and answers on the procedure of paediatric investigation plan compliance verification at the European Medicines Agency

• EMA website, section ’Paediatic -use marketing authorisations’

3.25. When will I get a PIP compliance statement? Rev. Nov Oct 20265

The statement of compliance foreseen in Article 28(3) of Regulation (EC) No 1901/2006 is one of the prerequisites in order to be eligible for the paediatric rewards.

The following requirements have to be met for the paediatric investigation plan (PIP) compliance statement to be included in the technical dossier:

• The MAH to include in Module 1.10 of the dossier a positive outcome of full PIP compliance check by the PDCO;

• The results of all PIP measures should be included in the relevant modules of the dossier. If some results were already submitted, an overview table of the PIP results should be submitted in Module 1.10, indicating in which application(s) they were submitted, the status of the application(s) and the location of the last results submitted in the present application;

• The results of all studies conducted according to the PIP reflected in the SmPC and, as applicable, Package Leaflet. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The MAH should submit the results of PIP studies or the remaining results if some were already submitted, as well as the elements mentioned above as part of a suitable variation or group of variations.

In addition, the MAH should clearly indicate in the cover letter that a PIP compliance statement is being claimed with the submission of this Type II variation.

If all the above criteria are met, a PIP compliance statement will be included in the technical dossier.

The most appropriate variation classification will have to be submitted based on the proposed amendments to the product information. In some instances, a Type IB variation might be appropriate i.e. in situations when all data have already been assessed by the CHMP as part of a previous procedure and all results are already reflected in the product information.

For further details on the paediatric rewards please refer to “ Questions and answers on the procedure of PIP compliance verification at EMA, and on paediatric rewards ”.

3.26. How and when can I withdraw my Type II variation application? Rev. Nov 2025

If the MAH wishes to withdraw their application for a Type II variation during the validation and before the start of the procedure, it should inform the EMA procedure manager, submit an eCTD withdrawal sequence, and withdraw the application as per the IRIS guide for applicants.

If the MAH wishes to withdraw their application for a Type II variation during assessment, it should inform the Procedure Lead by providing a withdrawal letter stating that the MAH withdraws their application and indicate the reasons for the withdrawal.

MAHs can address the withdrawal request to the CHMP Chairman at any point during the assessment (from start of the procedure up until adoption of the CHMP opinion).

The withdrawal letter (as per the withdrawal letter template found in section 7 of the “Procedural advice on publication of information on withdrawals of applications” should be dated and signed by the

MAH/authorised representative of the MAH and send to the EMA Procedure Lead, the Procedure Assistant and product shared mailbox.

A fee may be charged depending on when the withdrawal of application is requested. For more

information, please refer to section 5 of the EMA’ guidance on fees for human medicines .

Of note, the Agency will charge the fee for the validated variation, irrespective of its outcome (i.e., positive, negative or withdrawal) and publish information on withdrawn applications accordingly.

MAHs are informed that letters for withdrawal of extension of indication or modification of indication

will be published on the EMA’s website (after redaction of protected personal data).

In addition, the MAH should submit within 15 days a consolidation sequence to remove the scientific and regulatory content of the withdrawn Type II application from the eCTD structure and include the

withdrawal letter in this sequence. The submission type should be “consolidating”.

However, not all of the content submitted in the withdrawn submission should be removed from the eCTD structure. It is useful to retain certain administrative information in the eCTD structure and some scientific or regulatory information may be used in future submissions. Therefore, the following rules should be applied: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In Module 1: The original cover letter, application and tracking table form should not be removed from

the eCTD structure. All other documents should be removed. Particular care should be taken to remove the versions of any labelling documents associated with the withdrawn variation.

In Module 2: All summary documents should be removed from the eCTD structure.

In Module 3: All content files associated with the withdrawn variation should be removed so that only

the previously approved/submitted content remains in the eCTD structure.

In Modules 4 and 5: The MAH should not remove from the eCTD structure any content unless the Agency specifically requests to remove it.

References

• Procedural advice on publication of information on withdrawals of applications

• Fees payable to the European Medicines Agency

• What we publish on medicines and when

3.27. Who is my contact at the European Medicines Agency during a Type II variation, including extension of indications? Rev. Mar 2024

The Product Lead (PL) is the primary contact for the applicant prior to submission and throughout the procedure for Type II variations related to the safety or efficacy of the medicinal product. However, if you have a procedural or regulatory pre-submission question when preparing your Type II variation application (Non-clinical/Clinical/RMP), please send it to us via email to [email protected]. Furthermore, a dedicated pool of Quality Specialists will be dealing with Quality Type II variations and related queries. If you have a pre-submission question when preparing your Quality Type II variation application, please send it via e-mail to the Quality Specialist assigned to your product.

The PL will serve as the main liaison person between the EMA product team, the Rapporteurs and the applicant. The PL, in close co-operation with the EMA product team and the rapporteurs, will ensure that the applicant is kept informed of all aspects related to the MAA evaluation of the application.

The applicant should contact the PL for all questions regarding the evaluation procedure, including

• Requests for scientific guidance in the pre-submission phase, such as the pre-submission meeting;

• Any type of procedural questions during the evaluation, such as availability of assessment reports and opinion documents;

• Discussion on timetables including requests for extension of clock-stops (Template for request of clock-stop extension) etc.

• Any question where guidance related to the evaluation procedure is needed. The PL will liaise with other EMA Product team members and redirect as appropriate.

At certain milestones during the evaluation procedure, the PL will contact the applicant for a direct exchange to facilitate the discussion on the scientific evaluation. These include:

• Preparation and conduct of clarification meetings (where applicant requests such meeting); European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Immediate feedback regarding scientific aspects from committee plenary discussions, where required;

• Expectations relating to the oral explanation, including topics to be addressed;

• Discussion of required post-authorisation measures;

• Late-stage revisions of the product information before adoption of the final opinion.

These interactions occur in close co-operation with the Rapporteurs. Occasionally other members from the EMA Product team may contact the applicant directly to facilitate the discussion on specific aspects.

When the applicant corresponds with other members of the EMA Product Team the PL should always be copied in the correspondence.

Please see other relevant questions and answers in the EMA pre-authorisation guidance “What is the

role of the EMA product team? ”, “Whom should I contact if I have a pre -submission question when preparing my Type II variation application (Non-clinical/Clinical/RMP)? ” and “Who is my contact at the

European Medicines Agency during a marketing authorisation application (MAA) evaluation procedure?”

and more information on ‘Contacting EMA: post -authorisation’ .

3.28. Whom should I contact if I have a pre-submission question when preparing my Type II variation application? Rev. Mar 2024

If you cannot find the answer to your question in the Q&A when preparing your application:

• for Quality variations, please send your question via e-mail to the Quality Specialist assigned to your product

• for Non-clinical/Clinical/RMP variations, please send your question via e-mail to [email protected].

The Agency aims to respond to your query within 10 working days. To help us deal with your enquiry, please provide as much information as possible including the name of the product in your correspondence. If you seek advice e.g. on the classification of change(s), or the acceptability of a single variation application vs a grouped variation application, please include your proposal. Your query will be channelled internally to the relevant service(s) that will respond to you.

Validation team: The validation of Type II variations (Non-clinical/Clinical/RMP) will be handled by a

dedicated team of Procedure Managers (PM). A PM will be nominated upon receipt of the variation application. You will be able to contact this PM directly if needed. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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4. Extension of marketing authorisation

4.1. When will my variation application be considered a Type II variation or an extension application? Rev. Mar 2026

Commission Regulation (EC) No 1234/2008 defines a Type II variation as a ‘major variation’ which

may have a significant impact on the Quality, Safety or Efficacy of the medicinal product.

The Variations Regulation and the Variations Guidelines set out a list of changes to be considered as Type II variations. In addition, any other change which may have a significant impact on the quality, safety or efficacy of the medicinal product must be submitted as a Type II variation.

Certain changes to a Marketing Authorisation, however, have to be considered to fundamentally alter the terms of this authorisation and therefore cannot be granted following a Type II variation

procedure. These changes are to be submitted as ‘Extensions of marketing authorisations’ and are

listed in Annex I of the Variations Regulation.

This Annex lists two main categories of changes requiring an extension of marketing authorisation:

1. Changes to the active substance(s)

2. Changes to strength, pharmaceutical form and route of administration

A modification to the existing Marketing Authorisation will have to be issued by the Commission.

The European Commission has published a guideline in order to clarify these terms ‘pharmaceutical form ’ and ‘strength ’ and to include relevant examples for such classification. (See also Guideline on the categorisation of New Applications (NA) versus Variations Applications (V), January 2002).

This guideline on categorization should be read in conjunction with the EDQM guidance on the Standard Terms, Regulation (EC) No 1234/2008 and Regulation (EC) No 1901/2006 and understood as follows:

Changes to a centralised marketing authorisation listed below should be submitted as variation(s) according to the guideline on the details of the various categories of variations to the terms of marketing authorisations:

• Addition or replacement of a presentation for a solution for injection with a different immediate container (e.g. vial, syringe, pre-filled pen, cartridge, ampoule…)

• Addition or replacement of a presentation for an eye drops solution with a different immediate container.

These changes would not fall into the scope of Article 8 of Regulation (EC) No 1901/2006 (please refer to ‘What is a 'new pharmaceutical form' in the context of Article 8? ’)

In cases of doubt, the MAH is advised to contact the Agency in advance of the submission.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• Guideline on the categorisation of New Applications versus Variations Applications, The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2C

• Regulation (EC) No 1901/2006

• EDQM Guidance – ‘Standard Terms – Introduction and Guidance for use’

4.2. Extension applications – will my invented name changes? Rev. Aug 2014

The (invented) name of the medicinal product will be the same for the “extension” as it is for the

existing Marketing Authorisation of the medicinal product. The addition of a qualifier (suffix) (e.g. Invented name + qualifier) is not possible within the same marketing authorisation as this would result in a different (invented) name.

It should be clear that the complete name of the medicinal product is commonly composed of the

“invented name, followed by the strength, pharmaceutical form”. The pharmaceutical form should be described by the European Pharmacopoeia’s full standard term. I f the appropriate standard term does not exist, a new term may be constructed from a combination of standard terms (should this not be possible, the Competent Authority should be asked to request a new standard term from the European Directorate for Quality of Medicines (EDQM) of the Council of Europe).

References

• Commission Regulation (EC) No 1234/2008

• “Guideline on the acceptability of names for human medicinal products processed through the

centralised procedure (EMA/CHMP/287710/2014 – Rev. 6)”

• A Guideline on Summary of Product Characteristics, The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2C

• Standard Terms, Council of Europe

4.3. Do I need to notify the Agency of my intention to submit an extension application? Rev. Jan 2021

Extension applications are generally supported by a substantial amount of data, especially if accompanied by an extension of indication or other changes to the authorised therapeutic indication. As a result, the assessment timeframe is typically the same as for an initial marketing authorisation

(see also question “How shall my extension applications be handled (timetable)”) and significant

assessment resources need to be committed for the assessment by the Rapporteur and often also from the Co-Rapporteur (see also question “Is the Co -Rapporteur involved in extension applications”). For

this reason, MAHs are requested to give advance notice of their intention to submit an extension application 6 months in advance of submission. This can be achieved by means of an email to the Product Lead, [email protected], [email protected], the Rapporteur, Co-Rapporteur and, if applicable, PRAC Rapporteur, summarising the scope of the intended application and European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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specifying the target submission date. The information will be used for planning purposes by the

Agency and the Rapporteurs’ assessment teams.

4.4. Is the (Co-) Rapporteur involved in Extension Applications? Rev. March 2013

The CHMP Co-Rapporteur is normally not involved in the assessment of an Extension Application.

However, in case the Extension application would be grouped with a Type II variation for a new indication, the CHMP Co-Rapporteur would normally be involved.

Furthermore, a PRAC Rapporteur may be involved, where applicable.

4.5. How shall I present my Extension Application? Rev. Jul 2026

Extension applications should be presented as follows in accordance with the appropriate headings and numbering of the EU-CTD format:

• Cover letter (for groupings, include a short overview of the nature of the changes and indicate whether it is submitted under Article 7.2(b), i.e. it falls within one of the cases listed in Annex III of the variations regulation or it is submitted under Article 7.2(c), i.e. the grouping has been agreed with the Agency).

• The completed electronic EU application form dated and signed by the official contact person as specified in Section 2.4.3. The EMA strongly recommends the use of a single electronic application form per submission, even if the submission concerns multiple strengths/pharmaceutical forms. The MAH should carefully fill-in the following sections of the application form i.e.:

− In case of an extension of application, section 1.3 “Yes” should be ticked;

− The precise scope of the change needs also to be filled-in;

− Relevant box(es) of section 1.4 for the legal basis should be ticked by analogy to the legal basis of the initial application for the medicinal product.

Note: If the extension application is grouped with other variation(s), the variation application form

should be appended to this application form. See also “What type of variations can be grouped?”

Any change not clearly covered by any scope of a variation included (except editorial), and that is not clearly described in the precise scope section of the application form and included in the present and proposed section should not be considered as accepted.

• Supporting data relating to the proposed extension must be submitted. Some guidance on the appropriate additional studies required for applications under Article 10 of Directive 2001/83/EC

or Extension Applications (also called “Annex I applications”) are available in Annex II to Chapter 1 of the Notice to Applicants.

• A full Module 1 should be provided, with justifications for absence of data/documents included in

the relevant section(s) of Module 1 (e.g. in case ‘user testing’ is considered not necessary by the

MAH, a justification should be included in section 1.3.4). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Update/Addendum to quality summaries/non-clinical overviews and clinical overviews, if appropriate, must be submitted using the appropriate headings and numbering of the EU-CTD format. When (a) non-clinical/clinical study report(s) are submitted, even if only one, their relevant summaries should be included in Module 2.

• Module 3 of the application should only contain the relevant quality information related to the proposed extension, unless the extension is part of a group.

In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file UI.

EMA is encouraging applicants to use the checklist to facilitate the preparation of the dossier and make the validation process more efficient. The filled-in checklist should be submitted as part of the Extension Application dossier.

In case that the changes affect the SPC, labelling and/or package leaflet, the revised product information (PI) Annexes must be submitted (see also: Extension applications - “When do I have to submit revised product information? In all languages?”).

Working documents outside the eCTD structure:

Word formats of certain documents are required to facilitate the assessment. Applicants should include the PI, the RMP, the Module 2.3 – Update or addendum to the quality summary, Module 2.4 - Update or addendum to the non-clinical overview, Module 2.5 – Update or addendum to the clinical overview, Module 2.6 – Non-clinical summary(ies), Module 2.7 – Clinical Summary(ies) as well as the summary

of the main efficacy results, when applicable in Word format as part of the ‘working documents’ outside

the eCTD structure. Further details can be found in the Harmonised Technical Guidance for eCTD

Submission in the EU. It is generally not necessary to include the RMP annexes in the ‘working document’ version (unless annexes are being revised).

The above requirements also apply to the submission of the validation checklist for Extension application(s) and the responses to List of Questions / List of Outstanding Issues.

Submission of responses to list of questions/list of outstanding issues:

The MAH should use the response template to respond to the List of Questions / List of Outstanding Issues. The MAH is expected to respond to all the questions directly in this response template document and submit both PDF and Word versions with their official responses in eCTD.

It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH and is crucial to the overall process.

For queries related to the presentation of the application, please contact the Agency. Alternatively, MAHs may request a pre-submission meeting with the Agency to clarify any outstanding points.

Please also refer to the following questions which address orphan and paediatric related aspects ‘Do I

need to confirm the maintenance of my orphan designation when applying for an Extension

Application?’ and ‘Do I need to address any paediatric requirements in my extension application?’.

References

• Presentation and content of the dossier - Part 1, Summary of the dossier Part 1A or Module 1: Administrative information application form, The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2B European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Procedures for Marketing Authorisation, The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2A, Chapter 1

• Electronic Variation application form

• Response template

4.6. What aspects should I consider at time of submission of an extension application if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication? Rev. May 2020

Article 8(1) of the Regulation (EC) No 141/2000 (“Orphan Regulation”) prevents the Agency and the

Member States from accepting, for a period of 10 years, another application for a marketing authorisation, or granting a marketing authorisation or accepting an application to extend an existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product.

Therefore, if your application concerns an extension of a marketing authorisation, as defined in Annex I

of the Regulation (EC) No 1234/2008 (“Variations Regulation”), e.g. a new pharmaceutical form or

route of administration, you will have to indicate in the respective application form if any medicinal product has been designated as an orphan medicinal product for a condition relating to the therapeutic indication proposed in your application.

In advance of submission of your application for an extension of your marketing authorisation, irrespective of whether your medicinal product has been designated as orphan or not, you are advised to check the Community register of orphan medicinal products, for information on medicinal products designated as orphan.

If any of the designated orphan medicinal products has been granted a marketing authorisation in the Union, and a period of market exclusivity is in force, you will have to provide in Module 1.7.1 a similarity report addressing the possible similarity between your medicinal products and the orphan medicinal product(s) which have received a marketing authorisation.

The assessment of similarity between two medicinal products takes into consideration the following criteria:

• Principal molecular structural features,

• Mechanism of action and

• Therapeutic indication.

The critical report provided in Module 1.7.1 should address the possible similarity between the proposed new medicinal product and the authorised orphan medicinal products for each of these criteria.

If significant differences exist within one or more of these criteria, the two products will not be considered as similar. These criteria are explained in the Guideline on aspects of the application of Article 8(1) and 8(3) of Regulation (EC) No 141/2000: Assessing similarity of If significant differences exist within one or more of these criteria, the two products will not be considered as similar. Commission Regulation (EC) No 847/2000 provides additional specific considerations for the definition of similar active substance applicable to chemical, biological and advanced therapy medicinal products. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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If your medicinal product is considered to be similar to any authorised orphan medicinal product, you will have to provide in Module 1.7.2 justification that one of the following derogations, laid down in Article 8(3) of the Orphan Regulation applies, i.e.:

(a) the holder of the marketing authorisation for the orphan medicinal product has given his consent for submission of your application, in which case a signed letter from the MAH of the orphan medicinal product should be provided confirming the consent for submission of an application for marketing authorisation;

(b) the holder of the marketing authorisation for the orphan medicinal product is unable to supply sufficient quantities of the medicinal product, in which case the applicant should provide a report including details of the supply shortage and justify that patients’ needs in the orphan indication are not

being met;

(c) the applicant can establish that their product, although similar to the orphan medicinal product already authorised, is more effective, safer or otherwise clinically superior, in which case a critical report justifying clinical superiority to the authorised product must be provided.

The assessment of similarity is conducted in parallel to the evaluation of the extension application and follows the same timetable. The assessment includes the consultation of the Quality Working Party or the Biologicals Working Party for the aspects concerning the similarity of the molecular structures of the products.

Please note that if the Agency identifies a possible similarity issue not addressed by the applicant before validation, the applicant will be asked to complete the application with information on similarity and, if applicable, on one of the derogations. Validation of the application will only proceed once the applicant has submitted either a report justifying the lack of similarity or information justifying one of the derogations in Article 8(3).

As considerable time may elapse between validation of an application and adoption of an opinion, if applicants become aware of medicinal products which have been authorised as orphans for a condition related to the therapeutic indication proposed in their application, this information should be communicated promptly to the Agency in order to arrange for the submission of updated application form and modules 1.7.1 and 1.7.2, as applicable.

In any case, the Agency will check at certain milestones of the procedure, i.e. adoption of list of questions, request for supplementary information and prior to adoption of a CHMP opinion whether new orphan medicinal products have been authorised for the same condition.

References

• Regulation (EC) No 141/2000 on orphan medicinal products

• Regulation (EC) No 847/2000 as amended by Regulation (EU) 2018/781

• Regulation (EC) No 1234/2008

• Community register of orphan medicinal products

• Guideline on aspects of the application of Article 8(1) and 8(3) of Regulation (EC) No 141/2000: Assessing similarity of medicinal products versus authorised orphan medicinal products benefiting from market exclusivity and applying derogations from that market exclusivity European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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4.7. Do I need to confirm the maintenance of my orphan designation when applying for an extension application? Rev. Mar 2026

If the product has been designated as orphan and the extension application also includes a new therapeutic indication or a modification of an existing one, in order to ensure that the Marketing Authorisation only covers indications that fulfil the orphan designation criteria foreseen in Art 3 of Regulation (EC) No 141/2000, a COMP review may be required as following:

• for a new therapeutic indication falling within a new orphan designation, i.e. an orphan designation other than the one(s) related to the already approved indication(s), the COMP will have to confirm the maintenance of the orphan designation before authorisation of the new indication. In this case, the sponsor should provide at the time of submission a maintenance report using the template provided on the EMA website. The maintenance report should be

submitted via the IRIS Platform.

• for a new therapeutic indication falling within an already authorised orphan designation, the COMP will have to consider if the specific scope of the application raises justified and serious doubts in respect to the fulfilment of the orphan designation criteria and indicate if a formal review process of the maintenance of the orphan designation is needed

To support this process, the MAH/sponsor is requested to provide at the time of submission of the application either a justification that the application does not raise doubts on the fulfilment of the orphan criteria or a maintenance report to justify that the orphan criteria are still met. The justification/ maintenance report should be submitted via the IRIS Platform.

Further to the COMP preliminary discussion based on the sponsor’s justification/ maintenance report, a

formal review process of the maintenance of the orphan designation for the applied indication will be triggered if it raises justified and serious doubts on the maintenance of the orphan designation. In this case, if previously only a justification was submitted, the MAH/sponsor will be requested to provide a maintenance report. The procedure for assessment will follow the usual procedure, as described in Orphan status management – BPD-H-008.

For the purpose of defining what is a new therapeutic indication or a modification of an existing one for the COMP review for post-authorisation extensions of indications, the Guideline on the elements required to support the significant clinical benefit in comparison to existing therapies of a new therapeutic indication in order to benefit from an extended (11-year) marketing protection should be followed.

In case of doubts, the Agency encourages applicants to contact the Orphan Medicines Office in advance of a planned submission in order to clarify orphan requirements. Please submit your message via EMA-info: Send a question to the European Medicines Agency.

Further information can be found on the dedicated EMA Website on Orphan designation.

References

• Regulation (EC) No 141/2000

• Commission Notice on the application of Articles 3,5 and 7 of Regulation (EC) No 141/2000 on orphan medicinal products

• Orphan status management – BPD-H-008 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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4.8. Can a non-orphan therapeutic indication be added to an already authorised orphan medicinal product? NEW Mar 2016

Please refer to question “Can a non -orphan therapeutic indication be added to an already authorised

orphan medicinal product?” in the questions and answer of Type II variations.

4.9. Can a new indication based on less comprehensive data be added to an already authorised medicinal product? NEW Nov 2016

Please refer to question "Can a new indication based on less comprehensive data be added to an already authorised medicinal product?" in the questions and answer on Type II variations.

4.10. Can I group the submission of Extensions with other types of variations? Rev. Oct 2013

Marketing authorisation holders may choose to group the submission of one or more extensions together with one or more other variations for the same product into one application, provided that this corresponds to one of the cases listed in Annex III of the Variations Regulation or when this has been agreed upfront with the Agency.

It is possible for a marketing authorisation holder to group extensions with other variation(s) submission (e.g. Type II, Type IB or IA variations), where applicable. Such grouped submissions will follow the review procedure of the highest variation in the group. Please also refer to ”What types of variations can be grouped?”.

However, no worksharing of extension applications is foreseen in the Variations Regulation.

References

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

4.11. How, when and to whom shall I submit my Extension Application? Rev. Feb 2019

Information is available on ‘Submitting a post -authorisation application’.

The MAH shall submit the Extension application in accordance with the recommended submission dates published on the Agency website (see "submission deadlines and full procedural timetables"). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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4.12. How shall my Extension Application be handled (timetable)? Rev. Jul Oct 2026

The MAH shall submit the Extension application(s) in accordance with the recommended submission

dates published on the Agency’s website.

The submission deadlines and full procedural detailed timetables are published as a generic calendar

on the Agency’s website (see: "submission deadlines and full procedural timetables"). The published

timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

The Agency shall ensure that the opinion of the CHMP is given within 210 days (less any clock-stops for the applicant to provide answers to question from the CHMP) in accordance with the following standard timetable. A positive opinion can be adopted either at Day 120 or Day 180 should no questions remain at these milestones. The duration of the clock-stop is described in the CHMP’s clock -stop rules. Any extension of the clock-stop must be agreed by the CHMP. If the MAH requests an extension of a clock-stop, the ‘Template for request of clock -stop extension’ should be complete d and submitted to the EMA. The CHMP will review the justification for clock-stop extensions. The MAHs are reminded that clock-stop extensions are agreed only exceptionally.

PRAC rapporteur and PRAC steps only apply when the PRAC is involved in the assessment of an

extension application, i.e. when an RMP is submitted within the extension.

DAY ACTION

1 Start of the procedure

80 – 82* CHMP members and Agency receive the Assessment Report and reviewed

product information from Rapporteur.

Following receipt of the Assessment Report(s) from Rapporteur, Tthe Agency

sends themthe Assessment Report to the MAH for information only. Please

notemaking it clear that it only sets out the Rapporteur’s preliminary conclusions

and therefore does not represent the position of the CHMP. The report in no way

binds the CHMP and is sent to the MAH for information only.

94 PRAC members and Agency receive the PRAC Rapporteur assessment report (as

part of the updated overview).

100** (Co-)Rapporteurs, other PRAC and CHMP members send commentsand Agency

receive comments from Members of the CHMP.

101 – 104 (if

applicable)

PRAC adopts the PRAC RMP Assessment Overview and Advice for D120 LoQ.

1125 CHMP members, PRAC members if applicable, and Agency receive a draft list of

questions (including draft overall conclusions and draft overview of the scientific data) from Rapporteur.

120 CHMP adopts the list of questions as well as the overall conclusions and overview of the scientific data to be sent to the MAH by the Agency.

Clock-stop European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Clock stop.

121* Submission of the responses and restart of the clock.

*In case of CHMP Co-Rapporteur involvement, CHMP receives the CHMP Co-rapporteur assessment

report (as part of the updated overview) and reviewed product information at D82.Target dates for the

submission of the responses are published on the Agency’s Website

**PRAC Rappporteur AR, comments from CHMP and PRAC members and draft LoQ (if applicable), are

not sent to MAHs.

After receipt of the responses, the CHMP will adopt a timetable for the evaluation of the responses. In general, the following timetable will apply:

DAY ACTION

121 Submission of the MAH’s responses*, including revised SmPc, labelling and

package leaflet texts in English.

Restart of the clock.

1570 CHMP, PRAC members and Agency receive the Joint Response Assessment

Reports from CHMP (Co-)Rapporteurs and PRAC Rapporteur.

The AgencyEMA sends the Joint Assessment Reports to the applicantMAH making

it clear that it for information only. Please note that it does not represent the

position of the CHMP sets out the Rapporteur’s preliminary conclusions. The

report in no way binds the CHMP and is sent to the MAH for information only.

160 Comments by PRAC members

166 (if

applicable)

PRAC adopts the PRAC RMP Assessment Overview and Advice for D180 LoOI.

167 Comments by CHMP members.

1720 CHMP, PRAC members and Agency receive the updated joint assessment report,

including the CHMP recommendation and scientific discussions, together with the

PRAC RMP Assessment Overview and Advice for D180 list of outstanding issue

(LoOI) Comments from CHMP Members to Rapporteur.

180 If applicable, CHMP adopts LoOI as well as the overall conclusions and review of

the scientific data to be sent to the applicant by the EMA.

CHMP may also invite the applicant to an oral explanation.

Clock stopdiscussion and decision on the need for an oral explanation by the

MAH. If oral explanation is needed, the clock is stopped to allow the MAH to prepare the oral explanation.

181 Submission of the MAH’s responses*, including revised SmP C, labelling and

package leaflets in English.

Restart of the clock with submission of responses andor oral explanation (if

applicable). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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1895 CHMP, PRAC members and Agency receive the Joint Response Assessment

Report from CHMP (Co-)Rapporteurs and PRAC RapporteurFinal draft of English

SmPC, labelling and package leaflet sent by MAH to the Rapporteur, Agency and other CHMP members.

197 Comments by PRAC and CHMP members.

202 CHMP, PRAC members and Agency receive the updated joint assessment report,

including the CHMP recommendation and scientific discussions.

By 210 Adoption of CHMP Opinion + CHMP Assessment Report + product information.

Adoption of a timetable for the provision of product information translations.

*The responses should be submitted using available templates.

In cases where the PRAC is involved in an extension application, e.g. when an RMP is submitted within the extension, the following timetables with PRAC milestones will apply:

DAY ACTION

1 Start of the procedure

80 CHMP members and Agency receive the Assessment Report from Rapporteur. The Agency sends the Assessment Report to the MAH making it clear that it

only sets out the Rapporteur’s preliminary conclusions. The report in no way

binds the CHMP and is sent to the MAH for information only.

87 PRAC Rapporteur circulates the RMP assessment report and proposed RMP LoQ

100 Rapporteur, other CHMP members and Agency receive comments from Members of the CHMP.

101-104 PRAC adopts PRAC RMP Assessment Overview and Advice for D120 LOQ

115 CHMP members and Agency receive a draft list of questions (including draft overall conclusions and draft overview of the scientific data) from Rapporteur.

120 CHMP adopts the list of questions as well as the overall conclusions and overview of the scientific data to be sent to the MAH by the Agency.

Clock stop.

121* Submission of the responses and restart of the clock.

*Target dates for the submission of the responses are published on the Agency’s Website

After receipt of the responses, the CHMP will adopt a timetable for the evaluation of the responses. In general, the following timetable will apply:

DAY ACTION

150 CHMP members and Agency receive the Response Assessment Report from Rapporteur. The Agency sends the Assessment Report to the MAH making it European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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clear that it only sets out the Rapporteur’s preliminary conclusions. The report in

no way binds the CHMP and is sent to the MAH for information only.

167 PRAC adopts PRAC RMP Assessment Overview and Advice for D180 LoOI

170 Comments from CHMP Members to Rapporteur.

180 CHMP discussion and decision on the need for an oral explanation by the MAH. If oral explanation is needed, the clock is stopped to allow the MAH to prepare the oral explanation.

181 Restart of the clock and oral explanation.

181 to 210 Final draft of English SmPC, labelling and package leaflet sent by MAH to the Rapporteur, Agency and other CHMP members.

197 PRAC adopts the final PRAC RMP Assessment Overview and Advice

By 210 Adoption of CHMP Opinion + CHMP Assessment Report.

Re-examination

Article 9(2) of Regulation (EC) No 726/2004, also applies to CHMP Opinions adopted for Extension applications. This means that the MAH may give written notice to the EMA/CHMP within 15 days of receipt of the opinion (after which the opinion shall be considered as final) that they wish to request a re-examination. The grounds for the re-examination request must be forwarded to the Agency within 60 days of receipt of the opinion.

In case the MAH requests that the Scientific Advisory Group (SAG or AHEG) is consulted in connection with the re-examination, the MAH should inform the CHMP as soon as possible of this request and at the latest with the submission of the detailed grounds for re-examination. This is necessary to allow for the SAG/AHEG consultation to be organised, and the outcome of this consultation duly taken into account by the CHMP, within the timelines established for the re-examination procedure.

A positive opinion may be subject to re-examination as long as the request for re-examination relates to aspects of the opinion for which there had been objections by the Committee, further to which the MAH opted to amend the application. In such case, the applicant will need to reserve the right to re-examination when submitting the amended documentation, e.g. revised product information.

The CHMP will appoint different CHMP (Co-) Rapporteurs, to co-ordinate the re-examination procedure. In case a PRAC Rapporteur is deemed necessary, a different PRAC Rapporteur will be appointed. Within 60 days from the receipt of the grounds for appealer-examination, the CHMP will consider whether its opinion is to be revised. If considered necessary, an oral explanation can be held within this 60-day timeframe.

In case of withdrawal of the request for re-examination, the initial CHMP opinion will immediately become the final CHMP opinion.

EMA charges a fee for a re-examination of an opinion. For more information, please refer to the Fee Q&As in Annex IV, Section 4, on the Fees payable to the European Medicines Agency page. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Decision-Making Process

Upon receipt of the final CHMP opinion, the commission shall, where necessary, amend the marketing authorisation to reflect the extension within the timeframes set-out in article 9(1) of Regulation (EC) No 726/2004 (i.e. within 67 days after adoption of the CHMP opinion). Detailed practical guidance on the post-opinion phase, including the linguistic checking of the amended product information annexes,

is available on the Agency’s website.

The outcome of the evaluation of an extension application in the centralised procedure will result in an extension or a modification of the initial marketing authorisation. Extensions may only be implemented once the Commission has amended the decision granting the marketing authorisation and has notified the holder accordingly.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

4.13. What fee do I have to pay for an Extension Application? Rev. Dec 2024

For more information on fees to be paid, applicable fee reductions and payment process, please refer to the Fee Q&A in Annex I, Section 4, and Annex IV, Section 6.1 on the Fees payable to the European Medicines Agency page.

References

• Fees payable to the European Medicines Agency

4.14. Do I have to submit mock-ups and specimens? Rev. July 2013

For information concerning submission of mock-ups and specimens in the framework of extension

applications, please refer to the document ‘Checking process of mock -ups and specimens of outer/immediate labelling and package leaflet of human medicinal products in the centralised procedure, 3.1 New marketing authorisation applications and extensions applications.

References

• The Checking Process of Mock-Ups and Specimens of outer/immediate labelling and package leaflets of human medicinal products in the Centralised Procedure (EMEA/305821/2006)

4.15. When do I have to submit revised product information? In all languages? Rev. Mar 2026

In case the Extension Application requires changes to the product information (e.g. new strength or pharmaceutical form), the same requirements as for a New Application apply: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• At submission and during assessment, only the English clean and highlighted versions of the Product Information in pdf within the eCTD sequence and the clean and highlighted versions in word format (working document) are submitted and reviewed. As an alternative to the submission of a highlighted Product Information as pdf within the eCTD sequence, proposed

changes can be documented in the ‘present/proposed table’ of the application form or in an

annex to the application form.

In addition, during the later stages of the procedure there is often a need for fast informal exchanges between the MAH and the Rapporteur in preparation of the final CHMP opinion. During this process the MAH can provide any revised versions of the Product Information as well as comments/justifications by Eudralink/email in Word format. These product information versions are

considered ‘working documents’ only and there is consequently no need to submit these updated

Product Information proposals as part of a formal eCTD sequence (unless part of formal responses to a CHMP List of Questions/Outstanding Issues).

• Translations of the agreed SPC, Annex II, labelling and package leaflet text in all languages are to be provided after adoption of the CHMP opinion. Icelandic and Norwegian language versions of the extension Annexes must be included.

More details on the translation requirements and on the linguistic review process, are available on the

Agency’s Website: The linguistic review process of product information in the centralised procedure -Human (EMEA/5542/02).

At submission and during assessment, the English product information Annexes should include any new presentations relevant to the extension application and approved presentations for the marketing authorisation.

After adoption of the CHMP Opinion the complete set of Annexes must be provided for each official EU language and presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document. Page numbering should start with "1" (bottom, centre) on the title page of Annex I. The electronic copy of all languages should be provided on the Gateway / Web Client package as part of the extension application.

The ‘QRD Convention’ published on the Agency’s website should be followed. When submitting the full

set of Annexes in PDF format, this should be accompanied by the completed formatting checklist. A user guide on how to generate pdf versions of the product information and annexes is also available.

The Annexes provided should only reflect the changes introduced by the Extension application concerned. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments in the texts (e.g. further to a specimen check) this should be clearly mentioned in the cover letter. Alternatively, a listing of proposed changes may be provided as a separate document attached to the cover letter. Any changes not listed, will not be considered as part of the extension application.

In cases where any other ongoing procedures may impact on the product information of the Extension Application, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedure(s) concerned.

For extension applications which affect the Annex A (e.g. introduction of a new strength), the following principles apply:

Upon adoption of the Opinion, the Agency will prepare and send to the MAH the revised English Annex A. After CHMP Opinion (Day 215), the MAH provides the Agency with the electronic versions of the European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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complete set of Annexes in all languages as well as the translations of the revised Annex A as a separate word document.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translation versions of the product information annexes in all the languages submitted at D215 as well as the final translations submitted at 235. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

References

• The linguistic review process of product information in the Centralised Procedure (EMEA/5542/02)

4.16. What is the procedure for assignment of new European Union sub-numbers for an extension including additional presentation(s)? New Nov 2012

At the time of the adoption of a CHMP opinion for an extension application which includes additional presentation(s), the Agency will assign the new EU sub-numbers and include them in the revised Annex A of the medicinal product, which will be transmitted to the Marketing Authorisation Holder together with the CHMP Opinion and respective annexes.

The Marketing Authorisation Holder should include the newly assigned numbers in all language versions of the Annex A and in all applicable sections of the product information, which are submitted following the CHMP opinion for linguistic review.

4.17. Will there be any publication on the outcome of my Extension application? Rev. Oct 2012

Information on opinions of extension application is not given in the meeting highlights following each CHMP meeting, unless they are grouped with a Type II variation in relation to new indications, changes to an existing indication, addition, change or removal of a contraindication.

References

• CHMP Committee meeting reports European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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4.18. Do I need to address any paediatric requirements in my extension application? Rev. Mar 2025

Regulation (EC) No 1901/2006 (the ‘Paediatric Regulation’) lays down obligations, rewards and

incentives for the development and placing on the market of medicines for use in children. The Paediatric Regulation places some obligations for the applicant when developing a new medicinal product as well as new uses of an authorised product, in order to ensure that medicines to treat children are subject to ethical research of high quality and are appropriately authorised for use in children, and to improve collection of information on the use of medicines in the various subsets of the paediatric population. The paediatric population is defined as the population between birth and the age of 18 years (meaning up to but not including 18-years).

As set out in Article 8 of the Paediatric Regulation, applications submitted for new indication(s), new pharmaceutical form(s) and/or new route(s) of administration concerning an authorised medicinal product protected either by a supplementary protection certificate or by a patent which qualifies for the granting of such a certificate must include one of the following documents/data in order to be

considered ‘valid’:

• The results of all studies performed and details of all information collected in compliance with an agreed Paediatric Investigation Plan (PIP).

This means that the application will have to include the PIP decision but also the results in accordance with the agreed PIP.

• A decision of the Agency on a PIP including the granting of a deferral

This means that the application will have to include the PIP decision including the deferral granted and if applicable, any completed studies.

• A decision of the Agency granting a product-specific waiver

• A decision of the Agency granting a class waiver (together with the Agency’s outcome letter if requested by the MAH)

This requirement applies irrespective of the type of application submitted for such a change(s) i.e. variation or extension (or new marketing authorisation application) and irrespective of whether the change is related to adult or paediatric use.

To define what is a ‘new indication’ for the purpose of the application of Article 8, please see the

webpage ‘Paediatric investigation plans: questions and answers’, section ‘Article 7 and 8: Definitions’.

Where results of PIP studies are submitted and do not support a paediatric indication, applicants are

requested to mention in the cover letter the following statement: ‘ Submission of paediatric study results performed in compliance with a paediatric investigation plan which do not support a paediatric indication ’.

Applicants should include in the clinical overview a rationale supporting the proposed changes to the Product Information. In particular, if the PIP is completed and the results of all studies are available, the applicant should discuss whether the generated data support or not the intended paediatric indication(s) stated in the PIP.

Inclusion of the results of all studies performed in compliance with an agreed Paediatric Investigation Plan in the Product Information is a prerequisite for benefiting from the paediatric reward (Article 36(1) of Regulation (EC) No 1901/2006). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In addition, in accordance with Article 8, the PIP or Waiver application and the related decision should cover both the new and existing indications, routes of administration and pharmaceutical forms of the authorised medicinal product, taking into account the Global Marketing Authorisation (GMA) concept

together with the notion of ‘same marketing authorisation holder’. Further information can be found in

the Procedural advice on paediatric applications which is available on the Agency’s website under ‘Paediatric m edicines’.

Those required data/documents should be included in Module 1.10 of the EU-CTD dossier. As for all applications including results of studies performed in compliance with an agreed PIP, the applicant should also include in Module 1.10 an overview table of the PIP results, indicating in which application(s) they were/are going to be submitted, status of the application(s), as well as their location in the present application.

The following types of application are exempted from the application of Article 8:

• Generics medicinal products (Art 10(1) of Directive 2001/83/EC)

• Hybrid medicinal products (Art 10(3) of Directive 2001/83/EC)

• Similar biological medicinal products (Art 10(4) of Directive 2001/83/EC)

• Medicinal products containing active substance(s) of well-established medicinal use (Art 10a of Directive 2001/83/EC)

Furthermore, when planning submission of their marketing authorisation application, the applicant has

to take into account also the need for a “PIP” compliance check to be done.

Such compliance check consists of verifying that the fulfilments of the measures as mentioned in the PIP decision including the timelines for the conduct of the studies or collection of the data are fulfilled. The compliance check procedure is explained in the document “Questions and answers on the procedure of paediatric investigation plan compliance verification at the European Medicines Agency”.

Applicants are strongly recommended to apply for the compliance check before submission of the marketing authorisation application to not delay the validation phase.

Further details on the format, timing and content of PIP or waiver applications as well as on the compliance check can be found in the Commission guideline. In addition, deadlines for submission of PIP or Waiver applications, application templates as well as Procedural Advice documents respectively regarding applications for PIPs, Waivers and Modifications and validation of new MAA, Variation/Extension applications and compliance check with an agreed PIP are available on the

Agency’s website in section “Medicines for children”.

References

• Regulation (EC) No 1901/2006

• Commission Guideline on “The format and content of applications for agreement or modification of

a paediatric investigation plan and request for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing signifi cant studies”

• Procedural advice on paediatric applications

• Questions and answers on the procedure of paediatric investigation plan compliance verification at the European Medicines Agency

• EMA website, section ’Paediatr ic-use marketing authorisations’ European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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4.19. Who should I contact if I have a question when preparing my application and during the procedure? Rev. Feb 2019

If you cannot find the answer to your question in the Q&A when preparing your application or during the procedure, please contact the Product Lead responsible for your product.

4.20. How and when can I withdraw my extension application? NEW Jun 2023

If the MAH wishes to withdraw their application for extension of marketing authorisation (MA) during assessment, it should inform the EMA Procedure Lead by providing a withdrawal letter stating that the MAH withdraws their application and indicating reasons for the withdrawal.

MAHs can address the withdrawal request to the CHMP Chairman at any point during the assessment (from validation of the application up until adoption of the CHMP opinion).

The withdrawal letter (as per the withdrawal letter template found in section 7 of the “Procedural advice on publication of information on withdrawals of applications”) should be dated and signed by the

MAH/authorised representative of the MAH and sent to the EMA Procedure Lead, the EMA Procedure Assistant and product shared mailbox.

Of note, the Agency will charge the fee for the validated extension of MA, irrespective of its outcome (i.e., positive, negative or withdrawal) and publish information on withdrawn applications accordingly.

MAHs are advised that letters for withdrawal of extension of marketing authorisation will be published

on the EMA’s website (after redaction of protected personal data).

In addition, the MAH should submit within 15 days from the date of withdrawal a consolidation sequence to remove the scientific and regulatory content of the withdrawn extension of MA application from the eCTD structure and include the withdrawal letter in this sequence. The submission type

should be “consolidating”.

However, not all of the content submitted in the withdrawn submission should be removed from the eCTD structure. It is useful to retain certain administrative information in the eCTD structure and some scientific or regulatory information may be used in future submissions. Therefore, the following rules should be applied:

In Module 1: The original cover letter, application and tracking table form should not be removed from

the eCTD structure. All other documents should be removed. Particular care should be taken to remove the versions of any labelling documents associated with the withdrawn extension of MA.

In Module 2: All summary documents should be removed from the eCTD structure.

In Module 3: All content files associated with the withdrawn extension of MA should be removed so

that only the previously approved/submitted content remains in the eCTD structure.

In Modules 4 and 5: The MAH should not remove from the eCTD structure any content unless the Agency specifically requests to remove it.

References

• Procedural advice on publication of information on withdrawals of applications European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Fees payable to the European Medicines Agency

• What we publish on medicines and when

• The EU Harmonised technical eCTD guidance version 5.0 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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5. Grouping of variations

5.1. What types of variations can be grouped? Rev. Mar 2025

Marketing authorisation holder can group several Type IA/ IA IN variations to the terms of the same marketing authorisation under a single notification to the same relevant authority:

• Several Type IA or IA IN affecting one medicinal product.

This means for instance that a Type IA IN variation can be included in an annual update, if submitted immediately after its implementation, and a Type IA variation which is normally not subject to immediate notification can be included in the submission of a related Type IA IN variation.

Article 7a of the Variations Regulation, as amended, sets out the possibility for a marketing authorisation holder to super-group the same or several Type IA/ IA IN variations to the terms of more than one marketing authorisation under a single notification to the same relevant authority:

• one Type IA or IA IN affecting several medicinal products from the same MAH authorised through the centralised procedure, provided that the variation is the same for all medicinal products .

• several Type IA and/or IA IN affecting several medicinal products from the same MAH authorised through the centralised procedure , provided that those variations are the same for all medicinal products.

MAH 1 Prod. 1 IA (1) IA (2)

MAH 1

Prod. 1 IA (1)

Prod. 2 IA (1)

MAH 1

Prod. 1

Prod. 2

IA (1)

IA (2)

IA (1)

IA (2) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Applicants belonging to the same mother company or group of companies and applicants having concluded agreements or exercising concerted practices concerning the placing on the market of the

medicinal product(s) concerned, have to be taken as “the same marketing authorisation holder”. 1

Please note that currently it is not operationally possible to have super-grouping of Type IA variations including simultaneously marketing authorisations approved via the centralised procedure and non-centralised procedure. Additional cases taking into account the experience acquired may be identified in the future and appropriate operational guidance will be provided in Agency and CMDh websites accordingly.

Articles 7.2(b) and 7.2(c) of the Variations Regulation set-out the possibility for a marketing authorisation holder to group several types of variations affecting one medicinal product , under a single notification/application.

Article 7.2(b) applies for groupings that are listed in Annex III of the Regulation whilst article 7.2(c) applies for groupings of variations which are not listed in Annex III, but which have been agreed with the Agency.

In the case of groupings under Article 7.2(c) it is recommended that the grouping is agreed between the holder and the Agency at least 2 months before submission.

Where the same Type IB or Type II variation, or group of variation(s) affect several medicinal products from the same MAH, the MAH shall submit these variations as one application for ‘worksharing’. Please also refer to “What is worksharing and what types of variations can be subject to worksharing?”

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning

1See Commission Communication 98/C 229/03 OJ C 229, 22.7.1998, p. 4.

MAH 1

Prod. 1

IB (1)

IB (2)

MAH 1

Prod. 1

II

IB

IA

MAH 1

Prod. 1

Ext

II

IB

IA European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

5.2. What groups of variations would be considered acceptable? Rev. Mar 2026

Related Type IA/ IA IN variations concerning one medicinal product can be submitted in one single notification as a group .

It must be noted however, that when submitting Type IA/ IA IN variations as part of a group, the legal deadlines for submission of each variation should be respected i.e. a Type IA IN should always be submitted immediately, whether or not it is grouped with other variations, and any Type IA variation should always be submitted within 12 months following its implementation.

For further information see also ‘When shall I submit my Type IA/IA IN variation(s) ?’ .

When super-grouping one or more Type IA/ IA IN variations affecting several centrally authorised medicinal products from the same MAH, the variation or group of variations must be the same for all medicinal products concerned.

Grouping of non-Type IA variations is only acceptable when they fall within one of the cases listed in Annex III of the Regulation, or, if they do not fall within one of those cases, when the grouping of the variations has been agreed between the Agency and the MAH before submission.

MAHs are advised to inform the Agency at least 2 months in advance of the submission of a group of variations which are not listed in Annex III of the Regulation, together with a justification as to why the holder believes that the proposed group should be acceptable.

When reviewing MAH proposals for grouping of variations, the Agency will consider the following general principles:

• Changes should be consequential and/or related i.e. meaningful to be reviewed simultaneously . Applicants are in principle encouraged to group related variations whenever possible e.g. variations affecting clinical safety, variations including only non-clinical studies or variations including only drug-drug interaction studies. In these cases, the scopes are related, and it would be meaningful for the respective variations to be reviewed simultaneously. A proposal to submit a grouped application cannot be based on convenience alone (e.g. the following cases would not in principle be acceptable: both variations result in changes to the Product Information or all variations affect the RMP).

• Quality, Non-clinical and Clinical changes can in principle not be grouped unless the quality changes are supported by the clinical data or vice versa. The updates should be related and

properly justified (please see also ‘What should I consider in case of a change in therapeutic

indication, posology or maximum daily dose (MDD) in relat ion to the quality documentation?’) .

• CHMP-led and PRAC-led Type II variations can in principle not be grouped unless exceptionally justified (i.e. the scopes are closely interlinked).

• Quality variations to the active substance can in principle not be grouped with finished product variations, unless justified. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• In any case, grouping shall not delay the submission and implementation of updates to the safety information for the medicinal product.

• Studies undertaken in different patient populations should in principle not be grouped unless the applicant can justify why it would be beneficial to assess them together (e.g. supportive of overall clinical safety).

Table 1 presents some examples of acceptable groups of variations listed in Annex III of the Regulation, with further clarification on how such groups will be considered in practice.

Table 2 presents some examples of other groups of variations, which the Agency would or not in principle consider acceptable.

These tables will be reviewed and updated regularly, in view of accumulated experience.

Table 1. Grouping examples according to Article 7.2(b) of the Variation Regulation (Cases for grouping variations listed in Annex III)

1 One of the variations in the group is an extension of the marketing authorisation.

Other clinical or non-clinical changes linked to the extension (e.g. a new indication) can be grouped with the Extension application. Quality changes affecting the drug substance and/or drug product can also be included in the group.

Example: Extension of the marketing authorisation for a new strength/pharmaceutical form + Type II variation for new therapeutic indication concerning the already authorised strength(s)/ pharmaceutical form(s)

2 One of the variations in the group is a major variation of Type II; all other variations in the group are variations which are consequential to this major variation of Type II.

“A consequential variation is regarded as a change,

which is an unavoidable and direct result of another

change (i.e. the ‘main change’) and not simply a change which occurs at the same time.”

Example: Type II for new indication + Type IB or IA for addition of a new pack size required for the use in this new indication. Grouping of non-consequential quality changes may also be acceptable, under Article 7.2(c) other groups to be agreed with the Agency.

Table 2. Grouping examples according to Article 7.2(c) of the Variation Regulation (Cases for grouping variations agreed by the Agency)

1 Grouping of variations relating to active substance or finished product (but not to both)

Grouping acceptable

Example: Type IB - extension of re-test period of the active substance + Type IB - changes in the storage conditions of the active substance.

2 Grouping of variations relating to active substance and linked variations relating to finished product

Grouping acceptable European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Example: Type IB - changes to a test procedure of the active substance + Type IA - deletion of a non-significant in-process control of the finished product.

3 Grouping of quality and administrative variations

Grouping acceptable (administrative change can be combined with quality change when PI Annexes are affected).

Example: Type IB - extension of the shelf life of the finished product + Type IA(IN) - change in the name of a manufacturer responsible for batch release + Type IA - change in ATC Code.

4 Grouping of several non-clinical studies

Grouping acceptable.

Example: Provision of final study reports for 7 non-clinical in vivo studies, one of which results in consequential changes to the SmPC. The study report affecting the PI should be submitted as part of one Type II variation under category C.4 and the remaining 6 reports as part of 6 Type II variations under category C.12 (one variation per study report). As all 7 studies are non-clinical the scopes are related, and it is considered meaningful for these variations to be reviewed simultaneously. Thus, the MAH should submit one grouped application including one Type II variation under category C.4 and six Type II variations under category C.12.

5 Grouping of several drug-drug interaction studies e.g. Type II - interaction study with Rifampicin +Type II - interaction study with oral contraceptive

Grouping acceptable; 1 Type II variation scope per interaction study but Type II variations can be grouped in 1 application.

6 Grouping of several safety changes with similar implementation timelines

Grouping acceptable, provided that the variations are to be led by the same committee

Example 1: Update of section 4.4 of the SmPC with regard to venous thromboembolic events and haemorrhage events, and update of section 4.8 of the SmPC to include unrelated new ADRs, all

following an update of the MAH’s product core safety data sheet based on three different sets of

data.

The addition of information on venous thromboembolic events to SmPC section 4.4 is based on the analysis of one data set and requires one Type II variation under category C.4.

The addition of information on haemorrhage events to SmPC section 4.4 is based on the analysis of another data set and therefore requires one additional Type II variation under category C.4.

The addition of the new ADRs is in this case not consequential to the changes to SmPC section 4.4 above and is supported by another data set. Thus, the addition of the new ADRs to SmPC section 4.8 constitutes one additional scope and will therefore require an additional variation under category C.4.

The applicant should in this case submit one grouped application including 3 Type II variations under category C.4. The three variations are all related to clinical safety, they will be assessed by the CHMP and a common assessment is expected and is consequentially meaningful.

Example 2: Update of section 4.8 of SmPC to add three new ADRs - dyspnoea and chromaturia

following a review of the MAH’s safety database upon request by PRAC following a PSUSA procedure and Kounis syndrome following the MAH’s own signal detection. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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As the three ADRs are supported by two separate data sets the MAH should submit two variations; one Type II variation under category C.3.c to add dyspnoea and chromaturia and one Type II variation under category C.4 to add Kounis syndrome. Both variations are related to clinical safety, but the assessment of the first variation is to be led by the PRAC while that of the second one will be performed by the CHMP; hence, the grouping is not acceptable in this case.

7 Grouping of several variations affecting the product information with different recommended or expected approval timelines

Grouping not acceptable

Example 1: Type IA(IN) to implement the outcome of signal assessment and Type II safety variation.

The implementation of the signal recommendation (which includes all language translations) is meant to allow the immediate implementation of the updated Product Information wording. Grouping with a Type II variation would delay the implementation, therefore this is not acceptable.

Example 2: Type IB variation to implement agreed wording in the Product Information and Type II (non) clinical variation.

In principle, the grouping is not acceptable as it would delay the implementation of the agreed wording due to longer timelines and possible need for linguistic review or the Type II variation.

Example 3: Type II variation to propose an extension of the authorised indication. In addition, the

applicant proposes an update of the SmPC regarding hepatotoxicity based on a review of the MAH’s

safety data base undertaken upon request by the CHMP following a previous PAM assessment, and an update of section 4.4 of the SmPC regarding pulmonary toxicity following a literature review.

Given the long assessment timelines for an extension of indication application and the fact that a grouped approach would delay the implementation of new safety information, the proposed grouping would not be acceptable. Hence, the extension of indication application should be submitted as a separate stand-alone Type II variation under category C.6.a.

As the two safety topics are supported by different sets of data they should be submitted as part of two separate Type II variations under category C.4. However, as both scopes concern clinical safety they can be submitted as one grouped application.

Thus, the applicant should submit one stand-alone Type II variation under category C.6.a and one grouped application including two Type II variations under category C.4.

8 Grouping of variations affecting unrelated areas of the dossier

Not acceptable for grouping

Example 1: Type II variation under category C.4 to provide 3-year clinical data based on an interim study report from study A with consequential changes to sections 4.8 and 5.1 of the SmPC. In addition, the applicant proposed to provide the final CSR for clinical study B with consequential changes to SmPC section 5.1, and the final CSR for a drug-drug interaction study C with consequential changes to SmPC section 4.5, as well as to take the opportunity to condense the existing text in SmPC section 4.8, to align the annexes with the latest QRD templates and to implement editorial changes in the SmPC. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The provision of the interim data from study A and the consequential PI changes constitutes one Type II variation under category C.4.

The provision of the final CSR from study B with a consequential update to section 5.1 of the SmPC constitutes a separate assessment and therefore a separate Type II variation under category C.4 is required.

As both studies A and B are clinical (safety and/or efficacy) and affect SmPC section 5.1 it would be meaningful for these variations to be reviewed simultaneously.

The final clinical study report for study C concerns a drug-drug interaction study which is not considered consequential or related and will require different expertise for the assessment (clinical pharmacology or non-clinical, depending on the nature of the drug-drug interaction study). Therefore, a separate Type II variation under category C.4 should be submitted.

The remaining proposed changes are considered relatively minor and can be included as part of the proposed application without the need for any additional scope i.e. any additional variation.

Thus, the applicant should in this case submit one grouped application including 2 Type II variations under category C.4 and one separate stand-alone Type II variation under category C.4.

9 Grouping of variations in unrelated populations Not acceptable for grouping

Example 1: Data package supportive of 2 different indications e.g. renal cell carcinoma + non-small cell lung cancer. This would not be an acceptable grouping. Separate variations should be submitted. This is because the two indication changes may follow different timelines (i.e. number of Requests for Supplementary Information) and have different outcomes, so that the approval of one indication could be delayed because of the other.

Example 2: Provision of the final CSRs for 6 clinical phase 2 and 3 studies undertaken in the same patient population without consequential changes to the PI.

The applicant should submit 6 Type II variations under category C.12. As all 6 studies are clinical and provide safety and/or efficacy data in the same patient population, the scopes are considered related and it is considered meaningful for these variations to be reviewed simultaneously.

Thus, the applicant should submit one grouped application including six Type II variations under category C.12.

5.3. How shall I present a grouped variations application? Rev. Jul 2026

Grouped variations applications should contain the elements listed in Annex IV of the Variations Regulation and should be presented in accordance with the appropriate headings and numbering of the EU-CTD format.

The submission requirements as set-out in the PAG sections for the different types of variations will also apply to grouped variations, but the application should be provided as one integrated submission package (i.e. one eCTD sequence) covering all changes resulting from the variations.

• One cover letter, clearly indicating that the application concerns a group of variations as well as which type of variation is the highest in the group. Indicate whether the grouping is submitted under Article 7.2(b), i.e. it falls within one of the cases listed in Annex III of the variations European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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regulation or it is submitted under Article 7.2(c), i.e. the grouping has been agreed with the Agency.

• In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file UI .

• The completed electronic EU variation application form declaring all variations included in the group

in the section ‘type of changes’, as well as a justification for the proposed grouping and, if appropriate, that the (super-)grouping is submitted as an annual update of Type IA variations in

the ‘precise scope and background’ section of the application form. Any change not clearly covered by any scope of a variation included (except editorial), and that is not clearly described in the precise scope section of the application form and included in the present and proposed section should not be considered as accepted.

• The present-proposed section of the application form should clearly identify the relevant CTD sections in support of each variation

• If the group contains an Extension, also the Module 1.2 New Application Form duly completed for the Extension should be provided (see also ”How shall I present my extension application?”).

• Supportive documentation for all variations concerned, submitted as one integrated package (i.e. there is no need to submit a separate documentation package for each variation in the group). For example, the clinical overview and summaries should cover all data submitted as part of a grouped application i.e. all variations included. Hence the applicant should not submit several separate overviews/summaries.

• If applicable, one revised summary of product characteristics, labelling and/or package leaflet, including all changes applied for.

• Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected, the need for the provision of mock-ups or specimens should be discussed with the EMA ([email protected]) on a case-by-case basis.

Please also refer to “How shall I present my Type II Variation application?”

For a (super-group of) Type IA/ IA IN variation(s) concerning several marketing authorisations, please

refer to “ When shall I submit my Type IA/IA IN variation(s)?” and Harmonised eCTD Guidance.

References

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• Harmonised Guidance for eCTD Submissions in the EU

5.4. What procedure number will be given to grouped variation applications? Rev. Jul 2026

• Several (Type IA/ IA IN / IB/ II) variations affecting one medicinal product:

A procedure/case number will be assigned by the EMA upon receipt of an eCTD application. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• One or more Type IA/ IA IN variations affecting several medicinal products:

The EMA will allocate a ‘high -level’ cross -products procedure/case number shortly before submission.

To submit your request, raise a ticket via EMA Service Desk. Please click on “Finance Services”, then

the t ype of question to be selected is “Request for high -level procedure or ASMF number” followed by

sub-option “ Super Grouping (Type IA grouping)” .

If you do not have an EMA Account, you may create one via the EMA Account Management portal.

Please note that requesting this high-level number in advance is mandatory for submissions sent via the eSubmission Gateway or Web Client since this number must be included in eSubmission Gateway XML delivery file User interface .

5.5. Shall grouped variations be subject to a worksharing procedure? Rev. Mar 2025

Grouped variations shall be subject to a worksharing procedure, provided that the same group of variations applies to all medicinal products concerned by the worksharing procedure. However, groups including an extension application are excluded from worksharing.

Based on Articles 7a and 20 of the Variations Regulation when the grouping only consists of Type IA/ IA IN variations affecting several marketing authorisations, this is considered as a “ super-group” of variations and not a “worksharing” procedure. However, it is possible to include a group of Type IA/

IA IN Variation(s) with a Type IB or Type II variation, which is submitted for a worksharing procedure.

5.6. How will grouped variation applications be handled (timetable)? What will be the outcome of the evaluation of a grouped variation application? Rev. Jul 2025

A grouped variation application will be handled and will follow the review procedure of the ‘highest’

variation type in the group.

For example:

• a group of a Type II and 3 Type IB variations will follow the timetable of the Type II variation.

• a group of an extension and a Type II variation will follow the timetable of the extension.

When the group follows the timetable of the Type II variation, weekly-start timetables may apply to the assessment following the same principles as those applied to the assessment of Type II variations.

The assessment timetable may be reduced having regard to the urgency of the matter, particularly for safety issues, or may be extended to 90 days (for agreed grouping of variations or for Type II variations concerning changes or additions to the therapeutic indication).

For more information, please refer to the following questions and answers from the post-authorisation guidance for T ype II variations: ‘ Which submission dates (weekly or monthly) are applicable for my Type II variation and when shall I submit my application?’ and ‘ How shall my Type II application be handled (timetable)? ’European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In case of grouped Type IA/ IA IN variations, the Agency will issue a Notification reflecting which variations are accepted or rejected. The MAH shall immediately cease to apply the rejected variation(s) concerned.

For grouping of other types of variations, where not all of the changes applied for can be positively validated, all valid and not valid variations will be clearly listed in the validation letter.

Upon finalisation of the review of the grouped variations, the Agency will issue an opinion/notification

reflecting the final outcome of the procedure and in accordance with the ‘highest’ remaining

approvable variation in the group. Such opinion/notification will therefore also list any variations which are not considered approvable, unless these have been withdrawn from the group by the holder during the procedure.

For example:

• Extension + Type II --> extension evaluation procedure. Extension receives a negative assessment outcome (e.g. quality issues); Type II (e.g. new indication) is however positive.

MAH withdraws the extension from the group --> CHMP will adopt a positive opinion on the Type II variation only.

MAH does not withdraw the extension from the group --> CHMP will adopt a ‘composite’ opinion

reflecting both the negative extension outcome as well as the positive Type II.

• Type II + Type IB --> Type II evaluation procedure. Type II receives a negative assessment outcome; Type IB is however positive.

MAH withdraws the Type II from the group --> Agency will issue a positive notification on the Type IB variation.

MAH does not withdraw the Type II from the group --> CHMP will adopt a ‘composite’ opinion

reflecting both the negative Type II outcome as well as the positive Type IB.

In any case, the assessment report will mention the initial and complete scope of the application (listing all variations initially included in the group) and will clarify the procedural timelines and steps taken during assessment.

For CHMP opinions on extensions and Type II variations, the re-examination procedure set-out in Articles 9(2) and 34 (2) of Regulation (EC) No 726/2004 will apply. For further information please refer to the following questions and answers from the post-authorisation guidance for Type II variations

‘Which post -opinion steps apply to my Type II variation and when can I implement the approved

changes?’ and Extensions of marketing authorisations ‘ How shall my extension application be handled (timetable) ?’

5.7. How and when will the marketing authorisation be updated for grouped variations? Rev. Mar 2025

The post-opinion and decision-making process that will apply to grouped variations, will generally be

that of the ‘highest’ type of opinion/notification issued at the end of the procedure.

For information on the post-opinion and decision-making process for Type IA, IB and II variations,

please refer to the following questions and answers ‘ How and when will the updated annexes become European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

EMEA-H-19984/03 Page 105/305

part of the marketing authorisation?’ and ‘ Which post-opinion steps apply to my Type II variation and when can I implement the approved changes ?’

The decision granting the marketing authorisation following a grouped application will be amended, where necessary, within a year from the date of notification/CHMP opinion for the variation concerned with the exception of the following grouped variations:

• Groupings including an extension application, which will follow the decision-making process applicable to the extension application;

• Groupings including variation(s) listed in Article 23.1a(a), for which the amendments to the decision granting the marketing authorisation will follow a two-month timeframe;

Where a super-group of Type IA/ IA IN variations to the terms of several MAs have been approved, the Commission will update the MA with one decision per product concerned, following the yearly decision-making timeframes for Type IA/ IA IN variations.

5.8. What fee do I have to pay for grouped variations? Rev. Dec 2024

For information on fees to be paid, applicable fee reductions and payment process, please refer to the Fee Q&As in Annex I, Section 5, on the Fees payable to the European Medicines Agency page.

References

• Fees payable to the European Medicines Agency European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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6. Worksharing of variations

6.1. What is worksharing and what types of variations can be subject to worksharing? Rev. Nov 2025

Mandatory worksharing

In accordance with Article 20(1) of the Commission Regulation (EC) No 1234/2008, as amended (the

‘Variations Regulation’) , a Marketing Authorisation Holder (MAH) shall follow the worksharing procedure and submit the same Type IB or Type II variation, or the same group of variations affecting more than one marketing authorisation from the same MAH in one application.

Applicants belonging to the same mother company or group of companies and applicants having concluded agreements or exercising concerted practices concerning the placing on the market of the

medicinal product(s) concerned, have to be taken as “the same marketing authorisation holder”.

Extensions of Marketing Authorisations (so-called ‘line extensions’) are excluded from worksharing.

Based on Articles 7, 7a and 20 of the Variations Regulation, when a group of variations only consists of Type IA/ IA IN variations affecting several marketing authorisations, this is considered as a

“(super) group” of variations and not a “worksharing” procedure. However, it is possible to include a

group of Type IA/ IA IN variation(s) with a Type IB or Type II variation, which is submitted for a worksharing procedure. In such case, the review of the Type IA/ IA IN variation will be performed as part of the worksharing procedure.

A worksharing procedure can include centralised authorised products (CAP), decentralised procedure/mutual recognition products or purely national marketing authorisations.

In order to avoid duplication of work in the evaluation of such variations, a worksharing procedure has been established under which one authority acts as the ‘reference authority’ and examines the variation(s) on behalf of the other authorities. Where at least one of the marketing authorisations concerned is a CAP, the Agency will act as reference authority. The procedure to choose the reference

MAH 1 Prod. 1 IB (1) Prod. 2 IB (1) MAH 1 Prod. 1 II (1) Prod. 2 II (1) MAH 1 Prod. 1 Prod. 2 IB (1) IA (1) IB (1) IA (1) MAH 1 Prod. 1 II (1) IB (1) IA (1) Prod. 2 II (1) IB (1) IA (1) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure EMEA-H-19984/03 Page 107/305

authority where the worksharing procedure does not involve a CAP is described in CMDh BPG on Worksharing (Chapter 7 ).

Voluntary worksharing

Additionally, in accordance with Article 20(11) of the Commission Regulation (EC) No 1234/2008, as amended, in justified cases agreed by the Agency (and competent authorities of the Member States, if applicable) holders may choose to follow the worksharing procedure also where a minor variation of Type IB or a major variation of Type II, or a group of variations where at least one of the variations is a minor variation of Type IB or a major variation of Type II, that does not contain any extension, relates to several marketing authorisations owned by several holders.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

6.2. Which variation(s) should be submitted under mandatory worksharing? Rev. Mar 2025

In a worksharing procedure, it is required that the same change(s) will apply to the different medicinal products concerned from the same MAH, with either no or limited need for assessment of a potential product-specific impact. Therefore, where the ‘same’ change(s) to different marketing authorisations

require the submission of individual supportive data sets for each medicinal product concerned which each require a separate product-specific assessment, such changes will not fall under the mandatory worksharing.

Grouped variations should be subject to a worksharing procedure, provided that the same group of variations applies to all medicinal products concerned by the worksharing procedure.

Non-exhaustive examples of changes which should be submitted for evaluation under worksharing (if appropriate) are listed below:

Clinical/Pharmacovigilance

• Changes to multiple generic/duplicate MAs containing the same active substance.

• Changes to single-substance MA and fixed-combination MA containing the same active substance.

• Proposal for combination use, affecting both MAs.

• Introduction or changes to the pharmacovigilance system.

• Update to the RMP.

Quality

• Changes to ASMF. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Update of CEP certificate.

• Quality changes impacting the same active substance/excipients/raw material that do not require separate product-specific data.

6.3. What pre-submission steps will apply to a worksharing procedure? Rev. Mar 2025

In order to facilitate the planning of a worksharing procedure, MAHs are advised to inform the Agency at least 2 months in advance of the submission of a variation/group of variations to be subject to a

worksharing procedure, by means of a ‘letter of intent’.

The ‘letter of intent’ should provide the following information:

• Type(s) and scope of variation(s)

• Overview of MAs concerned

• Explanation that all MAs belong to the same MAH for a mandatory worksharing or an explanation as to why the holder believes that a worksharing procedure is suitable for voluntary worksharing

• Explanation / justification for suitability of voluntary worksharing

• Rapporteurs, Reference Member States (RMS) and National Competent Authorities of the medicinal products concerned, if applicable

• Intended submission date

• Contact person for the worksharing procedure

A ‘letter of intent’ template is available on the Agency’s website. To submit your request, raise a ticket via EMA Service Desk. Please click on “Finance Services”, then t he type of ticket request to be selected

is “Request for high -level procedure or ASMF number” followed by sub -option “Workshare Procedure number”. The letter of intent should be attached to the EMA Service Desk ticket.

If you do not have an EMA Account, you may create one via the EMA Account Management portal.

Upon receipt of the letter of intent, the Agency will review and decide whether the proposed worksharing procedure is acceptable. Subsequently, the Agency will initiate the Rapporteur appointment procedure.

Following an ‘Expression of Interest’ a Rapporteur (and , if relevant, a Co-Rapporteur when the application includes a new indication) will be appointed for the procedure. It is expected that the (Co-)Rapporteur will be one of the Rapporteurs of the centrally authorised medicinal products or a CHMP member representing one of the RMSs or National Competent Authorities for the nationally authorised products. The MAH will be informed accordingly.

A shorter pre-submission phase is envisaged, in cases where:

• a worksharing procedure relates to multiple MAs for the same medicinal product authorised via the centralised procedure only;

• the variations subject to the worksharing procedure concern the implementation of urgent safety-related changes; European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• the variations subject to the worksharing procedure concern the implementation of changes requested by the Authorities.

Worksharing procedure for multiple centrally authorised medicinal products (‘duplicates’)

The submission of a letter of intent is not required, however applicants are advised to request a WS number. The request should be submitted by raising a ticket via EMA Service Desk. Please click on

“Finance Services”, then t he type of ticket request to be selected is “Request for high -level procedure

or ASMF number” followed by sub -option “Workshare Procedure number” detailing the list of products, the intended submission date and the scope of variation they are planning to apply for (a draft cover letter is also accepted). Marketing Authorisation Holders are advised to submit such variations as usual.

6.4. How shall I present a variation application under worksharing? Rev. Jul 2026

The submission requirements as set-out in the PAG sections for the different types of variations will also apply to variations subject to worksharing, but the application should be provided as one integrated submission package (eCTD sequence) per product, covering all variations applied for. Please refer to the eCTD Variations Q&A document, for guidance on the submission of variations in eCTD format.

This will include a cover letter and electronic application form, together with separate supportive documentation for each medicinal product concerned and revised product information/risk management plan (if applicable) for each medicinal product concerned.

• One original cover letter addressed to the Agency and Competent Authorities of the Member States, in case nationally authorised medicinal products are part of the worksharing procedure, clearly indicating that the application is submitted for a worksharing procedure together with a short overview of all medicinal products concerned, with their respective Rapporteurs, Competent Authorities of the Member States, as applicable. In case nationally authorised medicinal products are part of the worksharing procedure, the MAH should also include a confirmation that the worksharing applications have been submitted to all Member States where the products concerned are authorised and that the relevant national fees have been paid (when a WS application contains at least 1 CAP, the submission should be made to EMA only using the eSubmission Gateway. For further information please consult the document: Dossier requirements for NAPs ). A letter with the worksharing applicant(s) and contact person for the worksharing procedure should be provided with the worksharing application. A template cover letter for worksharing procedures including

CAPs and nationally authorised medicinal products only is available on the Agency’s website.

• One completed electronic EU variation application form, listing all medicinal products concerned

and declaring all variations included in the group in the section ‘type of changes’, as well as a

justification for the proposed worksharing in case of different MAHs are involved (voluntary worksharing) (and a justification for the grouping if applicable) in the ‘precise scope and background’ section of the application form. Any change not clearly covered by any scope of a variation included (except editorial), and that is not clearly described in the precise scope section of the application form and included in the present and proposed section should not be considered as accepted. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• If nationally authorised medicinal products are part of the worksharing procedure, relevant product and Member State details should be provided as an Annex B to the application form (using the

template available on the Agency’s website)

• Supportive documentation for each product (including the revised summary of product characteristics, labelling, package leaflet, and/or risk management plan if applicable). This will allow the Agency and the national competent authorities to update the dossier of each marketing authorisation included in the worksharing procedure with the relevant amended or new information.

• Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected, the need for the provision of mock-ups or specimens should be discussed on a case-by-case basis by sending an e-mail to [email protected].

• In principle, identical modules 2-5 will have to be provided for each product included in the worksharing.

For queries relating to the presentation of the application, please contact the Agency (Contacting EMA: post-authorisation | European Medicines Agency (EMA) (europa.eu)).

References

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• eCTD Variations Q&A document

• Template cover letter for worksharing procedures including CAPs and nationally authorised medicinal products only

• Template for Annex B

• Dossier requirements for NAPs (referral, PASS107, workshare, signal detection procedures) and ancillary medicinal substances in a medical device

6.5. How and to whom shall I submit my variation application under worksharing? Rev. Mar 2026

The worksharing application must be submitted at the same time to all relevant authorities, i.e. in case the application consists of centrally and nationally authorised medicinal products, the submission should be made to EMA only using the eSubmission Gateway. All NAP submissions (worksharing containing at least 1 CAP) sent to EMA via eSubmission Gateway/Web Client will be considered delivered to all Competent Authorities representatives, alternates and experts of the scientific committees. All EMA submissions should be sent via EMA eSubmission Gateway/Web Client only .

Submission to the European Medicines Agency

The use of the eSubmission Gateway or Web Client is mandatory for all electronic Common Technical Document (eCTD) submissions through the centralised procedure. This applies to all applications for human medicines. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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More information on how to register and connect to the Gateway / Web Client can be found in the eSubmission website and detailed information on how to submit can be found in eSubmission Gateway guidance documents .

An automated acknowledgement is sent from the system confirming whether the submission has

passed the relevant technical validation criteria and whether it has been uploaded to the Agency’s

review tool and made available via the Common Repository.

Where applicable, revised product information Annexes (including Annex A, if applicable) should be included in electronic (Word and PDF) format in the same eSubmission Gateway or eSubmission Web

Client package within a folder called ‘working documents’. Wh ere applicable changes in Word

documents should be indicated using ‘Tools -Track Changes’. Clean PDF versions should have all changes ‘accepted’.

For Centrally Authorised medicinal products

An electronic copy containing the relevant eCTD sequence for each product, shall be submitted to the Agency. The coordinating Product Lead (if the worksharing procedure contains at least one Type II variation) or else the appointed Procedure Manager should be indicated in copy (“cc”) on the cover

letter.

For nationally authorised medicinal products

eSubmission Gateway / Web Client package of the Variation application form and supportive documentation for each product should be submitted to the Agency in accordance with the “Dossier

Requirements for referral, ASMF and NAP submissions (PASS107, Workshare, Signal Detection procedures) and ancillary medicinal substances in a medical device ” document . Paper submissions are not accepted.

Submission to the Competent Authorities of the Member States

Where nationally authorised medicinal products are part of the worksharing, the applications are submitted to the Agency only via the eSubmission Gateway and there should not be additional parallel submissions to Member States, even if some products are not relevant to some MSs. All submissions are available to all Competent Authorities of the Member States via the Common Repository. The Common Repository provides access to all involved Parties (the Agency, Member States and Committee Members) to receive the full data for the worksharing application.

If amendments are requested by the Agency as a result of the validation, updated documentation should also be submitted via the eSubmission Gateway/Web Client and it will be available to the network via the Common Repository.

Submission to the Rapporteur and Committee members

All submissions sent to EMA via eSubmission Gateway/Web Client will be considered delivered to all

Competent Authorities’ representatives and alternates.

The dossier requirements for post-authorisation submissions in the centralised procedure should be followed.

For a full overview of dossier requirements for Competent Authorities of Member States (Co-)Rapporteur and Committee members, including delivery addresses, please refer to the following document: Dossier requirements for Centrally Authorised Products (CAPs). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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For requirements for non-eCTD format submissions, please refer to the “Dossier Requirements for

referral, ASMF and NAP submissions (PASS107, Workshare, Signal Detection procedures) and ancillary medicinal substances in a medical device ” document .

References

• Commission Regulation (EC) No 1234/2008

• Electronic Variation application form

• Variation application form, The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2C

• Dossier requirements for Centrally Authorised Products (CAPs)

• Dossier Requirements for referral, ASMF and NAP submissions (PASS107, Workshare, Signal Detection procedures) and ancillary medicinal substances in a medical device

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• Article 5 Recommendation

• Harmonised Guidance for eCTD Submissions in the EU

• eSubmission website

• eSubmission Gateway Q&A

• eSubmission Gateway Web Client Q&A

• Common Repository website

6.6. What procedure number will be given to variation applications under worksharing? Rev. Oct 2020

The Agency will allocate a ‘high -level’ cross -products procedure number, which will be used for the handling of worksharing procedures affecting more than one medicinal product. A new procedure code

(abbreviation) is used for worksharing procedures i.e. “WS”. As the ‘high -level’ number cannot be allocated to one single product, the procedure number will therefore contain “xxxx” as a placeholder for the product number.

Example: EMEA/H/C/xxxx/WS/0003

For each medicinal product concerned by the worksharing procedure, the following worksharing

number (which includes a reference to the “WS” procedure to which it belongs) will be allocated:

Example: EMEA/H/C/prod_nb/WS0003/nn which was submitted as part of the 3 rd worksharing

procedure received by the Agency “WS0003” .

Worksharing applications for a group of variations will include the suffix “/G” e.g. EMEA/H/C/

xxxx/WS/0004/G and EMEA/H/C/prod_nb/WS0004/nn/G. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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For all worksharing procedures, including those which contain nationally authorised medicinal products,

the ‘high -level’ procedure number should be systematically obtained from the Agency shortly before

submission by sending your request via EMA Service Desk with a letter of intent, see question “What

pre-submission steps will apply to a worksharing procedure?” .

6.7. How will variation applications under worksharing be handled (timetable)? What will be the outcome of the evaluation of a variation application under worksharing? Rev. Nov 2025

The MAH must submit the variation application for worksharing, at the latest by the recommended

submission dates published on the Agency’s website (See also Human Medicines – Procedural Timetables / Submission dates).

The worksharing procedures will follow the assessment period of the highest type of variation included .

If a submission for a worksharing application does not include all marketing authorisations owned by the same holder affected by the proposed changes, the holder will have to revise its application to include all affected marketing authorisations.

In general, variations submitted for worksharing will follow the 60-day evaluation timetable of Type II variations and weekly-start timetables may apply to the assessment following the same principles as those applied to the assessment of Type II variations. The 60-day period may be reduced having regard to the urgency of the matter, particularly for safety issues, or may be extended to 90 days for Type II variations concerning changes or additions to the therapeutic indication or for grouping of variations accepted by the agency and not listed in Annex III of the Variations Regulation .

Type IB worksharing procedures with Type IB as the highest type of change applied will follow a 30-day timetable. However, in specific cases this can be extended to a 60 or 90-day timetable if needed .

For the detailed evaluation timetable, of Type IB and Type II Worksharing procedures, please refer to

the PAG for Type II variations “ How shall my Type II application be handled (timetable)? ”

Upon finalisation of the review of the variations subject to the worksharing procedure, the Agency will issue an opinion reflecting the final outcome of the procedure. Such opinion will also list any variations (e.g. as part of a group, or for a specific medicinal product) which are not considered approvable, unless they had been withdrawn by the holder during the procedure. The same general principles as for grouped variations apply - see the PAG on grouping “What will be the outcome of the evaluation of

a grouped variation application”?

Schematic structure of the CHMP Opinion and Annexes for an application under worksharing, consisting of centrally and nationally authorised medicinal products:

Note:

Opinion

cover

page

Annex A

CAP 1

Annex B

NAPs

PI

(Annexes I, II, III)

CAP 1

CHMP AR

Prods n

Annex A

CAP 2

PI

(Annexes I, II, III)

CAP 2 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The Annex A for each centrally authorised medicinal product included in the worksharing procedure will be annexed to the CHMP opinion

The Annex B includes information on the nationally authorised medicinal products included in the worksharing application (if applicable). A template for the Annex B is available on the Agency’s

website.

6.8. How and when will the marketing authorisations be updated following a worksharing procedure? When can I implement the approved changes? Rev. Jul 2026

Upon adoption of the CHMP Opinion on the worksharing procedure, the Agency will inform the MAH and Member States concerned (if applicable) as to whether the opinion is favourable or unfavourable (including the grounds for the unfavourable outcome), as well as whether the Commission Decision granting the Union marketing authorisations require any amendments.

Where the outcome of the procedure is favourable and the Commission Decision granting the Marketing Authorisation requires amendments, the Agency will inform the Commission accordingly.

Re-examination

Article 9(2) of Regulation (EC) No 726/2004 also applies to CHMP Opinions adopted for worksharing procedures. This means that the MAH may give written notice to the Agency/CHMP within 15 days of receipt of the opinion (after which the opinion shall be considered as final) that they wish to request a re-examination. The grounds for the re-examination request must be forwarded to the Agency within 60 days of receipt of the opinion.

In case the MAH requests that a SAG/AHEG is consulted in connection with the re-examination, the MAH should inform the CHMP as soon as possible of this request and at the latest with the submission of the detailed grounds for re-examination. This is necessary to allow for the SAG/AHEG consultation to be organised, and the outcome of this consultation duly taken into account by the CHMP, within the timelines established for the re-examination procedure.

The CHMP will appoint a different (Co-) Rapporteur, to co-ordinate the re-examination procedure. Within 60 days from the receipt of the grounds for re-examination, the CHMP will consider whether its opinion is to be revised. If considered necessary, an oral explanation can be held within this 60-day timeframe.

In case of withdrawal of the request for re-examination, the initial CHMP opinion will immediately become the final CHMP opinion.

EMA charges a fee for a re-examination of an opinion. For more information, please refer to the Fee Q&As in Annex IV, Section 4, on the Fees payable to the European Medicines Agency page.

Decision-Making Process for centrally authorised medicinal products

Upon receipt of a favourable CHMP opinion which requires amendments to the decision granting the marketing authorisation, the Commission shall amend the marketing authorisation for each centrally authorised medicinal product to reflect the approved variation(s) within 2 months, for the variations European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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listed under Article 23(1a)(a) or within one year for the other variations. A single decision will be issued for each centrally authorised medicinal product.

Article 23(1a)(a) provides for a two month timeframe for amending the decision granting the marketing authorisation for the following variations:

• variations related to the addition of a new therapeutic indication or to the modifications of an existing one;

• variations related to the addition of a new contra-indication;

• variations related to a change in posology;

• variations related to changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against human influenza;

• other Type II variations that are intended to implement changes to the decision granting the marketing authorisation due to a significant public health concern;

• variations related to the replacement or addition of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences of a human vaccine that has the potential to address a public health emergency;

• variations related to the replacement or addition of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences of a human vaccine that has the potential to address a public health emergency.

All the other variations will follow a yearly timeframe for update of the respective Commission decision.

The Agency applies the existing post-opinion timeframes, as set-out in the Linguistic review process of product information in the centralised procedure – Human. The QRD linguistic check will be performed on one set of Annexes of one centrally authorised medicinal product. In case of comments, it will be up to the MAH to correctly implement the same amendments in the other centrally authorised products, as appropriate.

The Agency, in cooperation with the QRD members and the MAH will aim at providing final, checked translations for all centrally authorised products included in the worksharing procedure to the MAH at opinion stage in case of a worksharing procedure for a Type IB variation or by Day +27 in case of a

worksharing procedure for a Type II variation. (See also: “When do I have to submit revised product information? In all languages?”). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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MA updating Process for nationally authorised medicinal products (if applicable)

Upon receipt of the final opinion, the Member States concerned shall approve the final opinion, inform the Agency accordingly and where necessary, amend the national marketing authorisations within 60 days, provided that the documents necessary for the amendment of the marketing authorisation have been transmitted to the Member States concerned .

Implementation

Type IB variations approved via a worksharing procedure, may be implemented upon receipt of the favourable CHMP opinion.

Variations listed in Article 23(1a)(a) may only be implemented once the Commission has amended the marketing authorisation and has notified the MAH accordingly.

Type II variations approved via a worksharing procedure, which do not require any amendment of the marketing authorisation or which follow a yearly update of the respective Commission Decision can be implemented 30 days after receipt of the favourable CHMP opinion.

The agreed change(s) should be included in the Annexes of any subsequent regulatory procedure.

Variations related to safety issues, including urgent safety restrictions, must be implemented without delay, within a timeframe agreed by the marketing authorisation holder and the Agency.

References

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

6.9. What fee do I have to pay for variation applications under worksharing? Rev. Dec 2024

For information on fees to be paid, applicable fee reductions and payment process, please refer to the Fee Q&As in Annex I, Section 5, on the Fees payable to the European Medicines Agency page.

There is no fee payable for Type IB worksharing applications.

References

• Fees payable to the European Medicines Agency European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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6.10. When do I have to submit revised product information? In all languages? Rev. Mar 2026

In case the Variation(s) subject to worksharing affects SPC, labelling and/or package leaflet, the revised product information Annexes must be submitted as follows:

a. Worksharing procedure for Type II variation(s)

At submission (Day 0)

• English language: complete set of Annexes for all CAPs electronically only in Word format (highlighted)

After CXMP Opinion (Day +5)

• All EU languages (incl. NO+IS): complete set of annexes of one CAP electronically only in Word format (highlighted)

After Linguistic check (Day +25)

• All EU languages (incl. NO+IS): complete set of annexes for all CAPs electronically only in Word format (highlighted) and in PDF (clean)

Only one centrally authorised medicinal product will undergo a linguistic check. In the cases where the changes to the product information may vary between products, the product with the most complex changes will generally be the one subject to linguistic check.

b. Worksharing procedures for Type IB variations

At submission (Day 0)

• English language: complete set of Annexes for all CAP electronically only in Word format (highlighted)

• All EU languages (incl. NO+IS): complete set of annexes of one CAP electronically only in Word format (highlighted)

Day +25 after start of procedure

• All EU languages (incl. NO+IS): complete set of annexes of all CAPs electronically only in Word format (highlighted) and in PDF (clean)

For such procedures a linguistic review will take place in parallel to the scientific assessment. It is therefore expected that the texts provided at Day +25 after start of procedure will be the final texts.

Overview:

Day Lang.* Type II variation(s) Type IB variation(s)

0 EN Electronically Electronically European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Word format (highlighted)

All CAPs

Word format (highlighted)

All CAPs

Other EEA / Electronically

Word format (highlighted)

One CAP

+5 All EEA After opinion

Electronically

Word format (highlighted)

One CAP

/

+25 All EEA After opinion

Electronically

Word format (highlighted)

PDF format (clean)

All CAPs

After start of procedure

Electronically

Word format (highlighted)

PDF format (clean)

All CAPs

• = complete set of Annexes i.e. Annex I, II, IIIA and IIIB submitted as one document per language

The ‘complete set of Annexes’ includes Annex, I, II, IIIA and IIIB i.e. all SPC, labelling and PL texts for

all strengths and pharmaceutical forms of the product concerned, as well as Annex II. The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU language. Page numbering should start with "1" (bottom, centre) on the title page of Annex

I. The ‘ QRD Convention ’ published on the Agency’s website should be followed. When submitting the

full set of Annexes in PDF format, this should be accompanied by the completed formatting checklist. A user guide on how to generate pdf versions of the product information and annexes is also available.

The electronic copy of all languages should be provided as part of the variation application in the eCTD for the product concerned, on Gateway / Web Client. Highlighted changes should be indicated via

‘Tools – Track changes’. Clean versions should have all changes ‘accepted’.

Icelandic and Norwegian language versions must always be included.

The Annexes provided should only reflect the changes introduced by the Variation concerned. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments in the texts (e.g. further to a specimen check) this should be clearly mentioned in the cover letter and in the

scope section of the application form. In addition, the section “present/proposed” in the application

form should clearly list the minor linguistic amendments introduced for each language. Alternatively, such listing may be provided as a separate document attached to the application form. Any changes not listed, will not be considered as part of the variation application.

In such cases and in cases where any other ongoing procedures may affect the product information Annexes, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedure(s) concerned. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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For those variations which affect the Annex A (e.g. introduction of a new presentation), the following principles apply:

Upon adoption of the opinion, the Agency will prepare and send to the MAH the revised English Annex A for each CAP reflecting the new/amended presentation.

After CHMP Opinion (Day +5), the MAH provides the Agency with the electronic versions of the complete set of Annexes in all languages, if applicable, as well as the translations of the revised Annex A for each CAP as a separate word document.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translation versions of the product information annexes in all languages submitted at Day+5 as well as the final translations submitted at Day+25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). The annotated product information files must include the statement containing the procedure number(s) and may be published on the EMA website as part of the product EPAR page. If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA, the publication on the EMA website and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

Reference

• The linguistic review process of product information in the centralised procedure - Human European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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7. Classification of changes

7.1. Administrative changes Rev. Nov 2025

7.1.1. How to apply for a change in name and/or address of a marketing authorisation holder manufacturing site? NEW Nov 2025

Classification category E.4 should be used as long as there is no change in the physical location of the facility, and all manufacturing operations remain the same. This scope is only for changes in name and/or address that are purely administrative in nature (e.g. the municipality decides to change the name of the street or there is a change in the postal code). If the facility moves to a different physical location, classification under the appropriate Q section should be used (e.g. Q.I.a.1 for a manufacturer or a batch control/testing site of an active substance, Q.II.b.1 for a manufacturer of a finished product, Q.II.b.2 for a release site or batch control/testing site for the finished product).

Classification category E.4 should also be used for administrative changes to the name and/or address of manufacturing sites for active substance or finished product intermediates or any other materials mentioned in the dossier.

In case the site impacted by the change in name and/or address is performing multiple activities, they can be included in the same Type IA submission as long as they are all part of the same classification category. For example:

a) The same change concerns the MAH and the batch release site: a grouping of a Type IA, E.4.a and a Type IA, E.4.b should be submitted, since the conditions to be fulfilled are different and need to be declared for each activity.

b) The same change concerns a site where manufacturing of final product, primary and secondary packaging and quality control are performed: a single Type IA, E.4.c can include all activities, since the conditions and documentation are the same. The company needs to confirm explicitly in the application form that conditions and documentation are met for all activities.

In case a CEP is used, changes in the name and/or address of the sites listed in the CEP are covered under scope Q.III.1 when the new version of the CEP is submitted. A parallel variation under classification category E.4 is not required.

An official document from a relevant official body including the new name and address needs to be provided (e.g. Chamber of Commerce registry, manufacturing authorization or importation (MIA), GMP

certificate…). A self -declaration issued by the MAH is not considered sufficient.

7.1.2. How to apply for the deletion of more than one manufacturing site?

Rev. Nov 2025

In case more than one manufacturer in one MA has to be deleted a single variation of Type IA under classification category E.5 to delete all manufacturing sites may be submitted. However, it has to be assured that there is still one approved manufacturing site left in the documentation performing the same function as the one(s) concerned by the deletion. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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7.2. Quality changes Rev. Nov 2025

7.2.1. Introduction of a new manufacturing site for the finished product. What changes can I submit under a single Type II scope? (Classification category Q.II.b.1) Rev. Nov 2025

Multiple related extensive changes could be considered for submission under a single Type II scope Q.II.b.1 – Change in the manufacturing site for part or all of the manufacturing process of the finished product.

Multiple related changes submitted under a single Type II should always be clearly identified in the application form as following: a clear description of all the related changes should be provided in the precise scope. All the related changes should be listed in the present/proposed table.

Changes affecting the FP not directly related to the introduction of the new manufacturing site such as changes in excipients, specification parameters /limits for the FP, container closure system including suppliers should be submitted as additional grouped variation scopes.

It should be highlighted, that for variations introducing additional manufacturing or batch control/testing sites (including sub-contractors), each additional site should be declared as a separate variation on the variation application form. Such variations can be submitted as a grouping application. The precise scope should include the full name and full address of the site, and clearly list all activities performed at each site.

Any pre-submission queries related to the intended submission of multiple related changes under one single Type II variation should be addressed to the Quality Specialist assigned to your product. See

also question ‘Who is my contact at the European Medicines Agency during Type II variation including

extension of indications?’.

7.2.2. Introduction of a new manufacturing site for an active substance. What changes are covered by a single Type II scope? (Classification category Q.I.a.1) Rev. Nov 2025

The introduction of a new manufacturing site for an active substance supported by an ASMF should be submitted under a single Type II scope Q.I.a.1.f.

The introduction of a new manufacturer of the active substance not supported by an ASMF or intermediate that requires extensive updates to 3.2.S section should be submitted under a single Type II, Q.I.a.1.b.

It should be noted that, in cases where the introduction of the new active substance manufacturer has an impact at the level of the finished product manufacturer (e.g. changes to the active substance specifications or related analytical methods) separate variations have to be submitted under the corresponding Q.I.b categories and may be grouped together, if related to the introduction of the new active substance manufacturer.

It should be highlighted that, for variations introducing additional manufacturing or batch control/testing sites (including sub-contractors), each additional site should be declared as a separate variation on the variation application form as a grouped application, and the precise scope should include the full name, full address of the site and list all activities performed at each site. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Any pre-submission queries related to upcoming submissions pertaining to such Type II changes should be addressed to the Quality Specialist assigned to your product . See also question ’Who is my

contact at the European Medicines Agency during T ype II variation, including extension of indications?’.

7.2.3. How should multiple changes to Module 3.2.S or the update of an ASMF, which is part of Module 3 of a marketing authorisation be submitted? (Q.I.z) Rev. Nov 2025

An update of Module 3.2.S can be submitted as a grouped variation application, if conditions 5 or 6 of Annex III of the Variation Regulation (EC) No 1234/2008 are met.

An update or change of a stand-alone ASMF is not foreseen and can only be addressed in connection with a marketing authorisation. The type of variation(s) is dependent on the type of changes introduced in the updated version. The update – including changes to the open and/or restricted part -can be submitted as a grouped application, if condition 5 of Annex III of the Variation Regulation (EC) No 1234/2008 is met.

In case of substantial changes or multiple minor changes to Module 3.2.S or the ASMF, it is recommended to submit a single Type II variation under category Q.I.z. It is a prerequisite for the

validation of these single variations that the “present/proposed” section of the application form is filled in correctly and completely.

In all cases, updates of the ASMF must be submitted by the ASMF holder (open and closed part to EMA, open part to marketing authorisation holder (MAH)) whilst the variation to the Marketing Authorisation has to be submitted by the MAH. We encourage a close dialogue between MAH and ASMF holder to ensure that the ASMF update has been submitted before or at the same time as the variation application to avoid validation issues. A clear present and proposed table listing all changes should be included in both submissions (a table of changes should be included in the ASMF submission and the

same table of changes and a present and proposed section for the applicant’s part should be included in the MAH variation application). The application form needs to include the specific ASMF version number the submission relates to.

Minor changes to the restricted part of an ASMF are not acceptable as Type IA variations and should be submitted using classification category Q.I.a.2.d.

Any pre-submission queries related to upcoming submissions pertaining to extensive changes to Module 3.2.S or extensive ASMF updates should be addressed to the Quality Specialist assigned to your product . See also question ’Who is my contact at the European Medicines Agency during a Type II

variation, including extension of indications?’.

7.2.4. How should I submit a revised Certificate of Suitability (CEP)? (Q.III.1a.2) Rev. Nov 2025

In line with the Marketing Authorisation Holder’s (MAH) obligation to keep the dossier up to date, a

new or revised Certificate of Suitability (CEP) for an active substance (AS), excipient or starting material/reagent/intermediate used in the manufacturing process of the AS should be submitted as a variation. It is however understood that only the versions of the CEP (i.e. revised certificates) which were used in the manufacturing process of a batch of finished product (FP)/ AS need to be included in the dossier, provided that there are no quality and/or safety concerns that have led to the revision of the CEP .European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In case of CEP revision related to quality and/or safety issues, the revised CEP should be implemented immediately, and the appropriate variation should be submitted, even if the revised CEP is not linked to a specific production batch for the finished product.

CEP revisions should be submitted under the appropriate variation classification scope within subsection Q.III.1. Each CEP revision should be submitted as a variation scope, i.e. an update covering more than one CEP version should be submitted as a grouped variation.

When submitting a revision of an approved CEP, the MAH should refer to the previously agreed version

of the CEP within the ‘Present/Proposed’ section of the application form.

If with the submission one or more revisions of the CEP are omitted, the MAH should confirm in the

variation application form (section ‘Precise scope and background for change’) that substance/material

from the omitted CEP version(s) was not used in the manufacture of the FP and/or AS during the validity of this certificate(s). Additionally, it should be confirmed that any changes introduced by the omitted CEP revision(s), do not affect the quality of the AS and/or FP. In case such confirmation is missing, a negative Type IA notification may be issued.

The MAH should also clearly indicate in the ‘Present/Proposed’ section all changes introduced in the

CEP between the latest approved version and the new revision, including all revisions that were not notified. Any changes e.g. to manufacturing sites, additional residual solvents introduced in the CEP by subsequent revisions should be declared.

Example

Submission of a revised CEP version for an already approved manufacturer: R0-CEP-xxxx-xx-rev02 when the current certificate in the dossier is: R0-CEP-xxxx-xx-rev00.

If during the validity of R0-CEP-xxxx-xx-rev01, material of the CEP was used in the manufacture of the FP and/or the AS, then the MAH should submit a grouping of two IA variations to include both certificates (rev. 01 and rev 02) in the Module 3. The foreseen conditions for each of the respective variations should be met.

If during the validity of R0-CEP-xxxx-xx-rev01, material of the CEP was not used in the manufacture of the FP and/or AS, the MAH should only submit a single Type IA variation to include the revised certificate R0-CEP-xxxx-xx-rev02 in Module 3. The foreseen conditions for the variation should be met.

The MAH should also confirm in the variation application form that material/substance from R0-CEP-xxxx-xx-rev01 was not used in the manufacture of the FP and/or AS during the validity of this certificate and that changes introduced by the revision R0-CEP-xxxx-xx-rev01 do not affect the quality

of the AS and/or the FP. MAH should also clearly list within the ‘Present/Proposed’ section of the

application form all changes introduced to the CEP with revisions 01 and 02.

7.2.5. What is considered to be a non-significant or an obsolete in-process control, specification attribute or acceptance criteria? (Classification category Q.I.a.4.c, Q.I.b.1.d, Q.I.c.2.c, Q.II.b.5.c, Q.II.c.1.c, Q.II.d.1.d and Q.II.e.4.c) Rev. Nov 2025

Variation scopes Q.I.a.4.c, Q.I.b.1.d, Q.I.c.2.c, Q.II.b.5.c, Q.II.c.1.c, Q.II.d.1.d and Q.II.e.4.c of the EC 'Variations Guidelines 2025 ’, deal with the deletion of a non -significant or an obsolete in-process control (IPC) test, specification attribute or acceptance criteria. Provided all relevant conditions and documentation requirements are met, all these variations fall under the Type IA category (do-and-tell). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The variation categories listed above are intended to be used for non-significant or obsolete IPC test, specification attribute or acceptance criteria that are no longer in line with the technical and scientific progress and part of normal specifications for newer products but have remained for historical reasons in older products (e.g. description of odour and taste). It is not intended to include changes in relation to revisions of the control strategy with an intention to minimise redundant testing of parameters and attributes (critical or non-critical) that are tested at different stages during production, or cases where process/ product characterisation performed after authorisation has shown that the attribute/ parameter is non-critical. Such changes require regulatory assessment and are to be handled as Type IB or II variations as appropriate.

7.2.6. Which variation category should be used to remove/replace the Rabbit Pyrogen test from marketing authorisation dossiers? NEW Nov 2025

Please refer to the EMA’s webpage of ‘ Quality of medicines questions and answers: Part 1 - European Pharmacopeia (Ph. Eur.) - Phasing out Rabbit Pyrogen Test ’.

7.2.7. When applying for a new pack size, what is considered to be within /outside range? (Classification category Q.II.e.6) Rev. Nov 2025

The introduction of a new pack size (i.e. in addition to currently approved pack sizes) should be submitted as a variation scope Q.II.e.6.a.

A range is defined from the smallest to the largest approved pack size (i.e. not from ‘0’) for the same

pharmaceutical form and strength. The pack size equals to the number of units of the pharmaceutical form (e.g. tablets, sachets, ampoules, etc.) contained in the outer packaging. Pack sizes not included within this range are considered to be outside of the range.

For the addition of a new pack size where the number of units of the pack is within the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a Type IA IN variation Q.II.e.6.a.1.

For the addition of a new pack size where the number of units of the pack is outside the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a Type IB variation Q.II.e.6.a.2.

In support of a timely introduction of new pack sizes to the market, EMA accepts the following approach for the introduction of various pack sizes falling outside the range within a single grouped submission. The biggest or the smallest pack size per strength outside the range should be classified as Type IB variation Q.II.e.6.a.2. This presentation defines the new limits of the range so that any intermediate pack size for the strength and pharmaceutical form can be classified as Type IA IN

variation Q.II.e.6.a.1.

Example 1

The “Medicinal Product A” has currently two approved pack sizes of 30 and 60 tablets for the

pharmaceutical form “film coated tablets” and the strength “20mg” and the MAH intends to apply for

two new pack size(s) of 90 and 120 tablets at the same time.

The introduction of a new pack size of 120 tablets for the “20mg” strength is considered outside the

range of packs and should be classified as variation Q.II.e.6.a.2 (IB). This pack size defines a new limit for the range (30-120), so that the introduction of a pack size of 90 tablets as a grouped (or a latter) submission can be classified as a variation Q.II.e.6.a.1 (IAIN). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The MAH should therefore apply for a grouped variation of 1 x Type IB - Q.II.e.6.a.2 variation and 1x Type IA IN Q.II.e.6.a.1 variation.

Example 2

The “Medicinal Product B” has currently two approved pack sizes of 2 and 10 pre -filled syringes for the

pharmaceutical form “solution for injection” for both strengths of “20mg” and “40mg”. The MAH is

applying for four new pack sizes: 5 prefilled syringe s for the “20 mg” strength; 30 pre -filled syringes

for the “20 mg” strength; 5 prefilled syringes for the “40 mg” strength; 30 pre -filled syringes for the

“40 mg” strength.

For the “20mg” strength, the introduction of a new pack size of 5 pre -filled syringes strength is considered within the range of approved packs (2-10) and should be classified as variation Q.II.e.6.a.1 (IA IN ) and the introduction of a new pack size of 30 pre-filled syringes is considered outside the range of approved packs (2-10) and should be classified as variation Q.II.e.6.a.2 (IB).

For the “40mg” strength, the introduction of a new pack size of 5 pre -filled syringes strength is considered within the range of approved packs (2-10) and should be classified as variation Q.II.e.6.a.1 (IA IN ) and the introduction of a new pack size of 30 pre-filled syringes is considered outside the range of approved packs (2-10) and should be classified as variation Q.II.e.6.a.2 (IB).

The MAH should therefore apply for a grouped variation application under the scopes referred above.

It should be highlighted, that for variations introducing additional presentations or pack sizes for centrally approved products, each additional presentation or pack size should be declared as a

separate variation on the variation application form under the section ‘variations included in this

application’.

Changes to strength, pharmaceutical form and route of administration are to be submitted as an Extension of a marketing authorisation.

For additional guidance on changes to an existing presentation that can trigger new EU number(s) please see the EMA post-authorisation guidance for Type IA, Type IB and Type II variations.

7.2.8. How should I submit a new working cell bank (WCB)? (Classification category Q.I.a.2 a) Rev. Nov 2025

If a new WCB is introduced using the limits/conditions as detailed in an approved qualification protocol, the new WCB is covered by the existing quality assurance system and there is no need to submit a variation.

If the documentation of the WCB in the dossier does not include an approved qualification protocol for introducing new WCBs, the MAH should file a Type IB variation under Q.I.a.z.

To introduce a qualification protocol for preparation of a new WCB, the MAH should file a variation Type II Q.I.a.2.b. The addition of the new WCB can be covered as part of this single variation Type II.

Changes to an approved qualification protocol should be filed using Q.I.a.2.a, or Q.I.a.2.b, as relevant depending on the complexity of the change. The addition of a new WCB can be covered as part of this single variation. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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7.2.9. How should I submit a new in-house reference standard/preparation for a biological medicinal product or excipient? Rev. Nov 2025

If a new in-house reference standard/preparation for a biological active substance, excipient and/or finished product is introduced using the limits/conditions as detailed in an approved qualification protocol, the new in-house reference standard/preparation is covered by the existing quality assurance system and there is no need to file a variation.

For other changes to an in-house reference standard/preparation for a biological active substance, excipient and/or finished product, classification scopes under Q.I.b.3 should be used.

7.2.10. What changes in manufacturing sites, buildings and rooms are covered by the company Quality Assurance System (GMP)? Rev. Nov 2025

Provided that module 3 is not impacted, with the exception of section 3.2.A.1 (for biological medicinal

products), the changes listed below (not an exhaustive list) are covered under the company’s quality

management system and do not require a variation to the Marketing Authorisation:

• Transfer of a manufacturing activity from one building to another in the same authorised site

• Transfer of a manufacturing activity from one room to another in the same authorised building

• Transfer of QC activity from one building to another in the same authorised site

• New filing line identical to an already approved one in an authorised room, building, manufacturing site (in case of a duplication of line to increase the batch size of the final product, a variation under Q.II.b.4 should be submitted).

• New isolator in an authorised building

• New media or buffer preparation room in an authorised building

• Changes in the layout of an authorised manufacturing site

If as a result of any of the changes listed above, any amendments are introduced to module 3 (with the exception of section 3.2.A.1 for biological medicinal products), such as changes to the manufacturing site address detail, changes to the manufacturing process, changes to the batch size, etc., the MAH should file the appropriate variation(s).

7.2.11. Changes in equipment used in the manufacturing process. What changes are covered by the company Quality Assurance System (GMP)?

Rev. May 2018

Provided that the new equipment is equivalent to the one currently used, and operates in the approved

range of process parameters, the change is covered by company’s quality assurance system.

If the introduction of new equipment has any impact on the processes and details registered in module 3 (with the exception of section 3.2.A.1 for biological medicinal products), the MAH should submit the appropriate variation(s). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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7.2.12. How should I update section 3.2.A.1 for Biotech medicinal products? Rev. Nov 2025

Notice to applicants for Medicinal products for human use (Eudralex – Volume 2B) establishes that information on facilities and equipment should be included in Appendix 3.2.A.1 for biotech medicinal products.

Any update of this section can be included as part of any upcoming variation affecting Module 3. In case the MAH wants to update this section and does not foresee any upcoming variation affecting Module 3 in the short/medium term, the MAH may consider submitting a Type IB variation (Q.II.z).

7.2.13. What do I need to consider if there are any changes to my medical device post-authorisation? Rev . Nov 2025

Information on the lifecycle management of a medical device when used in combination with a

medicinal product can be found in ‘Questions & Answers for applicants, marketing authorisation holders

of medicinal products and notified bodies regarding medicines used in combination with medical

devices and consultation procedures for certain medical devices’.

7.2.14. How should I submit the transfer of test methods for testing of medicinal products to a new or already authorised testing site? Which variation classification category is applicable and what type of supporting documentation is expected? Rev. Nov 2025

Although, the need to submit a variation to approve an existing QC testing site for additional testing activities after analytical test transfer has been completed is not specifically foreseen by the EC Variation Classification Guideline submission of a variation following by analogy the existing foreseen variation category Q.I.a.1.i, Q.I.a.1.j, Q.II.b.2.a, Q.II.b.2.b, Q.II.b.2.c.2 or Q.II.b.2.c.3 may be necessary as outlined below under ii.

i. In case of physical, chemical and microbiological test methods to be transferred to a new

testing site (i. e. not yet listed in the dossier) submission of a variation is required (category Q.I.a.1.j, Q.II.b.2 or Q.II.b.2.c.2). The documentation to be submitted is defined in the EC Variation Classification Guideline.

ii. In the case of biological, immunological, or immunochemical test methods (e.g. in vivo bioassays, in vitro bioassays, enzymatic assays, binding assays, neutralisation assays, immunochemical assays) to be transferred to a new testing site or to an already approved

testing site, a variation of Type Q.I.a.1.i or Q.II.b.2.b or Q.II.b.2.c.3 is to be submitted.

The documentation should include at a minimum, the method transfer protocols in accordance with Eudralex Volume 4 Chapter 6 article 6.39 (which pre-define the acceptance criteria), from the old site to the new site (or new test laboratory). Depending on the variability of the specific method and the potential risk, to the quality, safety or efficacy of the product, posed by the proposed change, additional data such as a summary of the analytical method transfer test results may be required.

7.2.15. Do I need to record in the dossier a new manufacturing site for physical importation? NEW Mar 2021

The Member States shall ensure that the import of medicinal products into their territory is subject to an authorisation in accordance with Article 40(3) of Directive 2001/83/EC. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Please note that physical importation and batch certification of imported products are different operations that can take place at the same or different authorised manufacturing sites located in the in Union (EEA).

It is not a requirement to register in the dossier of your marketing authorisation the manufacturer(s) responsible for the physical importation of the finished product, hence no variations applications are required for changes in physical importation sites. The Manufacturing and Importation Authorisation (MIA) holder responsible for batch certification of imported medicinal products should ensure that the site(s) of physical importation is appropriately authorised for this operation. The physical importer needs to hold a MIA with an entry in section 2.3.1 according to the Union Format for MIAs. A technical agreement between the physical importer and the batch release site shall be in place. For more information on the certification by a QP and on batch release in the EU, also with regards to importation, see GMP annex 16.

7.3. (Non-) Clinical changes Rev. Nov 2025

7.3.1. What should I consider in relation to the quality documentation in case of a change in the clinical use of marketed products meaning change in therapeutic indication, posology or maximum daily dose (MDD)? NEW Nov 2025

In case of a change in the clinical use of marketed products, meaning change in therapeutic indication (including a change in the target population), posology or maximum daily dose, a review of the quality documentation should always be performed. In this review the MAH should perform an assessment of the impact on the quality documentation of the proposed clinical change. Confirmation that the assessment has been performed should be included as part of the clinical variation. This also applies to generic products and hybrids.

The review performed by the MAH on the quality documentation could lead to the following scenarios:

• The submission of a quality variation is not required (e.g. the change in MDD does not affect the authorised acceptance criteria and control strategy for impurities). A declaration confirming the conclusions of the assessment needs to be included in the Application Form or as a separate Annex in Module 1.

• The submission of the appropriate quality variation under the Quality Changes chapter is needed (e.g. acceptance criteria for an impurity should be changed). A quality variation should be submitted under the appropriate classification according to the Variation classification guideline and grouped with the clinical variation.

For both scenarios non-exhaustive examples are given below:

1. Changes to the clinical use of marketed products can warrant a re-evaluation of the mutagenic

impurity limits:

a. An increase in clinical dose, e.g. changes in the MDD could impact the authorised control strategy for mutagenic impurities, including N-nitrosamines, in active substances and medicinal products. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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b. An increase in duration of use, e.g. when a mutagenic impurity was controlled above the lifetime acceptable intake for a previous indication that may no longer be appropriate for the longer treatment duration associated with the new indication.

c. A change in indication from a serious or life-threatening condition where higher acceptable intakes were justified to an indication for a less serious condition where the existing mutagenic impurity acceptable intakes may no longer be appropriate, e.g. for products initially intended for advanced cancer only as defined in the scope of the ICH S9 guideline, where N-nitrosamine impurities controlled according to ICH Q3A(R2) and ICH Q3B(R2) guidelines is no longer applicable.

1. Changes to the clinical use of marketed products can warrant a re-evaluation of organic impurities limits according to ICH Q3A and Q3B guidelines since reporting, identification and qualification threshold are established based on the MDD.

2. Changes to the clinical use of marketed products can warrant a re-evaluation of elemental

impurities , as individual permitted daily exposures (PDEs) are set based on the MDD and the route of administration, according to ICH Q3D.

1. Changes to the clinical use of marketed products can warrant a re-evaluation of endotoxins limits for parenteral products considering the calculation formula included in European pharmacopoeia General chapter 5.1.10.

2. Changes to the clinical use of marketed products can warrant a re-evaluation of the appropriateness of the pharmaceutical form, container closure system or dosing devices

where a new target population is applied for (e.g. paediatric population, home versus hospital

setting); refer to question on ‘ Will I need to provide a (new or updated) EU declaration of conformity/certificate of conformity issued by a notified body/notified body opinion if there are changes to the device (or device part) after the initial marketing authorisation of the integral DDC?’ in ‘Questions & Answers for applicants, marketing authorisation holders of medicinal

products and notified bodies with respect to the implementation of the Regulations on medical devices and in vitro diagnostic medical devices (Regulations (EU) 2017/745 and (EU) 2017/746) ’.

1. Changes to the clinical use of marketed products can warrant a re-evaluation of the compatibility studies with reconstitution diluents in the extremes of concentration of the product to be administered due to a change in the posology/target population.

2. Changes to the clinical use of marketed products can warrant a re-evaluation of instructions for administration and the feasibility of dosing (e.g. with regards to volumes to be measured, measuring device to be included or recommended, and dilutions to be used).

3. Changes to the clinical use of marketed products can warrant a re-evaluation of the excipient safety and the need for excipient warnings, as excipient safety should be based on daily exposures (mg/kg), which are set based on the MDD and the route of administration. Excipient safety should also consider target population, changes in age range, in particular where younger subsets are included.

7.3.2. How should I submit a study protocol? Rev. Nov 2025

For imposed, non-interventional safety studies, the initial protocol submission should follow the provisions under Article 107n of Directive 2001/83/EC. Substantial amendments of such study protocol should be submitted under the provision of Article 107o of Directive 2001/83/EC (please also refer to guidance on PASS). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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For other studies (i.e. non-imposed studies and/or interventional studies), if the initial assessment or the amendment of a study protocol does not result in a consequential change of the condition as reflected in Annex II and/ or the description of the study in the RMP it can be provided as a post-authorisation measure (PAM) (please also refer to the EMA guidance on post-authorisation measures:

‘Under which procedure should I submit my PAM? ).

Once agreed, the MAH can take the opportunity of a regulatory procedure affecting the RMP to include the final updated protocol in the appropriate RMP annex(es).

If the study description in the Annex II condition and/ or in the RMP is affected, the study protocol/ or the protocol amendment together with the proposed updated Annex II and/or RMP should be provided as part of a Type II variation application under category C.9.c.

A change that affects the due date of the milestones for non-imposed studies and/or interventional studies listed in the Annex II and/or RMP can be submitted as Type IB variation under category C.9.b.

7.3.3. How should non-clinical and/or clinical study reports be provided? Rev. Nov 2025

In line with the 'Variations Guidelines’ all ‘final’ non -clinical or clinical study reports concerning a marketing authorisation granted under the centralised procedure will have to be submitted to the Agency as part of a Type II variation application, unless otherwise specifically covered in the annex to the classification guideline on variations or listed below:

• Results of imposed non-interventional safety studies covered by the Art. 107q of the Directive 2001/83/EC;

• Submissions of final study results in support of extension of marketing authorisation applications, annual renewals or annual re-assessments;

• Submission of study results related to paediatric population in line with Article 46 of Regulation 1901/2006. Submissions pursuant to Article 46 should continue to follow the procedure for post-authorisation measures, unless the MAH concludes that changes to the product information (PI) are warranted based on the data submitted. In such cases, the relevant variation should be submitted;

• Studies in the context of an environmental risk assessment (ERA). These are expected to be assessed during the initial marketing authorisation or relevant post-marketing procedures (e.g. extension of indication, extension applications). In the exceptional case that ERA study results are provided stand-alone, they should be submitted as a Type IB C.z variation;

• Results including reports from bioequivalence studies to support quality changes to the marketing authorisation should be submitted under the applicable variation category for quality changes.

As a general rule, the ‘final’ study report is considered the one including the primary analysis of the

study. In case the final study report has previously been submitted, further updates of data from the study without formal statistical significance after the primary analysis do not trigger additional variations, unless they lead to changes to the product information and/or to the Risk Management Plan (RMP). On the other hand, a formal extension study, generally with a different study design and objectives as compared to the initial study, is considered a separate study and it generally carries a separate study number. The submission of the final report for such an extension study triggers a variation. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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When a change to the product information is proposed as a consequence of the final study report, the Type II variation should be submitted under variation classification categories C.a (extension of indication), C (other changes involving the SmPC, Annex II, labelling and/or Package Leaflet) or C.9.c (changes limited to the Annex II conditions). When no changes to the product information are proposed, the variation should be submitted under category C.12.

When a final non-clinical or clinical study report is provided as part of a variation submitted under category C.12, it should be noted that one separate Type II variation per study report is required. This requirement applies also in situations where the CHMP has requested several non-clinical or clinical studies to be undertaken as part of a specific post-authorisation measure (PAM) in order to address a specific issue; one Type II variation under category C.12 per final study report will still be requested (provided that the product information remains unaffected).

It should be noted that these requirements also apply to all non-clinical studies, including the provision of final study reports for in vitro studies.

In case the final non-clinical or clinical study report leads to consequential changes to the RMP, the MAH can include an updated RMP version as part of the Type II variation regardless of whether it is submitted under category C.6, C.4, C.9 or C.12.

With regard to ‘interim’ non -clinical or clinical study results, the timelines of the progress reports for a given study should be pre-specified and indicated in the protocol. These progress reports may include available interim results, but there is in general no obligation or recommendation to include interim results in RMPs unless required as part of an agreed pharmacovigilance plan. In this case, for CAPs, the specified progress report(s)/interim results should be submitted as PAM unless the MAH considers that the interim data would require consequential changes to the product information and/or the RMP in which case a Type II variation should be submitted instead. On the other hand, interim results should be reported in relevant PSURs.

When interim results have been requested by the CHMP and are provided in order to address a specific post-authorisation measure (PAM), the data should be submitted in line with the requirements of the PAM procedure, unless the MAH considers that the interim data result in consequential changes to the product information and/or the RMP in which case a Type II variation should be submitted instead.

With reference to analyses across studies on specific topics (e.g. a biomarker report from more than one study) for which the individual final study reports have previously been submitted, the analysis should be submitted under category C.4 (in case of changes to the product information), under category C.9 (changes limited to the Annex II conditions) or as a PAM (no changes to the product information and/or the RMP are warranted). When the analyses should be submitted as variations, one variation scope per analysis (and not per study included in the analysis) should be submitted.

Final results from an imposed non-interventional post-authorisation safety study (PASS category 1 and 2 in the RMP, and reflected in Annex II) should be submitted within 12 months of the end of data collection unless a written waiver has been granted by PRAC, as appropriate (please refer to guidance on imposed post-authorisation safety studies). It should be noted that the submission of final results of imposed non-interventional studies should follow the relevant Art 107q of Directive 2001/83/EC procedure (please also refer to guidance on post-authorisation safety studies), regardless of whether or not the MAH considers that changes to the product information are warranted.

When a change to the product information is proposed for a medicinal product containing more than one active substance to implement changes that were already assessed by a EU competent authority European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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for a medicinal product containing one of the active substances and the same wording is proposed, the change and supportive data should be submitted as a Type II variation under category C.4.

Any pre-submission queries in this regard should be addressed to the Product Lead.

7.3.4. What changes to the product information (PI) can be included as part of one Type II variation? Rev. Nov 2025

In principle, one change to the PI supported by one set of data constitutes one assessment and subsequently one scope i.e. one Type II variation.

All data/study reports provided as part of a variation must support the same changes to the SmPC. If this is not the case, i.e. some data support one change (update A), and other data support another change (update B), it will be necessary to submit separate stand-alone variations or a group of variations, as appropriate; one variation for SmPC update A including the data supporting A, and one variation for SmPC update B including the data supporting B.

In the event that some of the data/study reports proposed to be part of an application do not support any of the proposed changes to the SmPC, the reports give rise to separate variation scopes (category C.12 – one variation per final study report as explained under ‘How should non -clinical and/or clinical

study reports be provided?’), which could potentially be grouped in the same submission or may need

to be removed from the proposed variation application and submitted as a separate appropriate application.

Thus, only when changes are consequential to the same supporting data, can one Type II variation application propose changes to several different sections of the SmPC as well as corresponding changes to the Package Leaflet. Any additional changes to the PI that are consequential to the assessment of another set of data will have to be submitted as part of a separate variation (stand-alone or part of a grouped application to be decided on a case-by-case basis).

Some theoretical examples are being provided below to illustrate the principles explained above.

Example 1

Proposed application: Provision of final clinical study reports (CSR) for 3 PK studies (studies X, Y, Z).

• If the data from the 3 CSRs support the same SmPC updates, the reports should be submitted as part of one single T ype II variation under category C.4 (scope = ‘update of the SmPC based on the results from studies X, Y and Z’).

• If two study reports (X, Y) support one SmPC change (update A), and the 3rd study report (Z) supports a different SmPC change, the applicant should submit one Type II variation under category C.4 for SmPC update A and one Type II variation under category C.4 for SmPC update B. The two variations can in this case be submitted as part of a grouped application, as it makes

sense to assess the 3 PK studies together (scope = ‘update A of the SmPC based on the results of

studies X and Y, and update B of the SmPC based on the results of study Z’).

• If two study reports (X, Y) support all proposed SmPC changes and the 3rd study report (Z) does not result in any consequential changes to the SmPC at all, the applicant should submit a grouped application including one Type II variation under category C.4 (studies X, Y) and one Type II variation under category C.12 (study Z). The two variations can in this case be submitted as part

of a grouped application, as it makes sense to assess the 3 PK studies together (scope = ‘update of European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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the SmPC based on the results of studies X and Y. The applicant also provides study Z as a

grouped variation as a common assessment of these changes is considered meaningful’).

Example 2

Proposed application: Provision of one CSR for study A supporting SmPC changes regarding efficacy in patient population A and overall clinical safety, and one CSR for study B supporting SmPC changes regarding efficacy in patient population B and overall clinical safety.

• In view of the fact that the efficacy data are unrelated and concern two separate patient populations, two separate assessments will need to be undertaken and two separate Type II variations will be required. However, as the scopes of the two variations are both partly related to overall clinical safety, it is meaningful to assess them together and the applicant should therefore provide the two variations as part of one grouped application.

• However, in the event that the data sets would be completely unrelated - e.g. because of different safety profiles in the two patient populations due to different posology - the reports should be provided as part of two separate stand-alone Type II variations; one for patient population A (efficacy and safety) and one for patient population B (efficacy and safety).

Example 3

Proposed application: Update of the SmPC section 4.8 in order to add three new ADRs; ‘dyspnoea’ and ‘chromaturia’ following a review of the MAH’s safety database undertaken upon request by PRAC

following a PSUSA procedure, and ‘Kounis syndrome’ following the MAH’s own signal detection.

• As the three ADRs are supported by two separate data sets the MAH should submit two variations as part of a grouped application; one Type II variation under category C.3.c to add ‘dyspnoea’ and ‘chromaturia’, and one Type II variation under category C.4 to add ‘Kounis syndrome’. Both

variations are related to clinical safety and it makes sense to assess them together hence the acceptability of the grouping.

Example 4

Proposed application: Type II variation under category C.6.a in order to propose an extension of indication, which will include both non-clinical and clinical studies.

• Provided that all non-clinical and clinical data that will be submitted as part of the application are supportive of the new claimed indication, the studies should be provided as part of the application without the need for any additional variation.

• However, in the event that e.g. one of the non-clinical studies is not supportive of the proposed extension of indication, it will need to be submitted as part of a separate variation application (stand-alone or part of a grouped application to be decided on a case-by-case basis).

Any pre-submission queries in this regard should be addressed to the Product Lead.

7.3.5. How do I submit changes to the Summary of Pharmacovigilance System for medicinal products for human use? Rev. Nov 2025

As of 1 February 2016, changes to the summary of the pharmacovigilance system – changes in QPPV (including contact details) and/or changes in the Pharmacovigilance Master File (PSMF) location are to European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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be notified to the authorities through the Art 57 database only without the need for any further variation.

Upon a change in the QPPV or location of the PMSF, the Art 57 database should be updated by the MAH immediately to allow continuous supervision by the Competent Authorities.

Please also refer to Question How to inform the authorities of a change in the summary of the pharmacovigilance system? in the Pharmacovigilance system section of the Post-Authorisation Guidance.

References

• News Item: Regulatory information – Green light for reliance on Article 57 database for key pharmacovigilance information on medicines for human use in Europe

• Art 57 Reporting requirements for Marketing Authorisation Holders

• Detailed Guidance on electronic submission of information on medicines

7.3.6. How should I submit data requested as a follow-up to a prior regulatory procedure? Rev. Nov 2025

Occasionally, the outcome of a regulatory procedure may require the MAH to follow-up on certain aspects in a subsequent regulatory submission. The type of submission required depends on the nature of the data requested and whether the implementation impacts the Product Information (PI) and/or the Risk Management Plan (RMP).

If the outcome of the prior regulatory procedure requests the submission of a (non-)clinical study report, this should always be submitted as a variation (unless this is a paediatric study submitted under Article 46 of the Paediatric Regulation (EC) 1901/2006). Any other requested information (e.g. cumulative safety review) should be submitted as a variation if it has impact for the PI or the RMP. In other cases, it can be accepted as a Post Authorisation Measure (PAM).

Similarly, if the prior procedure already recommends changes to the PI or the RMP, these should be submitted as variation, unless the MAH would like to provide a justification why such changes are not supported by the MAH. In the latter case, the rationale for not submitting a variation proposing the indicated PI and/or RMP changes and any requested data supporting the rationale can be submitted as a PAM. However, if the data requested involves the submission of a final (non-)clinical study report, a variation should always be submitted even if no changes to the PI and/or RMP are proposed (with the exception of submissions under Article 46 of the Paediatric Regulation (EC) No 1901/2006).

The classification of the variation depends on the nature of the prior procedure the outcome of which is being implemented:

• for implementation of the outcome of a Union referral procedure, the applicable variation category is C.1.

• for implementation of the outcome of a PSUR, PASS protocol or PASS results procedure, or the outcome of a PRAC signal recommendation, or to adapt to a joint recommendation of EU competent authorities, the applicable variation category is C.3. It should be noted that PI changes resulting from PSUR data should ideally be implemented within the PSUR procedure itself; only if additional data are required to support the PI changes which cannot be submitted and assessed during the PSUR procedure should a follow-up variation of the C.3 category be submitted. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• in case of a procedure under article 46 of Paediatric Regulation No (EC) 1901/2006, the applicable variation scope is C.3 only in case changes to the PI are proposed. In principle, it is expected that in most cases PI changes are to be proposed. In the exceptional case that no changes to the PI are proposed, a PAM procedure should be applied for (see also question How should non-clinical and/or clinical study reports be provided?)

• for the alignment of the PI of a generic, hybrid or biosimilar medicine to that of the reference product the applicable variation category is C.2 with the exception of the implementation of wording from PSUR and PASS procedures; the applicable scope category in such cases is C.3.

• any other prior regulatory recommendation should be implemented via: a C.4 variation category, if changes to the PI are proposed; a C.9 variation category, if changes to the conditions in Annex II of the PI or in the RMP are proposed; a C.12 variation category, if a final (non-)clinical study report is being submitted; a PAM, if a paediatric final study report is being submitted under the requirements of Article 46 of Paediatric Regulation 1901/2006 and in all other cases where requested data and analyses are being submitted without an impact to the PI (including Annex II) and the RMP (please also refer to question Under which procedure should I submit my PAM?).

7.3.7. What is considered a new or modified therapeutic indication? Rev. Nov 2025

Applications proposing changes to the therapeutic indication aiming to extend the target population (either by modifying an existing indication(s) or by extending in a completely new indication/target disease) trigger paediatric and orphan requirements (pl ease refer to questions ‘ What aspects should I consider at time of submission of a Type II variation if there are orphan medicinal products designated

or authorised for a condition related to my proposed therapeutic indication?’, ‘ Do I need to address any paediatric requirements in my T ype II variation application?’ , ‘What aspects should I consider at time

of submission of an extension application if there are orphan medicinal products designated or

authorised for a condition related to my proposed therapeutic indication?’ and ‘Do I nee d to address

any paediatric requirements in my extension application?’ in the post -authorisation guidance for Type II variations and Extension of Marketing Authorisations).

The EC Guideline on the elements required to support the significant clinical benefit in comparison to existing therapies of a new therapeutic indication in order to benefit from an extended (11-year) marketing protection and the EC Guideline on a new therapeutic indication for a well-established

substance provide a definition of what is considered a ‘new indication’. More specifically, a new (or

modified) indication is:

• a new target disease;

• different stages or severity of a disease;

• an extended target population for the same disease, e.g. based on a different age range or other intrinsic or extrinsic factors;

• a change from first-line treatment to second-line treatment (or second-line to first-line treatment), or from combination therapy to monotherapy, or from one combination therapy (e.g. in the area of cancer) to another combination;

• change from treatment to prevention or diagnosis of a disease;

• change from treatment to prevention of progression of a disease or to prevention of relapses of a disease; European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• change from short-term treatment to long-term maintenance therapy in chronic disease.

However, in some particular situations a case-by-case assessment may be needed to determine whether the target population is extended. For example, the following may not be considered a new indication:

• information on the use of the medicinal product in the authorised target diseases in patients with renal or hepatic impairment;

• information on the use of the medicinal product in the authorised target diseases in pregnant women;

• for vaccines, information on the concomitant administration with other vaccines.

In addition to applications extending the target population, orphan similarity requirements are also triggered by any extension of the Marketing Authorisation (line extension, please refer to question

‘What aspects should I consider at time of submission of an extension application if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic

indication?’).

Paediatric requirements are triggered by an extension of the Marketing Authorisation (line extension) for new pharmaceutical forms and/or new routes of administration (please refer to question ‘ Do I need

to address any paediatric requirements in my extension application?’) .

From a procedural point of view, extensions of indication can be submitted as Type II variations or extensions of the Marketing Authorisation depending on whether the change in the target population is accompanied by other changes e.g. changes to the strength, pharmaceutical form, route of

administration (please refer to question ‘Wh en will my variation application be considered a Type II

variation or an Extension application?’).

For extensions of the Marketing Authorisation, in case the change in the indication is only intended for the new pharmaceutical form/ strength being added, the extension of indication is covered by the scope of the MA extension application. In case the change(s) in the therapeutic indication also applies to existing presentations, the application should be presented as a grouping of a line extension(s) and C.6.a scope variation.

When the extension of indication is submitted as a Type II variation application, the C.6.a scope category (i.e. addition of a new therapeutic indication or modification of an approved one) typically applies. However, not all variations under the C.6.a scope category are actual extensions of indication (e.g. restrictions of an existing indication also fall under this scope category). The contrary is also the case: there are variations which aim to extend the target population, but which do not affect the wording of the approved therapeutic indication in section 4.1 of the SmPC. so the variation category is not C.6.a but rather C.4 (changes in the Product Information due to new quality, preclinical, clinical or pharmacovigilance data). Ultimately, if the ‘target population’ is extended, the orphan and/or

paediatric requirements are triggered, even though the variation may not have been submitted as a

C.6.a ‘extension of indication’.

In case of a change in therapeutic indication, a review of quality documentation should be performed. Any resulting change to the quality documentation (e.g. change to impurity limits) should be proposed with the submission of the relevant grouped quality variation. Please see also question on ‘What should

I consider in relation to the quality documentation in case of a change in the clinical use of marketed

products meaning change in therapeutic indication, posology or maximum daily dose (MDD)?’. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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7.3.8. When is the submission of assessments carried out on target patient groups in order to comply with Article 59(3) of Directive 2001/83/EC and any resulting change(s) to the Package Leaflet a stand-alone variation? NEW Nov 2025

Articles 59(3) and 61(1) of Directive 2001/83/EC, as amended, require that the package leaflet reflects

the results of consultations with target patient groups (‘user consultation’) to ensure that it is legible,

clear and easy to use and that the results of assessments carried out in cooperation with target patient groups are provided to the competent authority.

It is expected that ‘user consultation’ results in support of post -approval changes that require a

regulatory application are provided as part of the same application. However, if the ‘user consultation’

results need to be updated outside the scope of another regulatory procedure, it should be submitted as a stand-alone variation type IB, C.11.

• ‘User consultation’ results should not be provided as part of a type IA/IAIN variation. The review of

the results requires the involvement of the rapporteur as part of a type IB or type II variation.

• A stand-alone variation type IB, C.11 can be submitted both for cases where the ‘user consultation’

results affect the product information Annex III, as for cases that do not lead to an update of Annex III.

7.4. Editorial changes Rev. Mar 2026

7.4.1. What can be considered an editorial change and how can it be submitted as part of a Type IA/IB/II variation? Rev. Mar 2026

The European Commission 'Variations Guidelines’ specifies that “If amendments to the dossier only

concern editorial changes, such changes should generally not be submitted as a separate variation, but they can be included in a variation concerning that par t of the dossier”. Changes that can be classified

as a variation as per Variations Guidelines are not considered editorial changes and should be submitted under the appropriate variation category.

Editorial changes in module 3

Provided that the above condition is fulfilled, the following changes to the Module 3 may be considered editorial: adding headers for ease of use, reordering of existing information without changing the meaning, alignment of information among/within the sections provided that it can be demonstrated what is the correct reference that had been previously agreed (e.g. alignment of information in flow charts to process description), punctuation changes and grammar/orthographic corrections that do not alter the meaning of the text.

Examples of changes that cannot be considered editorial: removal of specification parameters or manufacturing description, update of information to bring the dossier content in line with the current manufacturing process, etc.

Editorial changes should always be clearly identified in the application form as follows: A brief description of the editorial changes should be provided in the Precise Scope. All the editorial changes should be listed in the present/proposed table , and a justification as to why the holder considers European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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them ‘editorial’ (i.e. why they should not trigger a specific variation) should be provided for each change.

In addition, the MAH should provide a declaration in the ‘Precise scope and background…’ section of

the application form confirming that the changes proposed as editorial do not change the content of the concerned part(s) of the dossier beyond the scope of the variation within which the editorial changes are being submitted.

The Agency strongly recommends the submission of editorial changes within procedures with an administrative validation phase e.g. Type IB or Type II variations. This allows the appropriate review of proposed editorial changes during the administrative validation phase and the consequential amendment of the submission prior to assessment, if needed. The editorial changes proposed should affect the same part of the dossier concerned by the variation procedure i.e. fourth level of the eCTD dossier ( e.g. “3.2.S.x” or “3.2.P.x” ). For example, if a variation affects section 3.2.S.2.1 editorial changes can be submitted in sections from 3.2.S.2.1 to 3.2.S.2.7.

Exceptionally, the Agency may accept minor editorial changes as part of IA variations, if affecting the same eCTD section impacted by the variation submitted (i.e. at the fifth level 3.2.S.2.1). This is due to the fact that IA notifications are of administrative nature and do not have a validation phase. In case of doubt on the acceptability of editorial changes in future Type IA applications, please contact the Agency by raising a ticket via EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post -authorisation - Human”, followed by the

sub-option: “Variation IA queries”.

If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".

MAHs are reminded to follow this guidance and ensure the high quality of variation applications in support of a timely processing of submissions.

The Agency expects MAHs to keep proportionality between the submissions of editorial changes versus the change which is the scope of the variation application. If the editorial changes affect sections in module 3 not impacted by any upcoming variation, the MAH may consider submitting these changes as a separate Type IB variation (Q.I.z or Q.II.z respectively).

Editorial changes in modules 4 and 5

Editorial changes in module 4 or 5 are in principle not foreseen.

Only in case of alignment of information within the dossier, provided that it can be demonstrated which is the correct reference that has been previously agreed, a change to a report in module 4 or 5 can be accepted as editorial and the update submitted as part of an upcoming type II non-clinical or clinical variation submitted under the C scope categories that involves the relevant committee for the specific study. If no such variation is foreseen, a type IB variation C.z can be submitted.

Other updates cannot be considered editorial and require assessment under a variation, for example correction of information in module 4 or 5, updated calculation, etc.

Editorial changes should be clearly identified in the application form as follows: A brief description of the editorial changes should be provided in the Precise Scope. The editorial changes should be listed in European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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the present/proposed table , and a justification as to why the change is editorial should be

provided .

In addition, the MAH should provide a declaration in the “Precise scope and background…’ section of

the application form confirming that the changes proposed as editorial do not change the content of the dossier beyond the scope of the variation within which the editorial changes are submitted.

Please contact the Agency in advance of an upcoming submission by raising a ticket via EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post -authorisation - Human”, followed by the relevant sub -option: “Variation IA queries” or “Variation IB queries”.

If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".

Editorial changes to the product information in module 1.3

Formatting changes, correction of typographical errors and/or mistakes to the English Product Information (PI) or translations of the Product Information are considered editorial changes provided that the meaning of the text is not altered. These changes can be included within the scope of any upcoming variation impacting the product information.

Changes in the scientific content cannot be accepted as an editorial change. These changes should be classified under the scope of the relevant variation as per Variations Guidelines (e.g. Type II C.4). If no relevant scope is available, a variation Type IB C.z may be appropriate.

Proposed changes that may require confirmation by the rapporteur or linguistic review will only be accepted by the Agency when submitted within the scope of an upcoming variation Type IB or Type II under chapter C which impacts the product information and where linguistic review is foreseen, if applicable.

Editorial changes should generally not be submitted as a separate variation and therefore no reference to a variation category is required. Should there be no upcoming variation to include the editorial changes, these could also be submitted as a stand-alone IB C.z if they affect the English SmPC. If they affect the PIL/labelling of all language versions an Art. 61(3) notification should be submitted. If other languages are affected but not the English version and in case no variation affecting the product information is upcoming, the MAHs are advised to contact the Agency to discuss how to handle these necessary changes.

The MAH should liaise with the Agency without delay if the mistake concerns an incorrect or missing important information (e.g. contra-indication or adverse event) in the EN or any of the other languages, that could affect the safe and effective use of the medicinal product and/or lead to a potential medication errors (e.g. wrong strength, wrong posology, wrong route of administration).

The editorial changes should be clearly identified in the application form as editorial changes. A brief description of the editorial changes should be provided in the precise scope of the application form. Furthermore, editorial changes should be presented in the present/proposed table or provided as a separate Annex. A statement confirming that the proposed editorial change(s) do(es) not change the content of the previously approved Product information should be provided. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Any changes proposed by the applicants as editorial will be carefully considered by the Agency at time of submission and may be subject to further assessment at the same time as the variation. Proposed editorial changes that cannot be accepted as such will be rejected. In case of doubt, applicants can contact the Agency in advance of the planned submission by raising a ticket via EMA Service Desk,

selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post -authorisation - Human”, followed by the relevant sub -option: “Variation IA queries” or “Variation IB queries”.

If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".

References

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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8. Pre-submission queries service

8.1. What is the pre-submission queries service? Rev. Jul 2025

The pre-submission queries service is a service set up to respond to pre-submission queries that marketing authorisation holders (MAHs) may have in relation to the following post authorisation procedures: Types IA and IB variations, marketing authorisation transfers, Article 61(3) notifications, PSURs for Nationally Authorised Products (NAPs), and post-authorisation safety studies (under Article 107n/q) for Nationally Authorised Products.

The service aims to provide timely regulatory procedural pre-submission guidance to MAHs to facilitate the validation of these post-authorisation applications. It allows MAHs to receive specific regulatory guidance on planned applications and to discuss any pre-submission questions with the EMA before submitting an application.

This service does not address pre-submission queries for renewal applications (including annual re-assessment and annual renewal procedures), extension applications, post-authorisation measures (PAMs) and PSUR for centrally authorised products. In case of questions for these applications, please contact the Product Lead responsible for the product.

For Type II variations, please refer to question on “Who is my contact at the European Medicines Agency during a Type II variation, including extension of indications?”.

For initial marketing authorisation applications a Product Lead is assigned at the eligibility stage of the application and can be contacted for any pre-submission queries. For further information please refer

to question on “Who is my contact at EMA during an application evaluation procedure?”.

For PSURs for Nationally Authorised Products (NAPs), and post-authorisation safety studies (under Article 107n/q) for Nationally Authorised Products please submit your query using the AskEMA feature.

8.2. How should I send queries to the pre-submission queries service? Rev. Jul 2023

You should send queries by raising a ticket via the EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post -authorisation -

Human”, followed by the applicable sub-option:

• for Type IA variations: “Variation IA queries ”

• for Type IB variations: “Variation IB A&B scopes queries ” or “Variation IB C scopes queries ”

• for Marketing authorisation transfers: “MAH transfer queries ”

• for Article 61(3) notifications: “Article 61(3) notification queries ”

• for new EU numbers : “New EU number request ”

• for Article 5 procedures : “Article 5 procedure request ”

If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account". European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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To help the service deal with your query, please provide as much relevant information as possible in your correspondence, not forgetting to include the name of the product.

If you are uncertain about the type of intended submission, send your query using the sub-option most likely related to your procedure. If the pre-submission query is related to more than one procedure (e.g. both a Type IA and Type IB variation), please only raise one ticket. We will provide a consolidated response.

The pre-submission queries service should always be the first point of contact for the above-mentioned procedures, including for products with a high number of upcoming post-authorisation procedures requiring detailed discussion where the product team would be involved. For PSURs for Nationally Authorised Products (NAPs), and post-authorisation safety studies (under Article 107n/q) for Nationally Authorised Products please submit your query using the following web form (https://www.ema.europa.eu/en/about-us/contact/send-question-european-medicines-agency).

8.3. How will my query be handled by the pre-submission queries service?

A team of procedure managers with in-depth regulatory knowledge of procedures monitors all queries we receive. Your query will be assigned to a procedure manager specialising in the procedure concerned by your query. An internal peer review process of the response is in place to ensure consistency in the advices provided.

Queries received & advice provided to the MAHs are also recorded to ensure consistency of the responses provided and identify areas for improvement of the existing post-authorisation guidance published on the Agency website.

8.4. When can I expect to receive a response to my query? Rev. May 2020

The procedure manager will endeavour to send a response within 10 working days of the receipt of the query. You will receive along with your response the contact details of the procedure manager who handled your query in case you need further clarification, such as teleconference, related to the same query.

For complex queries where more internal consultation than usual is required, it may take more than 10 days to send a response. In those cases, you will be informed of the extra consultation and of the delay in sending you a response. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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9. Changing the (Invented) Name of a Centrally Authorised Medicinal Product

9.1. Can I change the (Invented) Name of my CAP? Rev. Nov 2025

A medicinal product is authorised under the Centralised Procedure with a single name. In accordance with Commission Regulation (EC) No 1234/2008, the (invented) name of a medicinal product may be changed after authorisation through a Type IA IN Variation (No A.2-/E.1).

This can be done either in case of a marketing authorisation being granted under INN (common name) together with a trademark or the name of the MAH or in case the MAH wants to change the initial invented name.

Such a Type IA IN variation is possible provided that the check by the Agency on the acceptability of the new name had been finalised and was positive before implementation of the new name. Immediately upon implementation of the change, the MAH must submit a Type IA IN variation notification to the Agency for review (see PAG on Type IA variations).

References

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• Guideline on the acceptability of invented names for human medicinal products processed through the centralised procedure

9.2. Is the Invented Name (IN) checking procedure mandatory for the new proposed IN? Rev. Oct 2013

The checking procedure for the proposed IN is mandatory and is the same as that applied for new medicinal product applications, as described in the Agency pre-submission guidance (see also How will I know if the proposed (trade) name of my medicinal product is acceptable from a public health point of view?).

Therefore, Marketing Authorisation Holders are advised to submit the new proposed IN at the latest 4-6 months prior to their intended implementation of the new name and Type IA IN variation application since a final positive outcome of the checking procedure is required before implementation and submission of the Type IA IN Variation.

In order to enable applicants to propose names that will be acceptable for centrally approved medicinal

products, it is crucial that the “Guideline on the acceptability of invented names for human medicinal

products processes through the centralised proced ure” (CPMP/328/98), is followed.

References

• Commission Regulation (EC) No 1234/2008

• Guideline on the acceptability of invented names for human medicinal products processed through the centralised procedure European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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9.3. How shall I present my IN change application? Rev. Nov 2025

The application will follow the standard Type IA variation dossier requirements as described in this

guidance: See “How shall I present my Type IA Variation Notification”. In addition, Module 1.2 should

contain a copy of the Agency’s letter of acceptance of the new name. More information is available on

‘Submitting a post -authorisation application’.

References

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

• Electronic Variation application form

• Variation application form, The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2C

• Guideline on the acceptability of invented names for human medicinal products processed through the centralised procedure

9.4. Do I need to submit amended mock-ups/specimens with my variation? Rev. Oct 2013

For information concerning submission of mock-ups and specimens in the framework of post-authorisation procedures, please refer to checking process of mock-ups and specimens of outer/immediate labelling and package leaflet of human medicinal products in the centralised procedure, 3.4 other post authorisation procedures.

References

• Checking Process of Mock-Ups and Specimens of outer/immediate labelling and package leaflets of human medicinal products in the Centralised Procedure (EMEA/305821/2006) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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10. Annual Re-assessment

10.1. What is the annual re-assessment? Rev. Dec 2015

In exceptional circumstances and following consultation with the applicant, an authorisation may be granted subject to certain conditions, so called specific obligations (SOBs), in particular relating to the safety of the medicinal product, notification to the national competent authorities of any incident relating to its use, and action to be taken.

Such a marketing authorisation may only be granted when the applicant can show that they are unable to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use and must be based on one of the grounds set out in Annex I of Directive 2001/83/EC (rarity of the condition, state of scientific knowledge, ethical grounds).

Continuation of such a marketing authorisation shall be linked to the annual re-assessment of the conditions mentioned above. The SOB(s) may include an identified programme of studies to be conducted within a specified time period and aim at the provision of additional safety and efficacy data, e.g. a registry or an observational cohort study, where data is collected and reported annually based on an agreed protocol.

The outcome of the annual re-assessment will reflect the status of fulfilment of the SOB(s) and the impact of the SOB data on the benefit / risk profile of the medicinal product and will conclude on whether the marketing authorisation should be maintained, varied or suspended based on the review of these two elements.

References

• Directive 2001/83/EC, Article 22 and its Annex I, Part II.6

• Regulation (EC) No 726/2004, Article 14(8)

• Guideline on procedures for the granting of a marketing authorisation under exceptional circumstances

10.2. Are the CHMP Co-Rapporteur and the PRAC involved in the assessment? Rev. Apr 2021

The CHMP Co-Rapporteur is not systematically involved in the evaluation of the annual re-assessment application. The PRAC is systematically involved in the assessment and will focus on the assessment of the SOB data and any methodological aspects of the generation of these data in case they are falling within the definition of a non-interventional post-authorisation safety study (PASS). In this case the PRAC provides its expertise to the CHMP in terms of the assessment of the non-interventional PASSs and any potential changes to additional pharmacovigilance and risk minimisation activities proposed in the Risk Management Plan.

Note: For ATMP products, the CAT is the lead committee for the assessment of this type of products. References to the CHMP should be understood as CAT for ATMPs. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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10.3. How shall I present my annual re-assessment application? Rev. May 2020

Annual re-assessment applications should be presented as indicated below, in accordance with the appropriate headings and numbering of the EU-eCTD format.

In order to ensure that annual re-assessment applications are complete and correct before submitting them to the Agency, it is strongly recommended to use the pre-submission checklist for annual re-assessment of an MA under exceptional circumstances applications.

Module 1: 1.0 Cover letter with the following documents attached:

• A chronological tabulated summary table of the SOBs stating the following for each: description, reference number (preferably SIAMED number), due date indicated in Annex II of the Product Information, date of submission and procedure within which the SOB was submitted (if appropriate), and status.

• Revised list of pending SOBs (where applicable).

• A present/proposed table listing any changes introduced to the product information (incl. any minor linguistic amendment introduced for each language), if applicable.

The cover letter should indicate the time period covered by the annual re-assessment application.

In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file UI .

Note: The Cover Letter should be signed by the person designated as MAH contact with the EMA. The Annual Re-Assessment application is not an opportunity to notify the Agency of changes in contact person, which should be notified separately. More

information is available on ‘Contacting EMA: post -authorisation’.

1.3 Product Information

1.3.1 Summary of Product Characteristics, Labelling and Package Leaflet

• If no changes to the PI (SmPC, Annex II, outer/inner labelling and Package Leaflet) are proposed by the MAH, clear reference to it should be made in the cover letter.

• If changes to the PI are proposed as part of the Annual Re-Assessment, a version of the PI in English, highlighting the changes proposed by the MAH

should be provided in the eCTD and Word format. In addition, a ‘clean’ version

of the PI should be provided in the eCTD and in Word format.

• Note: All other language versions are only to be submitted after adoption of the opinion (See also question - “When do I have to submit (revised) product information? In all languages?”)

The Annexes provided should only reflect the changes introduced by the Annual Re-Assessment. However, if the PI update is already warranted by the annual re-assessment data, the MAH can also take the opportunity to implement changes due European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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to the revision of the SmPC guideline, other relevant guidelines impacting on the product information, or EMA/QRD product information templates and minor linguistic amendments. This should be clearly mentioned in the cover letter and list of such changes provided as an attachment to the cover letter. Any changes not listed will not be considered as part of the application.

1.4 Information about the Expert

1.4.3 Information about the Expert – Clinical (incl. Signature + CV)

1.8.2 Risk Management Plan

If an update of the RMP is proposed by the MAH as a consequence of SOB data submitted with the annual re-assessment application, section 1.8.2 should contain the

updated RMP (‘clean’ version). A version of the RMP, highlighting the changes

proposed by the MAH should also be provided in Word format.

Module 2: 2.5 Addendum to Clinical Overview

The Expert report addressing the data as well as the status of fulfilment of the SOBs and their impact on the overall benefit/risk balance of the medicinal product, in the form of a Clinical Overview update or addendum, based on the following structure (headings):

• Summary of information previously submitted to address ongoing SOBs

• Data submitted with the annual re-assessment to address outstanding SOBs

• Critical evaluation of status of fulfilment of each pending SOB

Clinical summaries and clinical study reports should not be included in section 2.5 but in the respective dedicated eCTD sections; see below.

2.7 Clinical Summaries

Clinical summaries will generally need to be updated, as appropriate, when new clinical study reports are submitted.

Module 5: 5.3.5 Reports of Efficacy and Safety Studies (as appropriate) submitted to fulfil SOBs:

5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

5.3.5.2 Study Reports of Uncontrolled Clinical Studies

5.3.5.3 Reports of Analyses of Data from More Than One Study

5.3.5.4 Other Clinical Study Reports

References

• Directive 2001/83/EC, Article 22 and its Annex I, Part II.6

• Regulation (EC) No 726/2004, Article 14(8)

• The EU Harmonised Technical eCTD Guidance European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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10.4. Can I submit a PSUR with my annual re-assessment application? Rev. Dec 2015

PSUR cannot be submitted within the annual re-assessment application.

10.5. Can I submit an RMP with my annual re-assessment application? Rev. Aug 2017

If SOB data submitted with the annual re-assessment warrant an RMP update, an updated RMP should be submitted. In such cases, it is recommended to liaise with the Agency in advance of the planned submission to agree on the details of such an update. When updates to the RMP are not warranted by newly submitted SOB data, an RMP should not be submitted within the annual re-assessment application.

If an updated RMP is already warranted as a consequence of the annual re-assessment data provided, some additional changes to the RMP may also be included in that RMP update (for further guidance

please see question “Which changes can be included in an RMP update without the need for an

additional variation?”).

10.6. When, how and to whom shall I submit my annual re-assessment application? Rev. Jun 2022

When: The annual re-assessment application should be submitted on the anniversary date of the Commission Decision granting the Marketing Authorisation. Flexibility in the submission date could however be envisaged, in order to synchronise the annual re-assessment submission with the submission of data from the SOBs. The annual re-assessment application submission could be adjusted within a maximum of +/- 2 months in such cases. The DLP of the annual re-assessment should not exceed 70 days prior to the submission.

Marketing Authorisation Holders are therefore advised to discuss and agree the annual re-assessment submission date with the Agency and the Rapporteur well in advance of the submission.

The MAH shall submit the annual re-assessment application at the latest by the recommended submission dates published on the EMA website. See also Human Medicines – Procedural Timetables / Submission dates).

How and to whom : More information is available on ‘Submitting a post -authorisation application.’

Identical annual re-assessment applications for multiple Marketing Authorisations must be submitted separately. Each Marketing Authorisation is considered to be a stand-alone dossier. For this reason, no cross-references will be accepted and applications must be submitted for each concerned product as a complete and stand-alone document. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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10.7. How shall my annual re-assessment be handled (timetable)? Rev. Apr 2021

The EMA will acknowledge receipt of a valid application of an annual re-assessment and shall start the procedure in accordance with the recommended starting dates published on the EMA website.

The submission deadlines and full procedural detailed timetables are published as a generic calendar on the EMA website (see: submission deadlines and full procedural timetables).

The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

The annual re-assessment procedure will involve the CHMP and the PRAC.

The following timetable shall apply:

DAY ACTION

Day 1 Start of procedure (see published dates on EMA website)

Day 60 Receipt of CHMP Rapporteur and PRAC Rapporteur Joint Assessment Report.

Circulation CHMP and PRAC members.

Day 66 Comments from CHMP and PRAC members on the Joint Assessment Report.

Day 73-76 Discussion at PRAC Meeting (if required).

Day 90 At CHMP: - If no outstanding issues: adoption of opinion. - If outstanding issues: adoption of List of Outstanding Issues + decision on possible oral explanation by MAH

Day 91 MAH provides answers to list of outstanding issues to CHMP /PRAC Rapporteurs, CHMP/ PRAC members and EMA.

Day 96 CHMP Rapporteur and PRAC R apporteur Joint Assessment Report.

Circulation CHMP and PRAC members

Day 98 Comments from CHMP and PRAC members on the Joint Assessment Report

Day 103-106 Discussion at PRAC (if required)

Day 120 Adoption of CHMP opinion / possible oral explanation by MAH

Note: For Advanced Therapy Medicinal Products (ATMPs), the CAT is the lead committee for the assessment of this type of products (see: Timetable: Annual reassessment – ATMP).

10.8. What could be the outcome of my annual re-assessment? Rev. Dec 2015

Depending on the assessment, one of the following outcomes can be envisaged: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Maintenance of the MA considering that:

– SOBs remain in place unchanged

– Data from the SOBs do not require changes to the MA (e.g. changes to benefit risk profile of medicinal product and product information)

All SOBs will be reviewed again at the time of the following annual re-assessment together with their impact on the benefit/risk profile of the medicinal product.

• Variation of the MA considering that:

– SOBs need to be modified; and/or

– Data from the SOBs warrant changes to the MA (e.g. changes to benefit risk profile of medicinal product and/or product information)

All SOBs will be reviewed again at the time of the following annual re-assessment together with their impact on the benefit/risk profile of the medicinal product.

• Suspension/revocation of the MA considering that:

– Data from the SOBs affect the benefit/risk profile of the medicinal product to the extent it warrants the suspension/revocation of the MA for the medicinal product

or

– The status of compliance with the SOBs is unsatisfactory and it is therefore considered that conditions to the marketing authorisation have not been fulfilled.

• Exceptionally, the CHMP may consider that all specific obligations have been fulfilled and comprehensive data on the efficacy and safety of the product is available. In such cases the CHMP may recommend granting a Marketing Authorisation not subject to specific obligations.

The Agency will subsequently forward the opinion to the European Commission, the Member States, Norway and Iceland and the Marketing Authorisation Holder together with the CHMP assessment report. The Decision-Making Process of the European Commission starts once the opinion with annexes in all official EU languages has been received.

When the annexes to the Marketing Authorisation have not been affected by the annual re-assessment, no Commission Decision will be issued.

References

• Directive 2001/83/EC

• Annex I to Directive 2001/83/EC, Part II.6

• Regulation (EC) 726/2004

10.9. Can I submit my annual re-assessment within the renewal? Rev. Dec 2015

The annual re-assessment of medicinal products authorised under exceptional circumstances cannot be part of the 5-year renewal procedure, as their scope is different. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CPMP/2990/00) Rev.

10.10. Do I have to pay fees for an annual re-assessment? Rev. Dec 2024

There is no fee payable for the annual re-assessment of a marketing authorisation under exceptional circumstances.

References

• Fees payable to the European Medicines Agency

10.11. What impact do ongoing Variation(s) (Type IA/IB or Type II) have on the annual re-assessment? Rev. Dec 2015

In case that an ongoing variation (Type IA/IB or Type II) affects the product information and is not yet finalised at the time of the submission of the annual re-assessment application, the last product information adopted/accepted by the EC/CHMP/EMA should be used in the submission of the annual re-assessment application by the MAH.

If the variation procedure is finalised (notification of a Type IA/IB or opinion of the Type II) before or upon finalisation of the annual re-assessment procedure, the accepted/adopted variation changes should be used in the product information adopted with the annual re-assessment.

MAHs are advised to contact the Agency in order to discuss how to optimally handle the above situations.

10.12. Do I have to submit mock-ups and specimens? Rev. Dec 2015

No mock-ups or specimens are required for the annual re-assessment of a marketing authorisation under exceptional circumstances.

10.13. When do I have to submit (revised) product information? In all languages? Rev. Apr 2021

Proposals for changes to the Annexes prompted by data submitted with the annual re-assessment application may be submitted as part of the annual re-assessment procedure. In such cases, the revised product information will be considered in the annual re-assessment opinion and implementation of changes will not initiate a separate variation procedure ( see also Question “How

shall I present my annual re-assessment application?”, Section 1.3.1) .

At submission

In case the annual re-assessment affects the SmPC, Annex II, labelling and/or package leaflet, the revised product information Annexes must be submitted as follows: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Language Format

EN (only) - As part of the eCTD

• Word format (highlighted and clean)

English language (only): complete set of Annexes within the eCTD sequence and in Word format (clean and highlighted showing the changes proposed as part of the Annual Re-Assessment).

In case the annual re-assessment results in changes to the SmPC, Annex II, labelling and/or package leaflet, the revised complete set of Annexes must be submitted as follows:

After CHMP Opinion (Day +5)

Language Format

All EU languages (incl. EN, NO and IS)

Via Eudralink- Word format (highlighted)

All EU languages (incl. EN, NO and IS)

Via Eudralink- Word format (highlighted)

• PDF format (clean)

All EU languages (incl. EN, NO and IS): complete set of Annexes in Word format (highlighted) and in PDF (clean)

After Linguistic check (Day +25)

Language Format

All EU languages (incl. EN, NO and IS)

Via Eudralink

• Word format (highlighted)

• PDF format (clean)

All EU languages (incl. EN, NO and IS): complete set of Annexes in Word format (highlighted) and in PDF (clean)

Translations of the adopted product information in all EU languages (incl. EN, NO and IS) are to be provided electronically (in one Eudralink package) to the Member States Contact Points for Translations by Day +5 and copied to the EMA procedure assistant.

The ‘complete set of Annexes’ consists of Annex, I, II, IIIA and IIIB i.e. all SmPC, labelling and PL

texts for all strengths and pharmaceutical forms of the product concerned and Annex related to the Art. 127a if appropriate.

Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB, and if applicable, Annex related to the Art, 127a) as one Word document for each official EU language. Annex related to the 127a (when

applicable) must be presented as a separate PDF document with “127a” removed from the title page

together with the Word files highlighted with tracked changes. All translations should be numbered as one document, starting with "1" (bottom, centre) on the title page of Annex I and Annex (127a) when

applicable. The ‘QRD convention’ published on the EMA website defines format and layout of the PI. The PDF user guide should also be followed as it provides guidance on how to correctly prepare the PDF versions. When submitting the full set of Annexes in PDF format, this should be accompanied by European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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the completed Day +25 checklist. Highlighted changes should be indicated via ‘Tools – Track changes’. Clean versions should have all changes ‘accepted’.

The revised Annex A, where applicable, is to be provided to the Agency as a separate Word document in all EU languages. See point 1.12 below.

The Decision-Making Process of the European Commission starts once the opinion with Annexes in all official EU languages, as appropriate, has been received. When the Annexes to the Marketing Authorisation have not been affected by the annual re-assessment, no European Commission Decision will be issued.

Note: Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translations submitted at Day +5 and the final translations submitted at Day +25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

Reference

• The new Linguistic Review Process of Product Information in the Centralised Procedure (EMEA/5542/02 Rev. 5)

10.14. Will there be any publication on the outcome of my annual re-assessment? Rev. Dec 2015

The EPAR (published on the EMA website) will be revised to reflect the CHMP conclusions in relation to the annual re-assessment procedure.

The CHMP meeting highlights published following each CHMP meeting gives information in its Annex on opinions in relation to annual re-assessment applications. This information includes the invented name of the product, its INN, the name of the MAH and the procedure outcome.

In case of an unfavorable opinion, recommending suspension or revocation of the MA, a Question and Answer (Q&A) document will be published by the Agency. This will include information and reasons for such an opinion. The information will be provided in lay language, so that it can be understandable for the general public.

References

• CHMP meeting highlights

• EPARs European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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10.15. Who should I contact if I have a question when preparing my application and during the procedure? Rev. Feb 2019

If you cannot find the answer to your question in the Q&A when preparing your application or during the procedure, please contact the Product Lead responsible for your product. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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11. Renewal

11.1. How long is my marketing authorisation valid for? Rev. Feb 2019

In accordance with Article 14 (1-3) of Regulation (EC) No 726/2004, a marketing authorisation (MA) is valid for five years from the date of notification of the Commission Decision to the marketing authorisation holder (MAH) and is renewable upon application by the MAH.

Notification dates of the Commission Decision are published in the Official Journal and can also be found in the EC Pharmaceuticals - Union Register for each product. Once renewed, the MA will be valid for an unlimited period, unless the Competent Authority decides on justified grounds relating to pharmacovigilance (e.g. exposure of an insufficient number of patients to the medicinal product concerned), to mandate one additional five-year renewal.

MAs under exceptional circumstances granted under Article 14(8) of Regulation (EC) No 726/2004 are also valid for 5 years.

Conditional MAs granted under Article 14-a of Regulation (EC) No 726/2004 do not fall under the above provisions. They are valid for 1 year and should therefore be renewed annually. For further

information on the ‘conditional’ MAs, see Q&A of the pre -submission procedural guidance ‘ Could my

application qualify for a conditional marketing authorisation?’.

References

• Article 14 (1-3) of Regulation (EC) No 726/2004

• Article 24 of Directive 2001/83/EC

• Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev.5)

11.2. When shall I submit my renewal application? Rev. May 2020

In order to remain valid, the renewal of the MA is required within five years of its granting. A renewal application must be submitted to the Agency at the latest 9 months before the expiry date of the MA. A renewal application should also be submitted for suspended MA. If a MAH does not submit the renewal application, the MA will expire on the last day of its validity.

The MA validity period is calculated from the date of notification of the Commission Decision to the MAH.

To ensure that the Commission Decision on the renewal application is issued before expiry of the MA, when planning for their renewal submission, MAHs should take into account the following principles:

• The renewal application must be submitted at least 9 months before the MA expiry date. Any anticipation in the submission of the renewal application by more than 2 months (i.e. earlier than 11 months before the MA expiry) will not be accepted by the Agency.

• The start of the evaluation process will be the nearest possible starting date to the submission of a

valid dossier, as published by the EMA in the “Human Medicines – Procedural Timetables /

Submission dates”).

• The PRAC/ CHMP assessment process can take up to 120 days of active time. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• The Decision-Making Process (including the Standing Committee consultation) for renewal procedures is 67 days.

References

• Article 14(2) of Regulation (EC) No 726/2004

• Guideline on the processing of renewals in the centralised procedure (EMEA/CPMP/2990/00 Rev. 5)

• Union Register of medicinal product: website of the European Commission

11.3. How shall I present my renewal application? Rev. May 2020

Renewal applications should be submitted in eCTD format and have to contain the documents listed in the Annex 2 of the Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev.5) and which are listed below:

Module 1:

1.0 Cover letter. The cover letter should be signed by the person designated as MAH contact with the EMA. (NB: the Renewal application is not an opportunity to notify the Agency of changes in contact person) In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file.

1.2 Renewal Application form. The electronic EU Renewal application form (eAF) should be signed by the person designated as MAH contact with the EMA and completed with the following annexes (the form is available on the EMA public website):

• List of all authorised product presentations for which renewal is sought in tabular format (following the template for Annex A to CHMP Opinion)

The MAH should complete and sign the renewal application form, appending a list of all authorised strengths, pharmaceutical forms and presentations of the product concerned for which renewal is sought. In cases where the MAH does not wish to renew certain product presentations (e.g. a certain pharmaceutical form, strength or pack-size), this should be clearly indicated in the cover letter and the concerned presentations should not be included in the appended list.

• Details of contact persons:

− Qualified person in the EEA for pharmacovigilance

− Contact person in the EEA with the overall responsibility for product defects and recalls

− Contact person for scientific service in the EEA in charge of information about the medicinal product

Note : The Renewal application is not an opportunity to notify the Agency of changes in contact persons. More information is available on ‘Contacting EMA: post -authorisation’.

• List of EU Member states/Norway/Iceland where the product is on the market and indicating for each country which presentations are marketed and the launch date

• Chronological list of all post-authorisation submission since granting the MA or since the last renewal: a list of all approved or pending Type IA/IB and Type II variations, Extensions, Art 61(3) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Notifications, USR, and PSURs, giving the procedure number (where applicable), date of submission, date of approval (if approved) and brief description of the change.

• Chronological list of conditions and Specific Obligations submitted since the granting of marketing authorisation or the last renewal indicating scope, status, date of submission and date the condition/ obligation was fulfilled (where applicable)

• Revised list of all remaining conditions and Specific Obligations (where applicable)

• A statement, or when available, a certificate of GMP compliance, not more than three years old, for the manufacturer(s) of the medicinal product listed in the application issued by an EEA competent authority or MRA partner authority. A reference to the Union EudraGMP database, if available will suffice.

• For manufacturing sites of the medicinal product not located in the EEA or in the territory of an MRA partner, a list of the most recent GMP inspections carried out indicating the date, the inspection team(s) and outcome of the inspection(s)

• In accordance with Article 46(f) of Directive 2001/83/EC manufacturing authorisation holders are required to use as starting materials only active substances which have been manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials as adopted by the Union.

The following declarations are required:

• A declaration by the Qualified Person (QP) of each of the manufacturing authorisation holders (i.e. located in the EEA) listed in the application form where the active substance is used as a starting material.

• A declaration by the Qualified Person (QP) of the manufacturing authorisation holder(s) listed in the application as responsible for batch release.

• These declarations should state that all the active substance manufacturer(s) referred to in the application form operate in compliance with the detailed guidelines on good manufacturing practice for starting materials.

1.3.1 Summary of Product Characteristics, Labelling and Package Leaflet

• If no changes to the PI (SmPC, Annex II, outer/ inner labelling and Package Leaflet) are proposed

by the MAH, a ‘clean’ version of the latest PI in English has to be provided (in Word format). This document is needed for the QRD review of the Product Information.

• If changes to the PI are proposed as part of the Renewal dossier, a version of the PI in English, highlighting the changes proposed by the MAH should be provided in Word format. In addition, a

‘clean’ version of the PI should be provided in the eCDT and Word.

• Note : All other language versions are only to be submitted after adoption of the opinion (See also

“When do I have to submit revised product information? In all languages?”).

1.4 Information about the Experts

1.4.1 Information about the Expert – Quality (incl. Signature + CV)

1.4.2 Information about the Expert – Non-Clinical (incl. Signature + CV) – if applicable

1.4.3 Information about the Expert – Clinical (incl. Signature + CV) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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1.8.2 Risk Management Plan:

An RMP is not systematically required as part of the renewal application. Three scenarios are possible:

• Where the MAH considers that no update to the RMP needs to be implemented, no RMP should be included in section 1.8.2 of the Renewal dossier. In this case, the MAH should specify this in the cover letter and provide a declaration in the clinical overview, confirming that the current approved RMP remains unchanged and applicable. Alternatively, if applicable, the MAH can state that an RMP update is being assessed in a procedure ongoing in parallel RMP changes are considered warranted.

• If an update of the RMP is proposed by the MAH with the Renewal application, section 1.8.2 should

contain the updated RMP (‘clean’ version). In this case, in addition, a version of the RMP,

highlighting the changes proposed by the MAH should be provided in Word format.

• Where there is no RMP for the medicinal product, this should be stated in the cover letter.

Module 2:

2.3 Addendum to Quality Overall Summary

The Addendum should include a declaration of compliance with Article 16(1) of Regulation (EC) No

726/2004, which obliges the MAH “…to take account of technical and scientific progress and introduce

any changes that may be required to enable the medicinal product to be manufactured and checked by

means of generally accepted scientific methods”.

The Addendum to the Quality Overall Summary should also include:

• Confirmation that all changes relating to the quality of the product has been made following applications for variations and that the product conforms to current CHMP Quality guidelines.

• Currently authorised specifications for the active substance and the finished product (with date of latest approval and procedure number)

• Qualitative and quantitative composition in terms of the active substance(s) and the excipient(s) (with date of latest approval and procedure number)

2.4 Addendum to Non-clinical Overview

An Addendum to the non-clinical Overview is not systematically required as part of the renewal application.

When new data are submitted in the non-clinical Addendum, a critical discussion must be submitted as part of the renewal application supporting the risk-benefit balance re-evaluation for the product taking into account any new non-clinical data accumulated since the initial MA or the last renewal, or any relevant new information in the public domain.

In case no new non-clinical data have been gathered since the initial MAA or since the last renewal, this should be stated in the Addendum to the Clinical Overview.

2.5 Addendum to Clinical Overview

A critical discussion should be provided within the Addendum to the Clinical Overview. It should address the benefit/risk balance for the product at the time of the Renewal, on the basis of the Periodic Safety Update Reports (PSUR) submitted and safety/efficacy data accumulated since the granting of the MA or since the last renewal, making reference to relevant new information in the public domain. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The discussion should clearly reflect the data previously included in the PSURs and the new data that have emerged since the DLP of the last PSUR up to the DLP of the renewal. The DLP of the renewal should not exceed 90 days prior to the renewal submission.

Note : MAHs are advised to consider the Good Vigilance Practice Module VII on PSUR as guidance for the preparation of the sections of the clinical overview described below.

The Addendum to the Clinical Overview should contain the following information:

• History of pharmacovigilance system inspections (date, inspecting authority, site inspected, type of inspection and if the inspection is product specific, the list of products concerned) and an analysis of the impact of the findings overall on the benefit/risk balance of the medicinal product.

• Worldwide MA status: overview of number of countries where the product has been approved and marketed worldwide.

• Actions taken for safety reasons during the period covered since the initial MA or since the last renewal until to the DLP of the renewal: description of all significant actions related to safety that had a potential influence on the benefit/risk balance of the approved medicinal product (e.g. suspension, withdrawal, temporary halt or premature ending of clinical trial for safety reasons,

issue requiring communication to healthcare professionals…). Actions taken from the DLP of the last PSUR up to the DLP of the renewal should be clearly identified and highlighted.

• Significant changes made to the Reference Information (RI) during the period covered since the initial MA or since the last renewal. In this section, new changes made from the DLP of the last PSUR up to the DLP of the renewal should be clearly highlighted.

• Estimated exposure and used patterns: data on cumulative exposure of subjects in clinical trials as well as of patients from marketing exposure for EU and non-EU regions. If the MAH becomes aware of a pattern of use of the medicinal product considered relevant for the implementation of the safety data, a brief description should be provided; such patterns may include in particular off-label use.

• Data in summary tabulations: Summary tabulations of serious adverse events from clinical trials as well as summary tabulations of adverse reactions from post-marketing data sources reported during the period covered since the initial MA or since the last renewal until to the DLP of the renewal.

• Summaries of significant safety and efficacy findings from clinical trials and non-interventional studies during the period covered by the renewal: description of any significant safety findings that had an impact on the conduct of clinical trials or non-interventional studies. It should also address whether milestones from post-authorisation safety studies, post-authorisation efficacy studies, studies included in the pharmacovigilance plan of the RMP and studies conducted as condition or specific obligations of the MA, have been reached in accordance with agreed timeframes. New data since the DLP of the last PSUR up to the DLP of the renewal should be highlighted.

• Overview of signals: High level overview of signals for which evaluation was completed during the period covered by the renewal and any action taken or planned; and high-level overview of ongoing signals (i.e. that are undergoing evaluation at the DLP of the renewal application) should be provided. The information should be provided in tabular format.

• Signal and risk evaluation: the MAH should summarise signals for which evaluation was completed during the reporting period of the renewal. For signals that became important identified or European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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potential risks or are related to a known risk, a characterisation of the risk should be provided. Evaluation of signals completed from the DLP of the last PSUR to the DLP of the renewal should be clearly highlighted. The MAH should discuss whether any changes are considered necessary to the existing safety concerns and whether any additional risk minimisation activities for the product are warranted, considering the data collected during the period covered by the renewal.

• Relevant information on patterns of medication errors and potential medication errors (even when not associated with adverse outcomes) during the period covered by the renewal. Such information may be relevant to the interpretation of safety data or the overall benefit/risk balance evaluation.

• Literature: review of important literature references published during the period covered since the initial MA or since the last renewal until the DLP of the renewal that had a potential impact on the benefit/risk balance of the medicinal product.

• Benefit evaluation: the MAH should summarise important efficacy and effectiveness information (including information on lack of efficacy) for the period covered since the initial MA or since the last renewal until the DLP of the renewal.

• Benefit/risk balance: a discussion on the benefit/risk balance for the approved indication should be presented, based on the above information.

• Late-breaking information: The MAH should summarise the potentially important safety, efficacy and effectiveness findings that arise after the DLP of the renewal but during the period of preparation of the addendum to the clinical overview.

The Clinical Expert Statement should:

• Confirm that no new clinical data are available which change or result in a new benefit-risk balance evaluation.

• Confirm that the product can be safely renewed at the end of a 5-year period for an unlimited period, or any action recommended or initiated should be specified and justified.

• Confirm that the authorities have been kept informed of any additional data significant for the assessment of the benefit/risk balance of the product concerned.

• Confirm that the product information is up to date with the current scientific knowledge including the conclusions of the assessments and recommendations made publicly available on the European medicines web-portal.

It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH and is crucial to the overall process. For queries relating to the application, please contact the Product Lead responsible for the product .

In order to ensure that renewal applications are complete and correct before submitting them to the Agency, it is strongly recommended using the pre-submission checklist for 5-year renewal applications.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CPMP/2990/00 Rev. 5)

• Electronic Renewal application form

• The EU Harmonised Technical eCTD Guidance European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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11.4. How and to whom shall I submit my renewal application? Rev. Feb 2019

How : The requirements for the submission of applications related to the centralised procedure are

provided on the EMA website. Information is available on ‘Submitting a post -authorisation application’.

To whom : To the EMA, CHMP, PRAC and CAT (when involved) members, submissions via the Common

Repository only.

11.5. How shall my renewal application be handled (timetable)? Rev. Aug 2016

The MAH must apply for a renewal no later than 9 months before the expiry date of the MA. The recommended submission dates published on the EMA website will apply in order to determine the start of the procedure.

The Agency will acknowledge receipt of a valid renewal application and shall start the procedure in accordance with the recommended starting dates published on the EMA website. The MAH will be informed of the adopted timetable at the start of the procedure.

The timetable for the scientific evaluation by the PRAC and the CHMP will be set in order to allow the Commission Decision to be adopted before the expiry date of the MA. Please refer to Annex 1 of the Guideline on the processing of renewals in the centralised procedure (EMEA/CPMP/2990/00 Rev. 5).

Full procedural detailed timetables are published as a generic calendar on the EMA website (see submission deadlines and full procedural timetables).

The published timetables identify the start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

The renewal procedure will involve the CHMP Rapporteur and the PRAC Rapporteur appointed for the medicinal product.

Day 1 Start of procedure (see published dates on EMA website)

Day 60 Receipt of Joint CHMP Rapporteur / PRAC Rapporteur AR.

Circulation to EMA, CHMP, PRAC members and MAH, highlighting major issues if any.

Day 66 Deadline for comments from CHMP, PRAC members on the Joint AR.

Day 73-76 When applicable, discussion at PRAC Meeting.

Day 76 Endorsement of the Joint Assessment Report (PRAC outcome)

Day 90 Discussion at the CHMP (if applicable): - If no outstanding issues: adoption of opinion.

• If outstanding issues: adoption of List of Outstanding Issues

Day 91 MAH provides answers to list of outstanding issues to CHMP /PRAC Rapporteur, CHMP, PRAC members and EMA. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Day 96 Revised AR from CHMP and PRAC Rapporteurs. Circulated to CHMP and PRAC members and MAH

Day 98 Comments from CHMP and PRAC members on the Joint Assessment Report.

Day 103-106 When applicable, discussion at PRAC meeting.

Day 120 Discussion at CHMP (if applicable) - Adoption of CHMP opinion

For ATMP, the CAT Rapporteur will assess the renewal application together with the PRAC Rapporteur

and will prepare a draft opinion for the CHMP as the basis for the CHMP’s final opinion. Further

information with regards to the CAT involvement is provided in the Procedural advice on the evaluation of advanced therapy medicinal product.

Re-examination

Article 9(2) of Regulation (EC) No 726/2004 applies to CHMP Opinions adopted for renewal applications. The MAH may therefore notify the EMA/CHMP of their intention to request a re-examination of the opinion within 15 days of receipt of the opinion; if such a request is not made within these 15 days, the opinion becomes final.

The detailed grounds for the request must be forwarded to the EMA within 60 days of receipt of the opinion. If the MAH wishes to appear before the CHMP for an oral explanation, the request should also be sent at this stage.

A new CHMP Rapporteur, CAT Rapporteur as applicable, and a new PRAC Rapporteur, different from those for the initial opinion will be appointed to co-ordinate the re-examination procedure, accompanied, if necessary, by additional experts.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CPMP/2990/00 Rev 5)

11.6. What fee do I have to pay for a renewal? Rev. Dec 2024

There is no fee payable for the renewal of a marketing authorisation.

References

• Fees payable to the European Medicines Agency

11.7. Can other non-renewal specific changes be included in the renewal application? Rev. Dec 2015

None of the changes introduced at renewal should substitute for the MAH's obligation to update the MA throughout the life of the product as data emerge.

Besides, major changes to the product, such as the introduction of a new indication and quality changes such as an extension of shelf life, should not be modified as part of the renewal procedure but have to be submitted and assessed through the appropriate variation procedure. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Where there are adequate and objective reasons not to renew the MA in its existing terms and changes are necessary to the SmPC, labelling and package leaflet arising from the renewal evaluation, the MAH may submit additional information and/or change the product information as part of the renewal process to address the concerns raised. Such changes will not initiate a separate variation procedure.

Other issues arising from assessment and changes due to the revision of the SmPC guideline, other relevant guidelines impacting on the product information, or EMA/QRD Product Information Templates should be considered within the renewal procedure.

The section “present/proposed” in the application form should clearly list any changes introduced to

the product information (including any minor linguistic amendment introduced for each language). Alternatively, such listing may be provided as a separate document attached to the application form. Any changes not listed will not be considered as part of the renewal application.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CPMP/2990/00 Rev. 5)

11.8. How to handle other ongoing variation applications during the renewal procedure and what impact may ongoing procedures have on the renewal procedure? Rev. Dec 2015

MAHs are advised to plan, when possible, the submission of variation applications outside the period of the submission of the renewal application and the renewal assessment procedure. However, where the need for a variation of the MA has been identified, in particular in the context of safety concerns, the MAH is advised to contact the Agency in advance of the submission of the variation application to agree on the procedural aspects for handling these parallel applications.

In case an ongoing variation (Type IA/IB or Type II) affecting the product information is not yet finalised at the time of the submission of the renewal application, the last product information adopted/accepted by the EC/CHMP/EMA should be used for the submission of the renewal application.

If a variation procedure is finalised before or upon finalisation of the renewal procedure, the accepted/adopted variation changes should be reflected in the product information adopted with the CHMP Renewal opinion.

In cases where any ongoing procedure may affect the product information, the MAH is advised to contact the Agency in advance of the submission or finalisation of the procedure(s) concerned.

11.9. Do I have to submit mock-ups and specimens? Rev. Aug 2017

The MAHs are reminded of the requirement to submit specimens at the time of the 5-year renewal application. These are to be submitted by post to the Agency.

For further information concerning submission of mock-ups and specimens in the framework of post-

authorisation procedures, please refer to the document ‘ Checking process of mock-ups and specimens of outer/immediate labelling and package leaflet of human medicinal products in the centralised procedure.

References European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

EMEA-H-19984/03 Page 165/305

• The checking process of mock-Ups and specimens of outer/immediate labelling and package leaflets of human medicinal products in the centralised procedure (EMA/305821/2006)

11.10. When do I have to submit revised product information? In all languages? Rev. Apr 2021

Where no amendments to the product information are proposed by the MAH, only a copy of the latest

approved product information (full set of Annexes, ‘clean’) in English must be submitted to the Agency

in Word format.

In case the renewal application includes proposals for changes to the SmPC, Annex II, labelling and/or package leaflet, the product information must be submitted as follows:

At submission

English language (only): complete set of Annexes within the eCTD sequence and in Word format (both clean and highlighted showing the changes proposed as part of the Renewal).

If changes are approved as part of the Renewal, the following steps will apply:

After CXMP Opinion (Day +5)

All EU languages (incl. EN, NO and IS): complete set of annexes in Word format (highlighted)

After Linguistic check (Day +25)

All EU languages (incl. EN, NO and IS): complete set of annexes in Word format (highlighted) and in PDF (clean)

Translations of the adopted product information in all EU languages (incl. EN, NO and IS) are to be provided electronically (in one Eudralink package) to the Member States Contact Points for Translations by Day +5 with a copy to the EMA Procedure Assistant and to the EMA Product Shared Mailbox.

The ‘full set of Annexes’ consists of Annex I, II, IIIA, IIIB and, if applicable, IV and 127a as

appropriate.

Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB, and if applicable, IV) as one Word document for each official EU language. Annex 127a (when applicable) must be presented as a

separate PDF document with “127a” removed from the title pa ge together with the Word files highlighted with tracked changes. All translations should be numbered as ONE document, starting with

"1" (bottom, centre) on the title page of Annex I and Annex (127a) when applicable. The ‘ QRD Convention ’ published on the EMA website defines format and layout of the PI. The PDF user guide should also be followed as it provides guidance on how to correctly prepare the PDF versions. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed Day +25 Checklist . Highlighted changes should be indicated via ‘Tools – Track changes’. Clean versions should have all changes ‘accepted’.

The revised Annex A, where applicable, is to be provided to the Agency as a separate Word document in all EU languages (see point 1.12 below) and in PDF (clean).

The Annexes provided should only reflect the changes introduced by the Renewal. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments to the texts (e.g. further to a specimen check), this should be clearly mentioned in the cover letter. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In addition, the section “present/proposed” in the application form should clearly list the minor

linguistic amendments introduced for each language.

Alternatively, such listing may be provided as a separate document attached to the application form. Any changes not listed will not be considered as part of the renewal application.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translations submitted at Day+5 and the final translations submitted at Day+25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CPMP/2990/00 Rev. 5)

• The new Linguistic Review Process of Product Information in the Centralised Procedure (EMEA/5542/02 Rev. 5)

11.11. When will the linguistic checking of the product information take place? Rev. Apr 2021

During the scientific renewal assessment, a detailed pre-opinion review of the English (EN) version of the product information will be performed by the Agency, the QRD (Quality Review Document)

members and representatives of Patients’ and Consumers’ Organisations. Technical Labelling Review

comments will be sent to the MAH by day 75. When providing a revised EN version for adoption of the opinion, applicants should inform the Agency if and why certain Technical Labelling Review comments are not taken into account.

Translations of the adopted product information in all other EU languages (including IS and NO) are to be provided electronically (in one Eudralink package) to the Member States Contact Points for Translations ( by Day +5 with a copy to the EMA Procedure Assistant and to the EMA Product Shared Mailbox.

The following checks post-opinion will apply:

Who When Scope

QRD/ ‘Member State’ Day +5 to +19 Detailed review of (highlighted changes in) all translations

EMA Day +25 to +27 Review of implementation of Member States comments European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Comments will be sent directly by the Member States to the MAH at the latest by Day +19, with a copy to the EMA Product Shared Mailbox.

The MAH will send the final translations with tracked changes, incorporating the Member States’

comments in Word format, as well as in PDF format (clean), electronically (in one Eudralink package) to the EMA Procedure Assistant with a copy to the EMA Product Shared Mailbox by Day +25. The Eudralink package should be presented in compliance with the Day +25 Checklist.

The Agency will check if all Member States’ comments have been implemented before sending the final

translations to the Commission. In order to facilitate and accelerate the check of the implementation of

the Member States’ comments, the applicant should i ndicate in QRD Form 2 for each language if all comments have been implemented or not. In the latter case, a justification as why certain comments are not reflected in the final texts should be provided for the appropriate language(s). Such justification(s) and/or alternative proposals should be discussed and agreed with the relevant Member State(s) before submitting final translations to the Agency.

In case the Renewal affects only the Annex II, no or a shorter post-opinion translation timetable may be considered by the Agency on a case-by-case basis.

Following receipt of the final translations from the EMA, the Commission will start the 22-day Standing Committee consultation, addressing only legal and public health matters (which means in principle no further linguistic review).

The Commission Decision on the renewal will be issued after consultation of the Standing Committee, by Day +67.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translations submitted at Day+5 and the final translations submitted at Day+25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

References

• The new Linguistic Review Process of Product Information in the Centralised Procedure (EMEA/5542/02 Rev. 5)

• SOP/EMEA/0046: PIQ/QRD Pre-opinion Review of Product Information for Renewal Procedures

• Procedure for review of information on medicinal products by Patient’s/Consumers Organisations

(PCOs) (EMA/174255/2010 Rev. 2)

• SOP/EMEA/0048: QRD Post-opinion Review of Product Information for post-authorisation procedures affecting the annexes, excluding Annex II applications. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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11.12. What do I need to do if I do not want to renew the Marketing Authorisation of certain product presentations or the entire product? Rev. Feb 2019

MAHs should only complete the renewal application form for those presentations which they would like to renew. In cases where the MAH does not wish to renew certain product presentations (e.g. a certain pharmaceutical form, strength or pack-size) this should be clearly indicated in the cover letter (see

also “How shall I present my renewal application”).

In case the MAH does not wish to renew the entire MA (i.e. all authorised presentations) a letter to this effect should be addressed to the rapporteur, Product Lead , EMA product shared mailbox and the contact point at the European Commission, at the latest 9 months prior to the expiry of the concerned MA, clearly stating the reasons for not requesting the renewal of the MA.

This is without prejudice of the MAH obligation to notify such action to the Agency according to the provisions set out in Article 14 (b) of Regulation (EU) No 726/2004. Please refer to the EMA questions and answers on Withdrawn product notification.

References

• Article 14(b) of Regulation (EC) No 726/2004

• Directive 2001/83/EC

11.13. Will there be any publication on the outcome of my renewal application? Rev. Dec 2015

The EPAR (published on the EMA website) will be revised to implement the CHMP conclusions in relation to the renewal procedure.

Besides, the CHMP meeting highlights following each CHMP meeting give information in its Annex on opinions in relation to renewal applications. This information includes the invented name of the product, its INN and the name of the MAH.

In case of an unfavourable opinion, recommending the suspension or the non-renewal of the MA, a Question and Answer (Q&A) document will be published by the Agency. This will include information and reasons for such opinion. The information will be provided in lay language, so that it can be understandable for the general public.

References

• CHMP meeting highlights

• EPARs

11.14. Who should I contact if I have a question when preparing my application and during the procedure? Rev. Feb 2019

If you cannot find the answer to your question in the Q&A when preparing your application or during the procedure, please contact the Product Lead responsible for your product. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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12. Annual renewal of conditional marketing authorisations

12.1. How long is my conditional marketing authorisation valid? Rev. Feb 2019

In accordance with Article 14-a of Regulation (EC) No 726/2004, a conditional marketing authorisation (MA) is valid for one year from the date of notification of the Commission Decision to the marketing authorisation holder (MAH), and is renewable, annually, upon application by the MAH.

The conditional MA validity period is expressed in Commission Decisions, as follows:

• Initial MA: by reference to the date of notification of the Commission Decision to the MAH. Notification dates of the Commission Decision are published in the Official Journal and can also be found for each product in the Union Register published by the European Commission.

• Renewal: By reference to the previous MA expiry date.

In order for a conditional marketing authorisation to remain valid, a renewal application has to be made annually (irrespective of whether the marketing authorisation is suspended).

The renewal decision will usually refer to the expiry date of the preceding marketing authorisation so that the renewed authorisation will be valid from the date of the previous expiry.

For further information on the ‘conditional’ marketing authorisations, see Q&A of the pre -submission

procedural guidance question ‘Could my application qualify for a conditional marketing authorisation?’.

References

• Article 14-a of Regulation (EC) No 726/2004

• Commission Regulation (EC) No 507/2006

12.2. When shall I submit my annual renewal application? Rev. Jun 2022

According to the legislation, MAHs must apply for an annual renewal at least six months before the expiry date of the conditional MA.

In case a MAH does not submit a renewal application, the conditional MA will expire automatically.

Once a renewal application has been submitted within this deadline, the conditional marketing authorisation shall remain valid until a decision is adopted by the Commission in accordance with Article 10 of Regulation (EC) No 726/2004.

In order to ensure that the Commission Decision on the renewal application can be issued ideally before expiry of the conditional MA, MAHs should take into account the following principles when planning for their renewal submission:

• The annual renewal application must be submitted at least 6 months before the MA expiry date. A submission of the annual renewal application more than 1 month in advance of the submission due date will not be accepted by the Agency.

• The DLP of the annual renewal should not exceed 70 days prior to the submission. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• The start of the evaluation process will be the nearest possible starting date, as published by the

EMA in the “Human Medicines – Procedural Timetables / Submission dates”).

• The CHMP assessment process can take up to 90 days.

• The Decision-Making Process (incl. Standing Committee consultation) for renewal procedures is 67 days.

In addition, as the quality of the annual renewal application will be key to ensure a timely start and finalisation of the annual renewal procedure, a pre-submission dialogue between MAHs and the Agency may be considered, approximately nine months in advance of MA expiry.

References

• Article 6 of Commission Regulation (EC) No 507/2006

• Union Register of medicinal product: website of the European Commission

12.3. How shall I present my annual renewal application? Rev. May 2020

In order to allow the CHMP to confirm the benefit-risk balance of the medicinal product and to review the specific obligations and their timeframes for completion, annual renewal applications should be presented as indicated below, in accordance with the appropriate headings and numbering of the EU-eCTD format.

In order to ensure that annual renewal applications are complete and correct before submitting them to the Agency, it is strongly recommended to use the pre-submission checklist for annual renewal of conditional marketing authorisation applications.

Module 1

1.0 Cover letter 2 with the following documents attached

• List of all authorised product presentations for which renewal is sought in tabular format (following the template for Annex A to CHMP Opinion)

Note : In cases where the MAH does not wish to renew certain product presentations (e.g. a certain pharmaceutical form, strength or pack-size), this should be clearly indicated in the cover letter and they should not be included in the appended list.

• Chronological summary table of the Specific obligations (SOBs) and other conditions to the MA stating the following for each: description (scope), reference number (preferably SIAMED number), due date indicated in Annex II of the Product Information, date of submission and procedure within which the SOB was submitted (if appropriate), date when the obligation or condition has been resolved (if applicable), and the current status.

• A present/proposed table listing any changes introduced to the product information (incl. any minor linguistic amendment introduced for each language), if applicable

2Please note that there is no application form available for annual renewals and that the application form for standard 5-year renewals available on the eSubmission website is not applicable to annual renewals of conditional marketing authorisations and therefore cannot be used European Medicines Agency post-authorisation procedural advice for users of the centralised procedure EMEA-H-19984/03 Page 171/305

• Advice provided by the Pre-submission query service and or Product Lead, if applicable

The submission should also contain a duly completed eSubmission delivery file in order to facilitate registration of the submission.

Note : The Cover Letter should be signed by the person designated as MAH contact with the EMA. The Annual Renewal application is not an opportunity to notify the Agency of changes in contact person, which should be notified separately. More information is available on ‘Contacting EMA: post -

authorisation’.

1.3 Product Information (PI)

1.3.1 Summary of Product Characteristics, Labelling and Package Leaflet

• If no changes to the PI (SmPC, Annex II, outer/ inner labelling and Package Leaflet) are proposed

by the MAH clear reference to it should be made in the cover letter. In addition, a ‘clean’ version of

the latest PI in English has to be provided in Word format.

• If changes to the PI are proposed as part of the Annual Renewal dossier, a version of the PI in English, highlighting the changes proposed by the MAH should be provided in the eCTD and in

Word format. In addition, a ‘clean’ version of the PI should be prov ided as Word format.

Note : All other language versions are only to be submitted after adoption of the opinion (See also

“When do I have to submit revised product information? In all languages?”).

The Annexes submitted should only reflect the changes introduced by the Annual Renewal data. Any updates to the product information not resulting from data submitted as part of the Annual Renewal should be submitted by use of the appropriate procedure (see question 1.7). However, minor linguistic amendments to the texts could be accepted in addition to changes introduced based on the annual renewal data, but this should be clearly mentioned in the cover letter and list of such changes provided as an attachment to the cover letter.

1.4 Information about the Expert

1.4.1 Information about the Expert – Quality (incl. signature + CV) – if applicable

1.4.2 Information about the Expert – Non-Clinical (incl. signature + CV) – if applicable

1.4.3 Information about the Expert – Clinical (incl. Signature + CV)

1.8.2 Risk Management Plan

An RMP is not systematically required as part of the Annual renewal application. Two scenarios are possible:

• Where no update to the RMP is to be implemented, an RMP update should not be included in the annual renewal submission. In this case, the MAH should specify this in the cover letter and declare in the clinical overview that the current approved RMP does not require changes. Alternatively, if applicable, the MAH can state that an RMP update is being assessed in a procedure ongoing in parallel and no additional RMP changes are considered warranted.

• If an update of the RMP is proposed by the MAH with the annual renewal application, section 1.8.2

should contain the updated RMP (‘clean’ version). In this case, a version of the RMP, highlighting

the changes proposed by the MAH should be provided in Word format.

Module 2 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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2.3 Addendum to Quality Overall Summary

An Addendum to the Quality Overview is not systematically required as part of the annual renewal application. It should be provided only in case important new pharmaceutical data are available.

2.4 Addendum to Non-Clinical Overview

An Addendum to the Non-clinical Overview is not systematically required as part of the annual renewal application. It should be provided only in case important new non-clinical data are available.

2.5 Addendum to Clinical Overview

A critical discussion should be provided within the Addendum to the Clinical Overview. It should address the current benefit/risk balance for the product on the basis of the data generated in SOBs and taking into account any other safety/efficacy data (including PSUR data) accumulated since the granting of the MA.

An Interim Report on the specific obligations should be included in a separate section in the clinical overview addendum, reflecting the situation as close as possible to the submission date. The interim report on the fulfilment of the specific obligations should include details for each specific obligation. The aim of this report is to inform about the status of fulfilment of specific obligations and the impact of data generated on the benefit risk-balance of the product. If data from a specific obligation is due at the time of annual renewal submission and have not been yet submitted, it can be included in the annual renewal submission dossier. Final reporting of clinical trials should follow the conventional format of study reports (see ICH Topic E3 Note for guidance on structure and content of clinical study reports, CHMP/ICH/137/95). Clinical Summaries and Clinical Study Reports should not be included in section 2.5, but in the respective dedicated eCTD Sections, see below. One single report should be submitted for the product including all remaining specific obligations. The structure and contents of the interim report will vary depending on the type of study and available data. For further guidance on the contents of interim report on the specific obligations, please refer to the CHMP Guideline on the scientific application and the practical arrangements necessary to implement Commission Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004.

2.7 Clinical Summaries

Clinical summaries will generally need to be updated, as appropriate, when new clinical study reports are submitted.

Module 5

5.3.5 Reports of Efficacy and Safety Studies (as appropriate) submitted to fulfil SOBs:

5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

5.3.5.2 Study Reports of Uncontrolled Clinical Studies

5.3.5.3 Reports of Analyses of Data from More Than One Study

5.3.5.4 Other Clinical Study Reports European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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12.4. How and to whom shall I submit my annual renewal application? Rev. Feb 2019

How : The requirements for the submission of applications related to the centralised procedure are

provided on the EMA website. Information is available on ‘Submitting a post -authorisation application’.

To whom : To the EMA, CHMP, PRAC and CAT (when involved) members, submissions via the Common

Repository only.

12.5. How shall my annual renewal application be handled (timetable)? Rev. Mar 2016

The MAH should submit the annual renewal application by the recommended submission dates published on the EMA website and, in any case, no later than 6 months before the MA ceases to be valid.

The Agency will acknowledge receipt of a valid annual renewal application and shall start the procedure in accordance with the recommended starting dates published on the EMA website. The MAH will be informed of the adopted timetable at the start of the procedure.

The timetable for the scientific evaluation by the CHMP will be set in order to ideally allow the Commission Decision to be adopted before the expiry date of the marketing authorisation.

Full procedural detailed timetables are published as a generic calendar on the EMA website (see submission deadlines and full procedural timetables).

The published timetables identify the start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

The renewal procedure will involve the CHMP Rapporteur as well as the PRAC Rapporteur who have been appointed for the medicinal product. In case of an advanced therapy medicinal product additional steps will be included to accommodate the lead assessment by Committee for Advanced Therapies.

DAY ACTION

D 1 Start of procedure

D 30 CHMP and PRAC Rapporteurs’ joint assessment report

D 35 Comments from PRAC and CHMP members

D 39 Updated CHMP and PRAC Rapporteurs’ joint assessment report

D 46 PRAC outcome

D 60 Adoption of CHMP opinion and CHMP assessment report (or request for supplementary information without a clock stop)

D 66 Submission of responses to request for supplementary information

D 75 CHMP and PRAC Rapporteurs’ joint assessment report

D 76 PRAC outcome European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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DAY ACTION

D 80 Comments from CHMP members

D 83 Updated CHMP and PRAC Rapporteurs’ joint assessment report

D 90 Adoption of the CHMP Opinion

12.6. What fee do I have to pay for a renewal? NEW Mar 2013

There is no fee payable for the annual renewal of a conditional marketing authorisation.

References

• Fees payable to the European Medicines Agency

12.7. Can other non-renewal specific changes be included in the annual renewal application? Rev. Mar 2016

None of the changes introduced at renewal should substitute for the MAH's obligation to update the marketing authorisation throughout the life of the product as data emerge.

In particular major changes to the product, such as the introduction of a new indication and quality changes such as an extension of shelf life, should not be modified through the annual renewal procedure but have to be submitted and assessed through the appropriate variation procedure.

Where there are adequate and objective reasons not to renew the marketing authorisation in its existing terms and changes are necessary to the SmPC, labelling and package leaflet arising from the renewal evaluation, the Marketing Authorisation Holder may submit additional information and/or change the product information as part of the annual renewal process to address the concerns raised. Such changes will not require a separate variation procedure.

Other issues arising from assessment of data required for the annual renewal and changes due to the revision of the product information in line with SmPC guideline, other relevant guidelines, or EMA/QRD Product Information Templates can be considered within the annual renewal procedure.

A present/proposed table clearly listing any changes introduced to the product information (incl. any minor linguistic amendment introduced for each language) should be attached to the cover letter.

12.8. How to handle other ongoing variation applications during the renewal procedure and what impact may ongoing procedures have on the renewal procedure? Rev. Mar 2016

Although MAHs are advised to avoid other procedures at the time of annual renewal, such situations cannot be excluded.

In case that an ongoing variation (Type IA/IB or Type II) affects the product information and is not yet finalised at the time of the submission of the annual renewal application, the last product information European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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adopted/accepted by the EC/CHMP/EMA should be used in the submission of the annual renewal application.

If the variation procedure is finalised before or upon finalisation of the annual renewal procedure, the accepted/adopted variation changes should be reflected in the annual renewal product information.

In cases where any other ongoing procedure may affect the product information, the MAH is advised to contact the Agency in advance of the submission or finalisation of the procedure(s) concerned.

12.9. Do I have to submit mock-ups and specimens? Rev. Mar 2016

No mock-ups or specimens are required for the annual renewal of a conditional marketing authorisation. For details of when to submit mock-ups and specimens in the post-authorisation phase of your medicinal product, please refer to the revised checking process of mock-up and specimens information on the EMA web.

References

• Checking process of mock-ups and specimens of outer/immediate labelling and package leaflet of human medicinal products in the centralised procedure (EMA/305821/2006/Rev. 2).

12.10. When do I have to submit revised product information? In all languages? Rev. Apr 2021

In case the renewal application affects SmPC, Annex II, labelling and/or package leaflet, the revised product information Annexes must be submitted as follows:

At submission

Language

EN (only) - As part of the eCTD

• Word format (highlighted and clean)

English language (only): complete set of Annexes within the eCTD sequence and in Word format (clean and highlighted showing the changes proposed as part of the Annual Renewal).

Where no amendments to the product information are proposed by the MAH, only an electronic copy of

the latest approved product information (full set of Annexes, ‘clean’) in English must be submitted to

the Agency in Word format.

If changes are approved as part of the Annual Renewal, the following steps will apply:

After CHMP Opinion (Day +5)

In case the annual renewal results in changes to the SmPC, Annex II, labelling and/or package leaflet, the revised complete set of Annexes must be submitted as follows: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Language

All EU languages (incl. EN, NO and IS)

Via Eudralink

• Word format (highlighted)

All EU languages (incl. EN, NO and IS): complete set of Annexes in Word format (highlighted)

After Linguistic check (Day +25)

In case the annual renewal results in changes to the SmPC, Annex II, labelling and/or package leaflet, the revised complete set of Annexes must be submitted as follows:

Language

All EU languages (incl. EN, NO and IS)

Via Eudralink

• Word format (highlighted)

• PDF format (clean)

All EU languages (incl. EN, NO and IS): complete set of Annexes in Word format (highlighted) and in PDF (clean)

Translations of the adopted product information in all EU languages (including English, Icelandic and Norwegian) are to be provided electronically (in one Eudralink package) to the Member States Contact Points for Translations by Day +5 with a copy to the EMA Product Shared Mailbox.

The revised Annex A, where applicable, is to be provided to the Agency as a separate word document in all EU languages (see point 1.12 below) and in pdf (clean).

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translations submitted at Day +5 and the final translations submitted at Day +25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CPMP/2990/00 Rev. 4)

• The new Linguistic Review Process of Product Information in the Centralised Procedure (EMEA/5542/02 Rev. 4.2)

12.11. When will the linguistic checking of the product information take place? Rev. Apr 2021

Translations of the adopted product information in all other EU languages (Including Icelandic and Norwegian) are to be provided electronically (in one Eudralink package) to the Member States Contact European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Points for Translations (list of members states contact points for translation) by Day +5 and copied to the EMA Procedure Assistant.

The following checks post-opinion will apply:

Check by When Who Scope

QRD/ ‘Member State’ Day +5 to +19 Member States Detailed review of (highlighted changes in) all translations

PIQ Day +25 to +27 EMA Review of implementation of Member States comments

Comments will be sent directly by the Member States to the MAH at the latest by Day +19, with a copy to the EMA Procedure Assistant.

The MAH will send the final translations with tracked changes, incorporating the Member States’

comments, electronically to the Product Lead secretary by Day +25.

The Agency will check if all Member States’ comments have been implemented before sending the final

translations to the Commission. In order to facilitate and accelerate the check of the implementation of

the Member States’ comments, the applicant should i ndicate in QRD Form 2 for each language if all comments have been implemented or not. In the latter case, a justification should be provided for the appropriate language(s) stating why certain comments are not reflected in the final texts.

In case the Renewal affects only the Annex II, no or a shorter post-opinion translation timetable may be considered by the Agency on a case-by-case basis.

Following receipt of the final translations from the EMA, the Commission will start the 22-day Standing Committee consultation, addressing only legal and public health matters (which means in principle no further linguistic review).

The Commission Decision on the renewal will be issued after consultation of the Standing Committee, by Day +67.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translations submitted at Day +5 and the final translations submitted at Day +25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

References

• The new Linguistic Review Process of Product Information in the Centralised Procedure (EMEA/5542/02 Rev. 4.2)

• SOP/EMEA/0046: PIQ/QRD Pre-opinion Review of Product Information for Renewal Procedures European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

EMEA-H-19984/03 Page 178/305

• Procedure for review of information on medicinal products by Patient’s/Consumers Organisations

(PCOs) (EMA/174255/2010 Rev. 2)

• SOP/EMEA/0048: QRD Post-opinion Review of Product Information for Renewal Applications, Annual Reassessments, Type II Variations (60/90 Days) and Referrals

12.12. What do I need to do if I do not want to renew the Marketing authorisation of certain product presentations or the entire product? Rev. Mar 2016

In cases where the MAH does not wish to renew certain product presentations (e.g. a certain pharmaceutical form, strength or pack-size) this should be clearly indicated in the cover letter (See

also “How shall I present my renewal application”).

In case the MAH does not wish to renew the entire Marketing Authorisation (i.e. all presentations) a letter to this effect should be addressed to the Agency and the European Commission at the latest 6 months prior to the expiry of the concerned Marketing Authorisation, clearly and in detail stating if the marketing authorisation is surrendered for any reasons beyond purely commercial ones.

This is without prejudice of the MAH obligation to notify such action to the Agency according to the provisions set out in Article 14 (b) of Regulation (EU) No 726/2004. Please refer to the EMA questions and answers on Withdrawn product notification.

References

• Article 14(b) of Regulation (EC) No 726/2004

• Directive 2001/83/EC

12.13. What do I need to do if all Specific Obligations have been completed? Rev. Feb 2019

Once the specific obligations have been fulfilled, the Committee may, following an application by the marketing authorisation holder, at any time adopt a recommendation for the granting of a marketing authorisation no longer subject to specific obligations and valid for five years. MAHs who consider that all Specific Obligations have been fulfilled should indicate this in the cover letter of the submission, in which final data from the last outstanding specific obligation is being submitted. This could be either within an annual renewal application or a variation, whichever is appropriate.

References

• Article 14-a(8) of Regulation (EC) No 726/2004

• Article 7 of Commission Regulation (EC) No 507/2006 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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12.14. Will there be any publication on the outcome of my annual renewal application? Rev. Mar 2016

The EPAR (published on the EMA website) will be revised to implement the CHMP conclusions in relation to the renewal procedure.

Besides, the CHMP meeting highlights following each CHMP meeting gives information in its Annex on opinions in relation to renewal applications.

In case of an unfavourable opinion, recommending suspension or non-renewal of the MA, a Question and Answer (Q&A) document will be published by the Agency. This will include information and reasons for such an opinion. The information will be provided in lay language, so that it can be understandable for the general public.

References

• CHMP meeting highlights

• EPARs

12.15. Who should I contact if I have a question when preparing my application? Rev. Feb 2019

If you cannot find the answer to your question in the Q&A when preparing your application or during the procedure, please contact the Product Lead responsible for your product. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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13. Post Authorisation Safety Study (PASS)

13.1. What is a non-interventional imposed PASS? NEW Jul 2017

A post-authorisation safety study (PASS) is defined in Article 1(15) of Directive 2001/83/EC as “ any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures ”.

A PASS is non-interventional if:

• the medicine is prescribed in the usual way in accordance with the terms of the marketing authorisation;

• deciding how to treat the patient is based on current practice and not a trial protocol;

• the prescription of the medicine is clearly separated from the decision to include the patient in the study;

• patients do not undergo additional diagnostic or monitoring procedures;

• data analysis uses epidemiological methods 3.

An EU competent authority may impose a non-interventional PASS, either as a condition of marketing authorisation (category 1) at the moment of granting the marketing authorisation or in the post-authorisation phase, or as a specific obligation in a conditional marketing authorisation or a marketing authorisation under exceptional circumstances (category 2). For more information, please refer to the good pharmacovigilance practices (GVP) Module VIII- Post-authorisation Safety Studies.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• GVP Module VIII - Post-authorisation safety studies

13.2. Under which procedure should I submit my non-interventional imposed PASS? Rev. Nov 2025

The rules governing non-interventional imposed PASS are set in Articles 107n-q of Directive 2001/83/EC.

Non-interventional imposed PASS will be assessed by the Pharmacovigilance Risk Assessment Committee (PRAC), except for studies to be conducted in only one Member State requesting the study according to Article 22a of Directive 2001/83/EC. Such studies should be submitted to the National Competent Authority (NCA) of the Member State in which the study is conducted, who will perform the assessment nationally.

3Systematic reviews and meta-analyses of safety data should be considered as non-interventional PASS. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure EMEA-H-19984/03 Page 181/305

The requirements for submission and assessment of protocols and final study reports for non-interventional imposed PASS:

13.2.1. Draft Protocols – Article 107n procedure

Before a non-interventional imposed PASS is conducted, the marketing authorisation holder(s) (MAH(s)) have to submit a draft protocol for review and endorsement by PRAC .

13.2.2. Substantial amendments of an agreed protocol – Article 107o procedure

After a study has commenced, the MAH has to submit any substantial amendment to the protocol, before its implementation, for review and endorsement by PRAC.

Amendments are considered substantial when the changes proposed are likely to have an impact on the safety, physical or mental well-being of the study participants or that may affect the study results and their interpretation, such as changes to the primary or secondary objectives of the study, the study population, the sample size, the study design, the data sources, the method of data collection, the definitions of the main exposure, outcome and confounding variables or the statistical analytical plan as described in the study protocol.

Changes in the milestones affecting the timelines for the submission of the final study reports should be considered as substantial amendments to the protocol and should consequently be submitted for assessment to the PRAC as an Article 107o procedure. Following the assessment and conclusion of the procedure, outcomes endorsing changes to the timelines on the submission of such final study results will be made public on the dedicated EMA webpage on PASS outcomes.

For centrally authorised medicinal products (CAPs) change of due date of the corresponding condition to the marketing authorisation (MA) will require a change of due date in the risk management plan (RMP) and in the Annex II of the MA. Therefore, a change of due date can be submitted via a variation application under C.9.

13.2.3. Final study results – Article 107q procedure

Upon completion of the study, the MAH has to submit a final study report within 12 months of the end of data collection to the PRAC (Article 107p of Directive 2001/83/EC).

Based on the results of the study and after consultation with the MAH(s), the PRAC may make recommendations concerning the marketing authorisation.

Importantly, only study reports that are considered final by the MAH(s) should be submitted to the Agency. For this purpose, the definitions included in Article 37(2) of Commission Implementing Regulation (EC) No 520/2012 ( “End of data collection means the date from which the analytical dataset is completely available” ) and GVP Module VIII (“ Analytical dataset: the minimum set of data required to perform the statistical analyses leading to the results for the primary objective(s) of the study ” –

Section VIII.A.1. Terminology) should be applied.

In cases where the analytical dataset is not complete and/or further data are still being collected by the MAH(s), the Agency should be contacted prior to submitting the final study report.

Interim results and/or feasibility studies of non-interventional imposed PASS do not fall under the provisions in Articles 107n-q of Directive 2001/83/EC. When those are requested to be submitted, European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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appropriate procedures should be followed (i.e. submission to NCA for nationally authorised products or to EMA for centrally authorised products refer to question on ‘ When and how should study progress reports and interim results be submitted? ‘).

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• Commission Implementing Regulation (EC) No 520/2012

• GVP Module VIII - Post-authorisation safety studies

13.3. What if the results of a non-interventional imposed PASS make a variation necessary? NEW Jul 2017

The results of non-interventional imposed PASS should be evaluated by the MAH(s), who should consider whether the results have an impact on the marketing authorisation. If the MAH(s) concludes that this is indeed the case, the MAH(s) should submit the results directly as an application for variation to the relevant competent authority.

Independently of the MAH(s) evaluation of the need for a variation, and following the assessment of the final study report, the PRAC may issue a recommendation to the Committee for Medicinal Products for Human Use (CHMP) for any regulatory action that is deemed to be appropriate.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

13.4. How shall I present my non-interventional imposed PASS and in which format? Rev. May 2020

The format of non-interventional imposed PASS protocols and final study reports (Articles 107n-q of

Directive 2001/83/EC ) is provided in Annex III of Commission Implementing Regulation (EC) No 520/2012.

Further guidance is provided in GVP Module VIII and in the EMA Guidance for the format and content of the protocols and the final study reports of non-interventional post-authorisation safety studies.

13.4.1. Protocols and protocol amendments (Articles 107n -o)

Draft protocols of non-interventional imposed PASS should be submitted as a separate document in module 1.8.2 of the common technical document (CTD). They should only be included as an annex to the risk management plan (RMP), once they are endorsed by PRAC, at the next regulatory opportunity.

In case national variants of a study protocol are necessary to ensure the appropriate implementation of the study requirements to the specificities of national law, they should be submitted in the form of a regional appendix to the main protocol. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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13.4.2. Final study results (Article 107q)

Imposed non-interventional PASS final study reports should be submitted in module 5.3.6 of the CTD.

Proposed changes to the product information as a result of the data within the PASS final study report can be submitted as part of the Article 107q procedure. The revised product information of the product(s) concerned should be presented in English language in module 1.3.

Where the proposed changes are not based on the data submitted within the final study report, these changes will not be considered and a variation will have to be submitted as appropriate to the relevant national competent authority.

A RMP update can also be submitted with a final PASS study report for single centrally authorised medicinal product or a mixture of CAPs belonging to the same global marketing authorisation (GMA) when the changes to the RMP are a direct result of data presented in the study report. In this case no stand-alone RMP variation is necessary. If the above does not apply, the updated RMP should be submitted as a stand-alone variation.

The submission should include a cover letter and in order to facilitate the registration of the submission, the eSubmission delivery file should be duly completed as required for the procedure. For joint studies, the contact point of the marketing authorisation holders or consortium may be contacted for financial purposes.

References

• Directive 2001/83/EC

• Commission Implementing Regulation (EC) No 520/2012

• GVP Module VIII - Post-authorisation safety studies

• Guidance for the format and content of the protocol of non-interventional post-authorisation safety studies

• Guidance for the format and content of the final study result of non-interventional post-authorisation safety studies

13.5. To whom should I submit my imposed non-interventional PASS? Rev. May 2020

The following requirements are related to the non-interventional imposed PASS protocols and final study report which are supervised by the PRAC.

• for CAPs and NAPs: to be submitted to EMA in eCTD format only via the eSubmission Gateway or eSubmission Web Client (as per Dossier requirements for centrally authorised products (CAPs) and Dossier requirements for NAPs (referral, PASS107, worksharing, signal detection procedures and ancillary medicinal substances in medical devices).

All submission for CAPs and NAPs sent to EMA via eSubmission Gateway/Web Client will be considered delivered to the PRAC Rapporteur and all members of the PRAC. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Any response to a request for supplementary information must be sent to EMA, the PRAC Rapporteur and all PRAC members as per above requirements.

All submissions should contain a cover letter and a duly completed eSubmission delivery file.

More information is available on ‘Submitting a post -authorisation application’.

References

• Dossier requirements for centrally authorised products (CAPs)

• Dossier requirements for referral, ASMF and NAP submissions (PASS107, workshare, signal detection procedures) and ancillary medicinal substances in a medical device.

• eSubmission Gateway or eSubmission Web Client

• Harmonised guidance for eCTD submissions in the EU

13.6. How do I submit a joint PASS? Rev. May 2020

If the same safety concerns apply to more than one medicinal product, the relevant competent authority shall, following consultation with the PRAC, encourage the MAHs concerned to conduct a joint PASS (Article 10a(1)(a) of Regulation (EC) No 726/2004, Article 22a(1)(a) of Directive 2001/83/EC) .

At the time of imposition of the study by the PRAC, EMA will support interactions between the MAHs concerned by sharing contact details among those that wish to participate in a joint study. A dedicated meeting with the PRAC Rapporteurs may be organised to support interactions between the MAHs and to provide suggestions for the joint study proposal.

Submissions of joint PASS follow the same requirements as single studies. A single contact person for the submission should be appointed amongst all MAHs concerned and specified in the cover letter. This person will be the primary contact point on all interactions with EMA and will receive the documentation relevant for the procedure. The responsibility to communicate with the rest of the participants in the joint study lies with the appointed contact person as per the specific contractual arrangements among MAHs.

For joint studies it is of particular importance to accurately reflect in the cover letter the full list of medicinal products and MAHs concerned by the joint study (the eSubmission delivery file should list all the concerned medicinal products ), as this will define the scope of the procedure, directly affecting the calculation of fees payable to EMA.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• GVP Module VIII - Post-authorisation safety studies European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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13.7. How will my non-interventional imposed PASS protocol be handled? Rev. Mar 2024

13.7.1. Submission

Upon receipt of a technically valid application, the EMA Product Lead (PL) will perform the validation of the initial application (including format of the protocol). Supplementary information may be requested by the PL in order to finalise the validation. The procedure will commence at the next available start date after all validation issues have been resolved. The Agency will inform the MAH of the outcome of the validation, the case number and procedural timetable.

For NAPs, a PRAC Rapporteur will be appointed upon receipt of a PASS protocol. The name of the appointed PRAC Rapporteur will be communicated to the marketing authorisation holder by EMA at the start of procedure. For CAPs, the PRAC Rapporteur will be the one already appointed for the product.

13.7.2. Assessment

The assessment under a 107n procedure is as follows, regardless of whether it refers to one or more centrally authorised medicinal products, a mix of centrally authorised medicinal products and nationally authorised products, or nationally authorised products only. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

EMEA-H-19984/03 Page 186/305 Receipt of PASS Protocol (107n) from MAH(s) Technical validation by the Agency Start Rapporteur preliminary assessment report 30 days Comments PRAC members 15 days Rapporteur updated assessment report 8 days PRAC recommendation At the next PRAC meeting

The assessment of a non-interventional imposed PASS protocol is performed by the PRAC. The timelines for assessment are 60 days, the following timetable shall apply:

Day Action

Day 0 Start of the procedure according to the published timetable

Day 30 PRAC Rapporteur’s preliminary assessment report

Day 45 PRAC members’ comments

Day 53 PRAC Rapporteur’s updated assessment report (if

necessary) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Day 60 PRAC Recommendation

The outcome is a legally binding PRAC letter to the MAH(s) with the following possibilities:

• a letter notifying the MAH that the study is a clinical trial falling under the scope of Directive 2001/20/EC;

• a letter of objection specifying the grounds of objection and the timelines for resubmission and reassessment of the protocol;

• a letter of endorsement of the draft protocol.

In the instances when PRAC adopts a letter of objection, submission of a revised protocol will be required usually within 60 days (which could be shortened or extended depending on the revisions). The revised protocol can then follow subsequent 60-day assessment procedures as per the timelines above until it is fully endorsed by the PRAC.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• Commission Implementing Regulation (EC) No 520/2012

• GVP Module VIII - Post-authorisation safety studies

• Timetables for non-interventional imposed PASS protocols and results

13.8. How will my imposed non-interventional PASS final study report be handled? Rev. Mar 2025

13.8.1. Submission

Upon receipt of a technically valid application, the EMA Product Lead (PL) will perform the validation of the application content. Supplementary information may be requested by the PL in order to finalise the validation. The procedure will commence at the next available start date after all validation issues have been resolved. The Agency will inform the MAH of the outcome of the validation, the case number and procedural timetable. For NAPs, a PRAC Rapporteur will be appointed upon receipt of a PASS final study report. The name of the appointed PRAC Rapporteur will be communicated to the marketing authorisation holder by EMA at the start of procedure. For CAPs, the PRAC Rapporteur will be the one already appointed for the product.

13.8.2. Assessment

The assessment under a 107q procedure is as follows, regardless of whether it refers to one or more centrally authorised medicinal products, a mix of centrally authorised medicinal products and nationally authorised products, or nationally authorised products only. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

EMEA-H-19984/03 Page 188/305 Receipt of PASS final study report (107q) from MAH(s) Technical validation by the Agency Start Rapporteur preliminary assessment report 30 days Comments from PRAC members 15 days Rapporteur updated assessment report 8 days PRAC Recommendation [or Request for Supplementary Information] At the next PRAC meeting PRAC recommendation received by CHMP/ CMDh If variation, suspension or revocation of the marketing authorisation is recommended 30 days CAP/NAPs CHMP Opinion sent to EC, marketing authorisation holder(s) and NCAs

CAP

EC decision addressed to Member States for implementation at national level

NAP

CMDh majority position sent to EC, marketing authorisation holder(s) and NCAs CMDh position CMDh consensus position sent to marketing authorisation holder(s) and NCAs 30 days NAPs only Implementation at national level EC decision to update centralised marketing authorisation European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The assessment of a non-interventional imposed PASS final study report is performed by the PRAC. The timelines for assessment are for up to 74 days followed by 67 days of European Commission (EC) decision making process (if applicable).

Day Action

Day 0 Start of the procedure according to the published timetable

Day 30 PRAC Rapporteur’s preliminary assessment report

Day 45 PRAC members’ comments

Day 53 PRAC Rapporteur’s updated assessment report (if

necessary)

Day 60 PRAC Recommendation

[or Request for Supplementary Information]

Day 74 CHMP opinion / CMDh position (in case PRAC recommends a variation, suspension or revocation of the MA)

If issues which prevent the adoption of a recommendation are identified, the PRAC will adopt a request for supplementary information together with a deadline for submission of the requested data by the

MAH and a timetable for the assessment of the MAH’s re sponses. The MAH will receive the adopted timetable together with the request for supplementary information. The clock will be stopped until the receipt of the requested supplementary information.

In case of major disagreement with the PRAC Rapporteur’s proposed recommendation as stated in the

updated assessment report, the MAH should contact the Risk Management Specialist no later than two working days following receipt of the report and indicate whether they would wish to make use of the opportunity of an oral explanation to defend their position before the PRAC. In the absence of a reply within two days, EMA will assume that no oral explanation is requested.

The MAH(s) should submit a clean and a tracked version of the agreed amended product information prior to the adoption of the PRAC recommendation.

In case the PRAC recommends any regulatory action, i.e. variation, suspension or revocation of the marketing authorisation, the PRAC recommendation will be transmitted to the CHMP if it includes at least one CAP or to the CMDh if it includes only NAPs. At its next meeting following the PRAC recommendation, the CHMP or the CMDh, as applicable, will adopt an opinion or a position, respectively. Subsequently, where the procedure includes at least one CAP, the EC will adopt a decision to the MAHs for the centrally authorised products and, as applicable, to the competent authorities of the Member States for nationally authorised products.

Where the procedure includes only NAPs, the procedure ends with the CMDh position in case of consensus and in case of a majority vote, the CMDh position will be followed by a EC decision to the Member States, which will have to be implemented according to the timetable indicated in the CMDh position or within 30 days of the CD receipt by the Member States. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Amendments to the summary of product characteristics (SmPC), labelling and package leaflet (PL) as a result of the PASS final study report assessment are directly implemented through the EC decision for centrally authorised products and through the appropriate variation at national level for nationally authorised products (including those authorised through the mutual recognition and decentralised procedures).

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• Commission Implementing Regulation (EC) No 520/2012

• Guideline on good pharmacovigilance practices (GVP) Module VIII - Post-authorisation safety studies

• Guidance to applicants /marketing authorisation holders (MAHs) on oral explanations at EMA

• Timetables for non-interventional imposed PASS protocols and results

13.9. How is the CHMP opinion / CMDh position structured and which annexes need to be translated?

The Annexes of both the CHMP opinion as well as the CMDh position will be translated into all EU languages following an agreed timetable. In addition, a linguistic review by Member States of these Annexes in all EU languages is performed after adoption of the CHMP opinion and CMDh position.

Procedures that contain only centrally authorised products (CAP(s))

• Annex B: Annexes I, II, IIIA, IIIB, IV (scientific conclusions and grounds for the variation of the marketing authorisation) and 127a (conditions addressed to Member States)

Procedures that contain a mix of centrally authorised products (CAP(s)) and nationally

authorised products (NAP(s))

For the CAP(s):

• Annex B: Annexes I, II, IIIA, IIIB, IV (scientific conclusions and grounds for the variation of the marketing authorisation) and 127a (conditions addressed to Member States)

For the NAP(s):

• Annex C:

• Annex I (scientific conclusions and grounds for variation to the terms of the marketing authorisations);

• Annex II (amendments to the product information of the nationally authorised medicinal products);

• Annex III (conditions to the marketing authorisations), as applicable.

Procedures that only contain nationally authorised products (NAP(s))

• Annex C: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Annex I (scientific conclusions and grounds for variation to the terms of the marketing authorisations);

• Annex II (amendments to the product information of the nationally authorised medicinal products);

• Annex III (conditions to the marketing authorisations), as applicable;

• Annex III or IV (timetable for implementation), as applicable.

The preparation of the translation process

In view of the short timeframe for finalisation of the translations and in order to optimise the quality of the translations, the MAHs are strongly advised to prepare for the translation process well in advance in the pre-opinion / position stage, i.e. just following adoption of the PRAC recommendation for variation.

In case of a procedure where several MAHs are involved, EMA will coordinate the translation process by approaching the MAHs individually and provide the timelines accordingly. MAHs should translate for their products all relevant Annexes.

During the translation process

Depending on the type of outcome and whether a EC Decision is required (CHMP opinion or CMDh position by majority), the timelines for the translation process vary depending on the need for a linguistic review as illustrated below :European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Is there an EC Decision? MAH will have 3 working days (5 calendar days) for translation Yes MAH will have 10 working days (14 calendar days) for translation No D05: MAH initiates linguistic review as per adopted TT D14: MAH initiates voluntary linguistic review as per provided TT D19-25: MAH integrates all comments and sends compiled PDF of all languages to EMA D28-34: MAH integrates all comments and sends compiled PDF of all languages to EMA D27: EMA sends linguistic package to EC, and finalises EPAR folder D35-45: EMA sends linguistic package to CMDh, prepares EPAR folder and publishes outcome on dedicated webpage EMA sends email to web-team requesting EPAR publication CD

a. In case of CHMP opinion or CMDh position by majority i.e. followed a EC Decision, the MAH has to provide the translations of the adopted Annexes in all EU languages (and in Icelandic and Norwegian – if applicable, as detailed below) according to the following timelines:

Day 5 (5 days after opinion/ position) Translations of the adopted Annexes in EN and in all other EU languages (and in Icelandic and Norwegian) are to be provided electronically (in one Eudralink package if applicable) to the Member States (MS) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Contact Points for Translations and to the EMA procedure assistant.

Day 19 (19 days after opinion/ position) Member States will send linguistic comments on the Annexes to the MAH by e-mail with a copy to the Mailbox.

Day 25 (25 days after opinion / position) The MAH(s) will implement the required changes, compile the translations and send it back to the EMA.

In case of disagreement between a Member State and the MAH, EMA will not interfere in the translation process. Disagreements should be solved directly with the concerned Member State.

In order to facilitate and accelerate the check of the implementation of the comments, the MAH should

indicate in “ QRD Form 2 ” for each language if all

comments have been implemented or not. In the latter case, a justification should be provided for the appropriate language(s) stating why certain comments are not reflected in the final texts.

b. In a case of CMDh position by consensus, Member States may perform a voluntary linguistic review in the translation process, therefore the following timelines apply:

Day 1 – 14 (1 to 14 days after position): MAH translates the adopted Annexes in all other EU languages based on the EN provided version. MAHs with marketing authorisations in Iceland and/or Norway will provide translations in these languages as well.

Day 15 (15 days after the position): Translations of the adopted Annexes in EN and all other EU languages (and in Icelandic and Norwegian, if applicable) are to be provided electronically (in one Eudralink package if applicable) to the Member States (MS) contact Points for Translations and to the EMA procedure assistant for voluntary linguistic check.

Day 28-34 (28-34 days after position) The MAH(s) will implement the required changes.

Translation of the adopted Annexes in EN and in all other EU languages (and in Icelandic and Norwegian) are to be compiled and provided electronically (in one Eudralink package if applicable) to the EMA procedure assistant. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Day 35-45 (35-45 days after position) EMA will send the package to the CMDh and prepare the translations for publication.

After the translation process

Once the translations are received from the MAH, the Agency will check if the comments received from

Member States’ have been implemented.

a) In case of a CHMP opinion or a CMDh majority position the Agency will compile the Annexes in all languages and send the final copies to the EC, members of the Standing Committee and the MAH(s) at Day 27 (27 days after opinion). Following receipt of the final compiled translations, the EC will start the 22-day Standing Committee consultation, addressing only legal and public health matters (which means in principle no further linguistic review).

b) In case of a CMDh position by consensus, the Agency will compile the Annexes in all languages, send the final copies to the Member States and, where applicable, the full set of Annexes will be published on the EMA website.

Standards of translation of Annexes

The structure of the English Annexes has to be strictly followed and should be exactly translated as per

the adopted English version (i.e. full product information or only amendments to the relevant sections of the product information).

For translations of Annexes QRD templates for each language should be used

The title pages should be adjusted and all brackets (i.e. <>) are taken out in the title.

Sections should not be left out, and Annex III should not be updated, e.g. the sections [to be

completed on a national level] simply to be translated as ‘to be completed on a national level’.

Good quality of the translations and compliance with the Member States’ comments are required to

facilitate the process.

If a translation is considered not to be of an acceptable quality, the Member State concerned will inform the MAH and the Agency within 3 days of receipt of the translation. The Agency will inform the MAH of the insufficient quality of the translations and the transmission to the EC will be delayed until receipt of the amended translation (which would be expected within 1 week). A revised timetable will then be prepared.

The MAHs are also strongly advised to liaise directly with the Member States in case of disagreement with any of the comments made or in case further clarification on some comments is required, and to

reflect the outcome in “ QRD Form 2 ”.

In addition, the MAHs are reminded that in case the complete product information is part of Annex III, it should be presented in strict compliance with the QRD Convention (e.g. format, layout and margins).

The Agency will monitor the quality of the translations, the review by the Member States and MAHs’ compliance with the Member States’ comments as part of the Performance Indicators.

References

• QRD Convention European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Product Information Templates

• Product Information: Reference documents and guidelines

• List of Member States contact points for translations (with guidance on the sending of product information to Member States)

• EC Guideline on the operation of the procedures laid down in Chapters II, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008

13.10. How shall I implement the outcome of a non-interventional imposed PASS final study report procedure? Rev. Mar 2026

Depending on the type of outcome and whether an EC Decision is required (i.e. CHMP opinion or CMDh position by majority/ consensus), the implementation of the outcome of a non-interventional imposed PASS results vary as illustrated in the table below . For NAPs, further guidance on implementing variation can also be found on the CMDh website (Question & Answers, Pharmacovigilance legislation) .

Of note, products that are not involved directly in the procedure (i.e. products not listed in the Annex to the CHMP opinion or CMDh position) might be affected by the outcome and should implement accordingly when the adopted changes are applicable to their MA.

CAP products NAP products

Product involved in procedure

Yes No Yes No

Implementing variation needed, type and classification

Not applicable; implemented through EC decision to MAH

Yes (if changes applicable)

IB C.3.b

Yes

• IA IN C.3.a (harmonised national translations available)

• IB C.3.b (adaptation of wording needed)

• II (new data submitted; classification dependent on proposed changes)

Yes (if changes applicable)

• IA IN C.3.a (harmonised national translations available)

• IB C.3.b (adaptation of wording needed)

• II (new data submitted; classification dependent on proposed changes) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Timeframe for submission of variation

Not applicable MAHs to submit variations within two months after receipt of the EMA communication encompassing the safety updates referred to in the relevant procedure

For CMDh position by consensus (no EC decision adopted):

As per the date indicated in the translation timetable i.e. 105 4

calendar days after adoption of the CMDh position (see Question 10).

For CMDh position by majority vote or CHMP opinion (EC decision adopted):

10 days after publication 5 of EC decision on EC website.

For CMDh position by majority vote or CHMP opinion (EC decision adopted):

60 days after publication of EC decision on EC website.

13.11. When should I register my studies in the HMA-EMA Catalogue of real-world data studies (previously EU PAS Register)? Rev. Jul 2026

In order to support transparency of all non-interventional PASS, The MAH(s) shall register all non-interventional PASS imposed in accordance with Article 10 or 10a of Regulation (EC) No 726/2004 or with Articles 21a or 22a of Directive 2001/83/EC in the HMA-EMA Catalogue of real-world data studies (which replaces the EU PAS register as the electronic post-authorisation study register maintained by the Agency).

According to article 36(5) of Commission Implementing Regulation (EC) No 520/2012, the MAH(s) shall enter the study protocol, the abstract of the final study report and the final study report in the HMA-EMA Catalogue of real-world data studies. MAH(s) shall submit the study protocol before the start of data collection and the abstract of the final study report within one month after finalisation of the final study report.

In addition, Annex III of Commission Implementing Regulation (EC) No 520/2012 specifies that the date of registration in the Catalogue shall be included as a milestone in the final study report of the imposed non-interventional PASS.

445 calendar days for translation publication + 60 calendar days from publication of translations 5See also Q 3.3 of the Q/A-LIST FOR THE SUBMISSION OF VARIATIONS ACCORDING TO COMMISSION REGULATION (EC) 1234/2008 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure EMEA-H-19984/03 Page 197/305

After the relevant PRAC recommendation, the Agency will contact MAH(s) to make sure the information is available in the database and, unless alternative timelines are agreed, will enter the information on its own initiative to fulfil its legal obligations under Article 26(1)(h) of Regulation (EC) No 726/2004.

More information on how to provide documents to the Catalogue of real-world data studies for PASS studies can be found at Support | HMA-EMA Catalogues of real-world data sources and studies (europa.eu).

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• Commission Implementing Regulation (EC) No 520/2012 (as amended by Commission Implementing Regulation (EU 2025/1466)

• Guideline on good pharmacovigilance practices (GVP) Module VIII - Post-authorisation safety studies

13.12. Are outcomes of non-interventional imposed PASS published? Rev. Jul 2026

Study protocols, abstracts of the final study report and the final study reports of imposed non-interventional PASS are publicly available in the HMA-EMA Catalogue of real-world data studies (which replaces the EU PAS Register ).

The outcomes of imposed non-interventional PASS final study results assessments for active substances found only in centrally authorised medicines are published as part of each medicine's

European public assessment report (EPAR).

The outcome for nationally authorised medicinal products included in 'mixed' procedures where centrally authorised products were also involved can be found on the Union register maintained by the EC.

EMA publishes the outcomes of final study results of non-interventional imposed post-authorisation safety studies (PASS) for NAPs on the EMA website.

References

• HMA-EMA Catalogue of real-world data sources and studies (europa.eu)

• Outcomes of imposed non-interventional post-authorisation safety studies

13.13. What fee do I have to pay? Rev. Mar 2025

For information on fees to be paid, applicable fee reductions and payment process, please refer to the Fee Q&As in Annex I, Section 15, on the Fees payable to the European Medicines Agency page.

For any remaining question, the dedicated EMA fees query form can be completed and submitted.

References European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Directive 2001/83/EC

• Regulation (EU) 2024/568

• New fee regulation: General questions and answers for all applicants

13.14. Who should I contact if I have questions regarding my submission? Rev. Mar 2025

For centrally authorised products, if you cannot find the answer to your question in this Q&A when preparing your application, please contact the EMA Product Lead (PL) assigned to your product.

PASS protocols and final study results for NAPs will be handled by the RMS. You will be able to contact this PL throughout the procedure.

For pre-submission queries that are not covered by this guidance please submit your query using the following web form.

In the web form you will be asked to provide your name, the name of your employer or organisation, contact details and the subject of your enquiry. You should type the full details of your query in the appropriate space. The use of key words in the subject line will help the Agency allocate your query to the correct person.

Please give as much detail as possible when completing your request and be sure to include your correct and complete contact details. If the contact details you provide are incomplete or inaccurate this may prevent the Agency from communicating with you. In case of incomplete or incorrect data in the web form, the request may not be processed.

For questions related to fees, please use the dedicated EMA fees query form instead .

For technical queries related to the submission please contact us through the EMA Service Desk portal.

13.15. Scientific advice for safety studies Rev. Mar 2025

The Agency encourages scientific advice on safety studies to further develop an integrated lifecycle approach in the advice on medicines across safety, quality, efficacy pre- and post-authorisation, and to support proactive pharmacovigilance planning, which is elaborated through the Scientific Advice Working Party (SAWP) with the Pharmacovigilance Risk Assessment Committee (PRAC) involvement.

Scientific advice on safety studies is a voluntary procedure for Marketing Authorisation Holders (MAH) or Applicants, and complementary to existing ones.

13.15.1. Why should I consider seeking scientific advice on PASS?

By engaging in scientific advice on PASS, Applicants or Marketing Authorisation Holders (MAHs) can benefit from

• a strengthened PRAC-SAWP interaction

• a lifecycle approach to medicines advice with integrated advice on all aspects of medicines development from involved Committees European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• support for proactive pharmacovigilance planning

• advice at an early or late stage of the protocol development

• targeted advice on key issues

• a well-defined procedural timetable

• a preparatory meeting with Agency secretariat to consider suitability and validity of the dossier

• a discussion meeting with involved regulators during the procedure

• engagement with patient representatives

• options to include other stakeholders such as HTAs or FDA further supporting optimised evidence generation.

•

13.15.2. Which post-authorisation safety studies could benefit from scientific advice ?

Applicants/MAHs are encouraged to request scientific advice (SA) from the Agency on specific aspects of PASS protocols, especially for complex or controversial issues or for innovative approaches or methodologies. Based on experience gained, scientific advice is encouraged to be sought for non –

imposed PASS i.e. the category III PASS.

Applicants/MAHs wishing to request scientific advice on specific aspects of PASS protocols /or joint protocols by a consortium of MAH for PASS imposed as conditions to the marketing authorisation (i.e. category I and II PASS), can also submit a SA request. This is without prejudice to the provisions laid down in Article 107n of Directive 2001/83/EC for protocols of non-interventional imposed PASS to be assessed and endorsed by the PRAC.

13.15.3. Does EMA expect all PASS studies to go through scientific advice?

Scientific advice is a voluntary procedure, and it is the choice of the MAHs or Applicants to submit scientific questions related to PASS / PASS draft protocol for scientific advice.

13.15.4. Could requests for ‘mixed’ advice be submitted e.g. questions on

pre-marketing and post-marketing phases, or questions on PASS and pivotal phase III studies, or questions on interventional and non-interventional studies?

Yes, such mixed advice requests are possible.

13.15.5. Can a draft PASS protocol be submitted for scientific advice although the marketing authorisation application is still under assessment?

Early submissions of PASS protocols for scientific advice are possible. However, Applicants should duly consider the best timing for their request for scientific advice, i.e. whether at the moment of the submission there are sufficient certainties about the status and the objectives of the study. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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13.15.6. Can scientific advice be sought for nationally as well as centrally authorised products?

Yes, scientific advice can be sought for nationally as well as centrally authorised products.

13.15.7. Who will assess the PASS protocols for SAWP?

As per existing scientific advice procedures, the assessment is led by SAWP delegates acting as SAWP coordinators. Two SAWP members/alternates are appointed as coordinators for each scientific advice procedure. A further PRAC peer-reviewer is appointed to provide additional product specific PRAC input.

13.15.8. How will the PRAC Rapporteur for a product be involved in the scientific advice?

The PRAC Rapporteur for a specific product is either appointed as the PRAC peer-reviewer or involved through the SAWP coordinators (i.e. assessment team from the same member state for a specific scientific advice procedure.

13.15.9. Is the necessary expertise available in SAWP to evaluate PASS protocols?

Expertise in pharmacoepidemiology needed to evaluate PASS protocols, is available through at least 2 joint SAWP - PRAC delegates who can also act as SAWP coordinators for a specific scientific advice product procedure.

13.15.10. What is the role of the PRAC within the scientific advice procedure for PASS protocols?

Scientific advice procedures for PASS will involve PRAC systematically in the procedure. All scientific advice documents will be available to the PRAC during the procedure. The questions will be referred for discussion to the PRAC, and a Final Advice Letter will be issued.

Each procedure will have a named PRAC peer-reviewer appointed to provide product specific PRAC input. The PRAC Rapporteur for a product will be systematically involved either as PRAC peer-reviewer or through the SAWP coordinatorship roles to ensure continuity across procedures through the lifecycle of the products.

13.15.11. For non-imposed PASS (category III), is it mandatory for companies to submit the study protocols to PRAC?

For category III studies, there is no legal obligation for companies to submit the protocol to the PRAC. However, the PRAC may request to review the protocol of some of these category III studies which are of interest for the committee and for which such submission of protocol is reflected as a milestone in the Risk Management Plan. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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13.15.12. What about non-imposed PASS protocols required to be submitted by the PRAC that have not been through an EMA scientific advice procedure?

The final protocols for non-imposed PASS required by the PRAC can continue to be submitted to the PRAC as a post-authorisation measure (PAM).

13.15.13. How do I apply for scientific advice on a PASS protocol?

An application for scientific advice should be submitted to the Agency via the IRIS platform together with a briefing document in accordance with published EMA scientific advice guidance and timelines. See link here.

13.15.14. What is the format of the briefing document?

The MAH or Applicant provides questions and an accompanying justification of the approach taken with the relevant introduction, background, annexes and references. Please see the published scientific advice briefing document template.

13.15.15. What kinds of annexes are required?

Protocols or synopses, SmPCs, Risk Management Plans (RMPs) and assessment reports pertinent to the topic should be annexed as appropriate. Ready availability of relevant documents and references facilitates assessment.

13.15.16. What type of question is expected to be raised for the concerned study protocols?

In general, any question pertaining to the draft protocol can be posed in the draft briefing document.

Feedback on whether the MAH or Applicant’s draft questions can be validated as posed or reworded will

be given at the validation stage.

13.15.17. Could questions be asked about the choice of the adverse reactions of interest?

In general, any question pertaining to the draft protocol can be posed in the draft briefing document. Feedback on whether questions can be validated as posed or reworded will be given at the validation stage. Specifically, scientific advice can be sought for the selection of adverse reactions of interest.

13.15.18. How will scientific advice procedures for safety studies be run?

In summary, scientific advice will follow the same procedure as other scientific advice with the exception of the appointment of PRAC peer-reviewer and involvement of PRAC.

The EMA Secretariat should be formally notified by submission of a scientific advice or protocol assistance request via the IRIS platform.

A preparatory meeting with Agency staff will be arranged, if requested, to consider the suitability and validity of the submission. Following the preparatory meeting and validation, an amended electronic final package is submitted and circulated to the appointed coordinators and experts in line with agreed timelines. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The SAWP Coordinators will then draft preliminary reports in response to the scientific advice or protocol assistance request taking into account the timetable for evaluation of such requests. In addition to the SAWP coordinators, a PRAC peer-reviewer is appointed to follow the procedure and contribute to the reports, plenary meeting discussions and discussion meeting with the MAH/Applicant when applicable. The preliminary reports are discussed in the SAWP and PRAC plenary meetings and are made available to other involved Working Parties, Committees, and experts, as appropriate. If considered necessary, a list of issues for discussion at the discussion meeting is sent to the MAH/Applicant. A discussion meeting with the MAH/Applicant and members of the SAWP is held the following month.

Following the discussion meeting with the MAH/Applicant, and further to the SAWP and PRAC plenary discussions, the SAWP Coordinators issue a draft joint report for comments by the involved participants.

All submission documents and reports are available to all PRAC members throughout the procedure. The final advice letter is adopted by the CHMP before sending to the MAH/Applicant.

For further information please refer to the steps of the scientific advice process.

13.15.19. Is a preparatory meeting always expected, or can the MAH/Applicant choose not to have one?

Requests for preparatory meeting are voluntary and, the MAH/Applicant can choose not to request one.

13.15.20. Is a discussion meeting with the MAH/Applicant during the procedure always expected?

The need for a discussion meeting is decided following the discussion of preliminary reports at SAWP plenary and it might not be considered necessary in some cases.

13.15.21. What is the nature of the discussion meeting?

Information regarding the discussion meeting is provided in the FAQ “ How do I prepare for a Discussion meeting? ” in the published scientific advice guidance.

13.15.22. Can additional data or amended protocols be submitted during the procedure?

Additional data or amended protocols can be submitted at a specific point during the scientific advice procedure further to the SAWP list of issues, when applicable (refer to the question on ‘ Is a discussion meeting with the MAH/Applicant during the procedure always expected ?’) . The MAH/Applicant may also propose in writing to the Agency additional points for discussion that are not part of the adopted list of issues and submit these in writing ahead of the Discussion meeting. Any amendment/change to the development program should be notified to the Agency /SAWP ahead of the discussion meeting.

13.15.23. Will the EMA support for these protocols be different from any other scientific advice?

Procedures for PASS protocols will not be handled any differently than for existing scientific advice procedures except the extension to and inclusion of PRAC interactions. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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13.15.24. Will fees be levied for scientific advice provided for PASS protocols?

Yes, in accordance with the Agency's Fee Regulation (EU) 2024/568 of the European Parliament and of the Council and its working arrangements, fees will be levied on MAH/Applicants seeking scientific advice on PASS protocols.

For further details on fees and fee incentives/reductions please consult the Agency’s webpage on Fees payable to the European Medicines Agency | European Medicines Agency (EMA) .

13.15.25. Where can I find further information about scientific advice?

Please see the published EMA scientific advice guidance for many FAQs.

13.16. When and how should study progress reports and interim results be submitted? Rev. Apr 2021

The timelines of the progress reports for a given study should be pre-specified and indicated in the protocol. These progress reports may include available interim results, but there is in general no obligation or recommendation to include interim results in RMPs unless required as part of an agreed pharmacovigilance plan. This is without prejudice that a variation as appropriate should be submitted should these interim results lead to product information changes or RMP changes.

For centrally authorised products, progress reports and interim results, when requested, should be submitted as post-authorisation measure (PAM) and should follow the timetable of PAMs assessed by PRAC. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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14. Post-authorisation efficacy study (PAES)

14.1. What is a PAES imposed in accordance with the Commission Delegated Regulation?

PAES imposed in accordance with the Commission Delegated Regulation (EU) No 357/2014 it is meant an efficacy study which is requested by a Competent Authority pursuant to at least one of the situations set out in this said regulation. The data resulting from such a PAES conducted within an authorised therapeutic indication are required to be submitted as they are considered important for complementing available efficacy data in the light of well-reasoned scientific uncertainties on aspects of the evidence of benefits that is to be, or can only be, addressed post-authorisation. The results of the PAES have the potential to impact on the benefit-risk of the medicinal product or product information.

Such efficacy study conducted post-authorisation can be imposed either:

at the time of granting the initial marketing authorisation (MA) where concerns relating to some

aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed; or

after granting of a MA where the understanding of the disease or the clinical methodology or the use of the medicinal product under real-life conditions indicate that previous efficacy evaluations might have to be revised significantly.

It is also possible to impose the conduct of post-authorisation efficacy studies in the specific situations of a conditional MA, a MA granted in exceptional circumstances, a MA granted to an advanced therapy medicinal product, the paediatric use of a medicinal product, a referral procedure initiated under Article 31 or Article 107i of Directive 2001/83/EC or Article 20 of Regulation (EC) No 726/2004, however these fall outside the scope of the Delegated Regulation.

References

• Regulation (EC) No 726/2004

• Directive 2001/83/EC

• Commission Delegated Regulation (EU) No 357/2014

• Draft scientific guidance on post-authorisation efficacy studies

14.2. How and where the PAES imposed in accordance with the Commission Delegated Regulation will be reflected in the marketing authorisation? Rev. Mar 2026

For centrally authorised medicinal products (“CAPs”), a PAES imposed as a condition to the MA is reflected in Annex II under section D “Obligation to conduct post -authorisation measures”.

The study objective and the deadline for the submission of the final study results are specified in the Annex II. At the beginning of the description of the study, such efficacy study imposed in accordance with the Delegated Regulation is explicitly named ‘Post -Authorisation Efficacy Study (PAES)’.

The imposition of such PAES shall meet one of the criteria set out in the Delegated Regulation. A justification will be provided in the CHMP assessment report. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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If the MAH has to submit the protocol for endorsement by the European Medicines Agency, this will be

reflected in Annex II in the wording of the condition (e.g. “according to an agreed protocol”).

Any post-approval amendments to the conditions in Annex II (objective and/or due date) should be duly justified and submitted as a variation, Type IB C.9.b for change in the due date or Type II C.I.c for changes other than the due date.

As for any imposed post-authorisation efficacy studies, those imposed in accordance with the Delegated Regulation should also be reflected in the risk management plan (“RMP”), part IV ‘ Plans for post-authorisation efficacy studies ’.

References

• Commission Delegated Regulation (EU) No 357/2014

• GVP module on RMP

14.3. Following which procedure will my imposed PAES protocol be assessed?

If the review of the imposed PAES protocol has been reflected in the Annex II, the MAH will have to submit a draft protocol to the European Medicines Agency as a post-authorisation measure (“PAM”).

Otherwise, the review of the protocol is not deemed necessary.

The MAH is generally advised to consider seeking scientific advice on the study design irrespective of whether the submission of the protocol has been requested, in order to discuss the design of the study and ensure that it meets the intended objectives.

In case the PAES is a clinical trial, it falls under the scope of Directive 2001/20/EC (to be superseded by the Clinical Trial Regulation (EU) No 536/2014) and is subject to the national clinical trial authorisations.

References

• Scientific advice procedure

• EMA post-authorisation procedural advice for users of the centralised procedure (PAG) – Post-authorisation measures (PAMs)

• Directive 2001/20/EC

• Regulation (EU) No 536/2014 on clinical trials for medicinal products for human use

14.4. When should I submit my imposed PAES protocol? Rev. Mar 2026

If the submission of the protocol has been requested in the Annex II, the MAH should submit the protocol in accordance with the timeframe specified in the RMP, part IV as timelines for protocol submission are not specified in the Annex II.

At time of imposition, the MAH is asked to propose appropriate dates for the submission of the protocol and the post-authorisation data that are proportionate to the uncertainty to be addressed. The proposed dates for submission are subject to agreement wi th the Agency’s Committee(s). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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If the MAH would be unable to provide the protocol by the specified deadline, the MAH must inform the Agency and the Rapporteur in writing as early as possible in advance of the submission due time. The delay must be duly justified and a new submission date should be proposed. Such request should be sent to your Product Lead and will be subject to agreement by the Committee(s).

If the submission date of the final study results mentioned in the Annex II is impacted, this requires the submission of a Type IB variation C.9.b.

14.5. In which timeframe will my imposed PAES protocol be evaluated (timetable)?

The evaluation of the PAES protocol will be led by the CHMP with consultation of other committees where foreseen. The evaluation will be handled as a 60-day PAM procedure, which follows the

timetables available on the Agency’s website.

The protocol assessment will start in accordance with the published timetable for PAMs which is available on the following webpage.

14.6. What are the possible outcomes of the evaluation of an imposed PAES protocol?

The CHMP, taking into account advice of other committees where provided, will conclude the assessment of the protocol according to the following options:

endorsement of the protocol;

objection to the protocol;

In case of endorsement, the assessment report may still include recommendations for amendments to the protocol. These recommendations are for consideration by the MAH and do not require resubmission of the protocol.

In case of objection, resubmission of an amended protocol for reassessment will be required.

14.7. Do I have to submit interim results?

There is no obligation to submit interim results, unless it has been requested by the Committee(s).

However, when requested, interim results should be submitted as a PAM (see: Under which procedure should I submit my PAM?) unless there is an impact on the product information. In such case a variation should be submitted. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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14.8. Do I have to submit the final results of my imposed PAES? Rev. Jun 2016

Upon completion of the study, a final study report shall be submitted by the deadline specified in Annex II via the appropriate variation procedure irrespective of changes to the product information.

The MAH should consider whether the final results have an impact on the marketing authorisation. If the MAH concludes that this is the case, the MAH should submit the results together with the proposed changes to the product information.

The classification of the variation will depend on whether there are proposed changes to the product information.

With the application submitted, the MAH should indicate in the table of the cover letter of the application which post-authorisation measure is being addressed and the full description of the relevant measure.

The CHMP will lead on the assessment of the study results and will conclude, taking into account advice of other Committees where provided.

In addition, it is reminded that the MAH should provide in the PSUR, as usual, a summary of the clinically important efficacy and safety findings obtained from the study during the reporting interval.

14.9. Do I have to pay fees for the protocol and final study results submission?

There is no fee payable for the protocol submission as a PAM procedure.

For the final study results submission, there are fees applicable to the related variation procedure.

14.10. How is a PAES enforced?

The Agency will keep a record of the post-authorisation measure and its due date in its database.

In case of overdue condition or a MAH being found non-compliant in satisfying such condition, the competent authorities will consider the need for appropriate actions to be taken.

In such situations, the Rapporteur (or a lead Rapporteur nominated by the Committee in case of more than one affected product) may draft an assessment report on the impact of the lack of data on the benefit/risk balance of the affected medicinal product(s). Based on the outcome of such assessment and/or discussion, one or more of the following actions may be taken:

• Letter to the MAH by the Chair of the Committee

• Oral Explanation by the MAH to the Committee

• Initiation of a referral procedure with a view to vary/suspend/revoke the MA

• Inspection to be performed upon request of the Committee(s)

Such regulatory action in regards to non-compliance of the MAH may be made public on the Agency website, e.g. in the EPAR(s) of the affected medicinal product(s). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

14.11. Will there be any publication on the outcome of my PAES protocol and final study results assessment?

Outcome of protocol assessment are not published on the EMA Website. However, in case of a clinical trial the protocol and summary will be available in the clinical trials database, as per usual procedure.

Outcome of final study results will be published in the EPAR under ‘Procedural steps taken and scientific information after the authorisation’. Relevant results of the study will be included in the

SmPC.

To support transparency on PAES that are outside the scope of Directive 2001/20/EC, study information (including for studies conducted outside the EU) should be made available in the EU electronic register of post-authorisation studies (EU PAS Register) maintained by the Agency. 6

References

• EPARs

14.12. Who should I contact if I have a question when preparing my application and during the procedure? Rev. Feb 2019

If you cannot find the answer to your question in this Q&A when preparing your application or during the procedure, please contact the Product Lead responsible for your product.

6http://www.encepp.eu/encepp_studies/indexRegister.shtml European Medicines Agency post-authorisation procedural advice for users of the centralised procedure EMEA-H-19984/03 Page 209/305

15. Post-Authorisation Measures (PAMs)

15.1. What are PAMs? Rev. Apr 2015

At the time of finalising a procedure or in follow-up of a signal evaluation, the Agency’s Committee(s)

may agree that the applicant/MAH should provide additional data post-authorisation, as it is necessary from a public health perspective to complement the available data with additional data about the safety and, in certain cases, the efficacy or quality of authorised medicinal products. Such post-authorisation measures (PAMs) may be aimed at collecting or providing data to enable the assessment of the safety or efficacy of medicinal products in the post-approval setting.

The existence of such a system of PAMs does not aim at promoting premature approvals of marketing authorisations or post-authorisation procedures. The background and rationale for requesting PAMs will be described in the relevant assessment, which will present the context and nature of the PAM. Based on the assessment of the committee(s), PAMs are classified into their appropriate legal framework under which they will be enforced.

The following diagram explains how PAMs are categorised; in addition, each PAM category is explained in the following sections:

Fig.: Schematic overview of decision tree for the classification of PAMs European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Consequently, PAMs fall within one of the following categories [EMA codes 7]:

• specific obligation [SOB]

• annex II condition [ANX]

• additional pharmacovigilance activity in the risk-management plan (RMP) [MEA] (e.g. interim results of imposed/non-imposed interventional/non-interventional clinical or non-clinical studies)

• legally binding measure [LEG] (e.g. cumulative review following a request originating from a PSUR or a signal evaluation [SDA], Corrective Action/Preventive Action (CAPA), paediatric [P46]

submissions, MAH’s justification for not submitting a requested var iation)

• recommendation [REC] e.g. quality improvement

Only certain medicinal products can be subject to specific obligations (see also ‘ What is a Specific Obligation? ’). PAMs other than specific obligations can be required for any type of authorisation and will be included in the opinion of an initial marketing authorisation or further to the committees’

assessment during post-authorisation.

The wording of the PAM will describe the issue under investigation that has led to the request together with a clear outline of the studies or activities expected to address it and the deadline for its submission. Compliance with these measures is defined by both the submission of the requested data and adherence to the agreed timeframe.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

15.2. What is a specific obligation [‘SOB’]? Rev. Dec 2017

Specific obligations can only be imposed on marketing authorisations granted under exceptional circumstances or on conditional marketing authorisations (see also questions on ‘Is my medicinal product eligible for approval under exceptional circumstances ?’ and ‘ Could my application qualify for a conditional marketing authorisation? ’ of the Agency’s pre -submission guidance). These are conditions to the marketing authorisation included in annex II.E of the Commission decision and form the basis of the annual re-assessment or the annual renewal. These may also be additional Pharmacovigilance activity and will be included as well in the RMP (category 2 studies).

Continuation of a marketing authorisation under exceptional circumstances or the renewal of a

conditional marketing authorisation will be determined by the MAH’s compliance with the specific

obligations, which are checked annually as part of either the annual reassessment or the annual renewal procedures.

As specific obligations are binding conditions to the marketing authorisation, any modification proposal by the MAH with regards to their description or due date (as described in Annex II of the product

7These codes relate to the Agency’s product and procedures tracking database called SIAMED and will be used, together with a numbering system, to identify each PAM of a medicinal product both in the database and in any correspondence of the Agency with the MAH European Medicines Agency post-authorisation procedural advice for users of the centralised procedure EMEA-H-19984/03 Page 211/305

information) has to be submitted within an appropriate procedure, i.e. either within the annual re-assessment, the annual renewal or a variation application.

Interim results not impacting on the product information or on the description of the specific obligation can be submitted as a PAM as described below, if they are not part of the annual reassessment or annual renewal. (see: How and to whom shall I submit my PAM data ?).

In case of interim results impacting on the product information, a variation should be submitted without waiting for the annual re-assessment or annual renewal.

Final results leading to the fulfilment of the specific obligation should be submitted within an appropriate procedure, i.e. either within the annual re-assessment, the annual renewal or a variation application.

Where a specific obligation falls within the definition of a non-interventional post-authorisation safety study (PASS) imposed after 2 July 2012, the MAH will have to follow the procedure for review of imposed PASS protocols and results as described in the Agency’s post -authorisation procedural advice on PASS and in the corresponding guideline on good pharmacovigilance practices (GVP): Module VIII -PASS.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 507/2006 on conditional marketing authorisation

• EMA post-authorisation procedural advice on PASS

• Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies

15.3. What is an annex-II condition [‘ANX’]? Rev. Jun 2016

The European Commission can impose on the marketing authorisation holder (MAH) the obligation to conduct post-authorisation measures. These obligations can be imposed at the time of the granting of the marketing authorisation or later, as conditions to the marketing authorisation. These are conditions to the marketing authorisation included in Annex II.D of the marketing authorisation. These may also be additional Pharmacovigilance activity and will be included in the RMP (category 1 studies).

Annex-II conditions are post-authorisation measures which, whilst not precluding the approval of a marketing authorisation or other post-authorisation procedures, are considered to be key to the benefit / risk balance of the product. These can consist of post-authorisation safety or efficacy study.

As annex-II obligations are binding conditions to the marketing authorisation, any modification

proposal by the MAH with regards to their description or due date has to be submitted as a variation application.

Interim results not impacting on the product information or on the condition as stated in the Annex II can be submitted as a PAM as described in question How and to whom shall I submit my PAM data? .European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Final results leading to the fulfilment of the Annex II condition should be submitted as a variation application.

Where an annex-II condition falls within the definition of a non-interventional PASS imposed after 2 July 2012, the MAH will have to follow the procedure for review of imposed PASS protocol and results

as described in the Agency’s post -authorisation procedural advice on PASS and in the corresponding guideline on good pharmacovigilance practice (GVP): Module VIII - PASS.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• EMA post-authorisation procedural advice on PASS

• Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies

15.4. What is an additional pharmacovigilance activity in the risk-

management plan [‘MEA’]? Rev. Aug 2020

Additional pharmacovigilance activities in the RMP (category 3 studies) may be non-clinical studies, clinical trials or non-interventional studies which are required to investigate a safety concern of a medicinal product. These studies are listed in the pharmacovigilance plan of the risk-management plan (RMP) and are either aimed at identifying and characterising risks, or at assessing the effectiveness of risk-minimisation activities.

All relevant milestones, together with their due dates should be included in the summary table of additional PhV activities in the RMP. The MAH has the obligation to provide the requested data within the stated timeframes.

Once additional pharmacovigilance activities have been agreed within the RMP, changes to these measures (e.g. proposals for adjusting due dates of agreed milestones, proposals to change the scope of agreed study or its duration, etc.) should be submitted via the appropriate variation procedure to amend the RMP.

Information not impacting on the product information or description/due date of the measure itself, (e.g. interim results) , can be submitted as a self-standing PAM as described in question How and to whom shall I submit my PAM data? .

Submissions of final study reports leading to the fulfilment of a MEA should be addressed via the appropriate variation procedure. (see also: Under which procedure should I submit my PAM?).

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• EMA pre-submission procedural advice on RMP

• Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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15.5. What is a legally binding measure [‘LEG’]? Rev. May 2020

Some post-authorisation measures (PAMs) are already defined as statutory obligations in the pharmaceutical legislation. As such, they have to be fulfilled by the MAH upon request of the Agency and its committees. Examples for such directly binding legal measures evaluated as PAMs are:

• Requests for provision of data as a stand-alone submission (e.g. cumulative review following a PSUR assessment).

• Requests for supplementary information to evaluate a signal (see EMA’s Questions and answers on

signal management)

• Requests for update of the product information

• Obligations to submit any data requested in relation to CAPA corrective action or preventive action (CAPA) in the context of inspections

• Submission of final results of study involving paediatric patients submitted in fulfilment of Article 46 of the Paediatric Regulation.

Where requested, these are directly addressed to the MAH by the Agency, either within the assessment

report of the committee(s) or within a letter informing about the Committee(s)’(s) conclusions and

have to be responded to within the stated time frame.

Requests for updates of the product information should be addressed via a variation; a scientific justification for not submitting a requested variation should be submitted as a PAM.

When responding to these requests, the MAH should select “pam -leg” as submission type when filling

in the eSubmission delivery file except for:

• Submission of final results of study involving paediatric patients submitted in fulfilment of Article 46 of the Paediatric Regulation where the MAH should select the “pam -p46” when filling in the

eSubmission delivery file.

• Provision of supplementary information to evaluate a signal or a scientific justification for not submitting a requested variation following a signal assessment, where the MAH should select

“pam -sda” when filling in the eSubmission delivery file .

In accordance with the Paediatric legislation, MAHs should submit paediatric studies within six months of their completion and irrespective of whether it is part of a PIP (completed or not yet completed) or not, or whether it is intended for submission later on as part of a variation, extension or new stand-alone marketing-authorisation application.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• Questions and answers on signal management

• Submission of Article-46 paediatric studies: questions and answers

• Communication from the Commission — Guideline on the format and content of applications for agreement or modification of a PIP and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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15.6. What is a recommendation [‘REC’]? Rev. Apr 2015

During the assessment of an application, the committee(s) may issue recommendations for further development of the medicinal product, e.g. either in terms of optimising some quality aspects or considerations for extending the patient population. Although these recommendations for further development are not binding to the marketing authorisation, they should be seen as important considerations in view of the potential future use of a medicinal product by the MAH.

This information can be submitted as a PAM however if data obtained in the framework of a recommendation has an impact on the authorised medicinal product and its product information, the MAH has the obligation to submit a variation application as appropriate (see: How and to whom shall I submit my PAM data? ).

As such, the committee(s) will keep an overview of all recommendations made to a marketing authorisation and monitor whether, how and when the MAH has addressed them. Therefore, MAHs are encouraged to use the template for the cumulative letter of recommendations to acknowledge these recommendations.

MAHs should specify the following in their letter of recommendations:

• a clear and concise description of each post-approval recommendation;

• the procedure number where the recommendation was given.

No deadline needs to be mentioned.

When data in relation to a recommendation is provided to the Agency, an updated Letter of Recommendation should be provided, in which the MAH should indicate the date of submission and its format (e.g. as self-standing data, within a variation, within a renewal etc.).

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

15.7. Can the classification of my PAM change during its lifecycle? Rev. Apr 2015

New data or information regarding the medicinal product becoming available can result in the committee(s) considering that a PAM should be reclassified. Such reclassification will be performed within the procedure discussing the impact of the new information that has become available and will be justified in the assessment report where the measure is, as a consequence, up- or downgraded.

15.8. When shall I submit my PAM? Rev. Mar 2026

The MAH shall submit the PAM data according to the timeframe specified by the Agency’s committee(s)

as specified either in the annex II, the RMP or the respective committee assessment. When requested, the MAHs should propose due dates for the submission of the post-authorisation data that are realistic and proportionate to the uncertainty to be addressed which are then subject to agreement with the

Agency’s committees. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Data submitted as PAM should be submitted as per the deadline specified by the Committee(s) and will start in accordance with the published submission dates for PAMs (see also Human Medicines -Procedural timetables / Submission dates). Assessment of PAM data submitted after the recommended submission date will start in accordance with the start date of the following month.

If the MAH is unable to provide the required data by the specified deadline, he must inform the Agency and the rapporteur in writing as early as possible in advance of the due time of submission. The reason for the delay must be justified and a new submission date proposed and is subject to agreement by the Committee(s). These submissions should be done as follows:

• Changes to the due date for a SOB, Annex II condition or category 3 study in the RMP should be submitted as Type IB variation category C.9.b, include the updated RMP and/or product information as applicable.

• Proposals for changes to directly legally binding measures (LEG including SDA) have to be notified

in writing, together with an appropriate justification, and have to be agreed as well by the Agency’s

Committee(s).

• In the case of a non-justifiable delay, the Agency’s committees will consider taking regulatory

action (see also next question).

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

15.9. Under which procedure should I submit my PAM? Rev. Mar 2026

The procedure under which the PAM should be submitted will depend on the content and type of information submitted as part of the PAM, as summarised in the table below:

PAM Submission Procedure/Type of application

Specific obligation

(category 2)

[SOB]

Non-interventional PASS See Post Authorisation Safety Study

• Protocol and substantial amendments

Article 107n-o

• Interim results SOB

• Final results Article 107p-q

Annex II E Interventional Efficacy Studies European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Protocol (where requested to be submitted)

Stand-alone PAM [SOB]

Where a protocol is not requested to be submitted by

the Agency’s Committee, the

MAH should consider seeking scientific advice

• Interim results Conditional renewal, annual re-assessment

(Note: if submission of interim results is requested outside of the timelines of the renewal or annual re-assessment, these can be submitted as stand-alone PAM, if no changes to the PI are proposed), alternatively a Type II would be required.

• Final results Conditional renewal, annual re-assessment or Type II variation, depending on the timelines.

Annex II condition (category 1)

[ANX]

Non-interventional PASS See Post Authorisation Safety Study

• Protocol and substantial amendments

Article 107n-o

• Interim results ANX

• Final results Article 107p-q

Other studies (including PAES)

• Protocol (where requested to be submitted)

Stand-alone PAM [ANX]

Where a protocol is not requested to be submitted by

the Agency’s Committee, the

MAH should consider seeking scientific advice European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Interim results

• No changes to PI

• Changes to PI

Stand-alone PAM [ANX]

Type II variation

Other studies: Final results Type II variation

Additional Pharmacovigilance activity in the RMP

(category 3)

[MEA]

Protocol (as requested by Committee and reflected as a milestone in the RMP)

Stand-alone PAM [MEA]

Where a protocol is not requested to be submitted by

the Agency’s Committee, the

MAH should consider seeking scientific advice

Interim results

• No changes to PI

• Changes to PI

Stand-alone PAM [MEA]

Type II variation

Final results Type II variation

Legally binding measure

[LEG]

(including [SDA] and [P46])

Provision of data requested by the Committee (e.g. cumulative review, CAPA, interim study results)

([SDA] when related to a signal assessment)

• with no changes to the PI Stand-alone PAM [LEG]/[SDA]

• with PI changes Type II variation

Final study report Type II variation

Justification for not submitting a variation

([SDA] when related to a signal assessment, otherwise [LEG])

Stand-alone PAM [LEG]/[SDA]

Submission of final results of study involving paediatric patients in accordance with Article 46 of the Paediatric Regulation [P46]

• No changes to PI Stand-alone PAM [P46]

• Changes to PI Type II variation

Recommendation

[REC]

Interim results

• No changes to PI Stand-alone PAM [REC] European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Changes to PI Type II variation

Final results Type II variation

ERA study results with no impact to PI

Type IB C.z variation

Recommendation [REC] - Quality

No changes introduced to Module 3 (confirmatory data e.g. confirmatory stability data (without claiming a change in shelf-life/ in-use shelf-life or storage conditions)

Stand-alone PAM [REC]

Changes introduced to Module 3 Respective variation as per the Variation Classification Guideline

Where the deliverable of a measure is submitted as part of another procedure, the structure of the submission package should follow the requirements of this procedure and the MAH should indicate in the cover letter of the application which PAM is being addressed, including the EMA reference number and the full description of the relevant PAM. The PAM submission form does not need to be included in the variation submission package. The MAH does not need to submit a separate ‘stand -alone’

submission of the PAM data.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• EMA post-authorisation procedural advice - variations

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

15.10. How shall I structure my PAM submission dossier? Rev. May 2020

The Agency will check PAM submissions with respect to the Guidelines on Variations to ensure that it does not fall within one of the classifications. In this regard, the Agency will reject any PAM submission that should be filed as a variation application. In such cases, the eCTD submission of the variation application should provide a reference to the PAM eCTD submission for this sequence to be closed. Where the MAH is requested to resubmit as a variation application, the start of the variation procedure will be upon receipt of the complete application according to the next upcoming starting date as per published timetable for Type II.

’Stand -alone’ PAM submission must include:

• a cover letter and a duly completed eSubmission delivery fileto facilitate registration European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• A completed PAM submission form with the full description and reference number of the PAM – as available. (The number to be quoted is the number attributed by the Agency at the time of adoption of the PAM including - for SDAs - the EPITT number). The description should mention the due date, including any agreed extension of it. This form will ensure the correct classification of the submission, involvement of designated Committees(s) and timetable to be applied.

• All supportive documentation relevant to the fulfilment of the PAM should be presented in accordance with the appropriate headings and numbering of the European Common Technical Document (EU-eCTD) format.

• Any scientific advice or protocol assistance obtained in relation to the fulfilment of PAMs concerned should be included.

References

• PAM submission form

• EMA post-authorisation procedural advice - variations

• Regulatory and procedural guidance on dossier format

15.11. How and to whom shall I submit my PAM data? Rev. Feb 2019

Information is available on ‘Submitting a post -authorisation application’.

15.12. How shall my submission of PAM be handled (timetable), and what could be the outcome of the evaluation? Rev. Jul 2021

This section only applies to submissions of PAM data as a ‘stand -alone’ submission.

Most PAMs will be evaluated by CHMP (and CAT if an advanced therapy medicinal product).

However, PRAC will lead the review of protocols or interim results of non-interventional safety studies and in any follow-up PAM to a procedure primarily assessed by PRAC (e.g: cumulative safety review requested further to the assessment of PSUR [LEG] or a signal [SDA]).

PAMs will be handled using one of the three timetables:

• CHMP led PAM assessment timetable

• PRAC led PAM assessment timetable

• Urgent PRAC led PAM assessment timetable, e.g. for urgent signal PAMs [SDA]

The submission deadlines and full procedural detailed timetables are published as a standard calendar on the EMA website (see: Human Medicines – Procedural Timetables / Submission dates).

The Agency will send to the MAH the final assessment report after CHMP adoption. The following outcome may be envisaged depending on the committee’s conclusion:

• the PAM is fulfilled and no further action is required; European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• the PAM is not yet fulfilled, as further clarifications or additional data are required. A request for supplementary information to be addressed by the MAH within a given timeframe will be issued and a follow-on PAM (such as MEA 00X. 1) created. The PAM will only be considered as fulfilled,

once all requests for supplementary information have been addressed by the MAH to the Agency’s committees’ satisfaction;

• PAM is fulfilled but follow-up regulatory action is required, e.g. a request for variation and this will result in a new PAM being issued.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

15.13. Do I have to pay fees for the PAM data submission? Rev. Apr 2015

There is no fee payable for a PAM stand-alone submission.

15.14. How are PAMs enforced? Rev. Mar 2026

The Agency will keep a record of the post-authorisation measure and its due date in its database. In addition, compliance with specific obligations is assessed annually, as part of the annual renewal (for conditional marketing authorisations) or annual reassessment (for marketing authorisations under exceptional circumstances).

In the case of an overdue post-authorisation measure or a MAH being found non-compliant in satisfying such a measure, the Agency will consider the need for appropriate actions to be taken including involvement of the relevant committee(s).

In such situations, the rapporteur (or a lead rapporteur nominated by the committee in case of more than one affected product) may draft an assessment report on the impact of the lack of data on the benefit/risk balance of the affected product or other analysis to support a discussion on the next steps

by the Agency’s committee(s). Based on the outcome of such assessment and/or discussion, one or

more of the following steps may be proposed:

• letter to the MAH by the chair of the committee

• oral explanation by the MAH to the committee

• regulatory action with a view to vary/suspend/revoke the MA

• inspection to be performed upon request of the committee(s).

Non-compliance of a MAH with a post-authorisation may be made public by the Agency on its website e.g. in the EPAR(s) of the affected product(s).

It should also be noted that non-compliance with certain marketing authorisation obligations may lead to the initiation of an infringement procedure in accordance with Article 84a of Regulation (EC) No 726/2004, read in conjunction with Commission Regulation (EC) No 658/2007.

References European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• Commission Regulation (EC) No 658/2007

15.15. Will there be any publication on the outcome of my PAM? Rev. Apr 2015

Outcome of PAMs are not published in the EPAR ‘Procedural steps taken and scientific information after the authorisation’. However, assessment reports for data submitted in accordance with Article 46 of

the Paediatric R egulation and PRAC recommendations on signals are published on the Agency’s

website.

Reference

• EPARs

15.16. Who should I contact if I have a question when preparing my application? Rev. Apr 2019

If you cannot find the answer to your procedural question in the post-authorisation measures: question and answers when preparing your application, please contact your Product Lead.

15.17. Who is my contact at the European Medicines Agency during post-authorisation procedures? Rev. Feb 2019

Information is available on ‘Submitting a post -authorisation application’. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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16. Risk Management Plan

16.1. When should I submit a new/updated RMP? Rev. Dec 2017

A new RMP or an update of the RMP, as applicable, may need to be submitted at any time during a

product’s lifecycle.

Since July 2012, all new marketing authorisations (MAs) applications should include an RMP. However, as the provision of an RMP was not mandatory before that date, there are still MAs for some centrally authorised products without an RMP. It should be noted, however, that for these products without RMP there are situations (e.g. new safety concerns, significant changes to the MA) that may trigger the need to introduce an RMP. For medicinal products with an RMP, whenever new data are provided as part of a regulatory application in the post-authorisation setting, the MAH should consider whether consequential significant changes to the RMP are needed. Should this be the case, a revised RMP should be included as part of the regulatory application as it is the responsibility of the MAH to update the RMP whenever new information is being received that have a significant impact on the content of the RMP.

An RMP update is expected to be submitted at any time when there is a change in the list of the safety concerns or when there is a new or a significant change in the existing additional pharmacovigilance or additional risk minimisation activities. For example, a change in study objectives, population, due date of final results, a due date for protocol submission for an imposed study, or addition of a new safety concern in the key messages of the educational materials would be expected to be reflected in an updated RMP with the procedure triggering those changes. The significant changes of the existing additional pharmacovigilance and risk minimisation activities may include removing such activities from the RMP.

An update of the RMP might also be considered when data submitted in the procedure results or is expected to result in changes of routine pharmacovigilance activities beyond adverse reaction reporting and signal detection activities, or of routine risk minimisation activities recommending specific clinical measures to address the risk. For example, an RMP update might be warranted with a significant change of the plans for annual enhanced safety surveillance (routine pharmacovigilance activity), or when monitoring of renal function is added as a recommendation in the Special warnings and precautions for use section 4.4 of the SmPC (routine risk minimisation activity). The need to update the plans to evaluate the effectiveness of risk minimisation activities should also be considered with such updates.

When an emerging safety issue is still under assessment (as defined in GVP Module VI), in particular in the context of a signal or potential risk that could be an important identified risk, an RMP update may be required if the emerging safety issue is confirmed and the important identified or potential risk requires to be added to the list of safety concerns in the RMP.

The need for an update to the RMP or a new RMP, including procedural aspects, should be discussed with the Agency, as appropriate, well in advance of the submission of an application, and in particular when involving a significant change to an existing marketing authorisation and/or parallel procedures warranting an RMP update. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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16.2. When is my RMP a stand-alone variation? Rev. Dec 2017

It is expected that for RMP updates which are consequential to the data provided in a regulatory application, the updated RMP should be provided as part of the same application (see also Question 4 below). However, if an RMP needs to be updated outside any regulatory procedure, this RMP should be submitted as a stand-alone variation.

A stand-alone variation for updates of the RMP may be foreseen or requested by the Agency in particular in the following situations:

• In case of changes to the safety concerns outside another procedure; for instance, if interim results of a study assessed as a post-authorisation measure (PAM) lead to changes in the safety specifications (i.e. the need to add, delete or reclassify safety concerns);

• As a follow-up of a PSUR or signal procedure.

RMP updates cannot be accepted together with the PSURs of medicinal products (centrally and/or nationally authorised) subject to a PSUR EU single assessment (PSUSA), unless the PSUSA procedure includes only CAPs which are part of the same global MA (e.g. duplicate MAs). MAHs should update their RMP through another upcoming procedure affecting the RMP or alternatively, through a separate variation which can be submitted after finalisation of the PSUSA procedure;

• In case of proposed changes to already previously agreed category 3 studies in Part III.4.3 of the RMP. This applies also when the MAH has provided an updated / amended protocol that has been assessed via the PAM procedure, and which has an impact on the description of the study in Part III.4.3.

16.3. What if my application does not include an updated RMP? Rev. Dec 2017

If the MAH considers that no update of the RMP is warranted at the time of submission of a regulatory application following the assessment of the application, the PRAC/CHMP may or may not agree with the view that no RMP changes are warranted. If not agreed, the MAH will be requested to provide an updated RMP in response to a CHMP Request for Supplementary Information (RSI) during the procedure.

It is essential to always strive to conclude the RMP assessment during the procedure i.e. a final updated RMP version should be provided for agreement prior to the CHMP Opinion. However, if the PRAC/CHMP agrees that the requested update may not be possible during the procedure taking the

procedural timelines into account, the RMP can instead be updated at the ‘next regulatory opportunity’,

i.e. as part of the next application or as a stand-alone variation.

In this regards, if relatively minor RMP changes are requested by PRAC/CHMP for implementation at

the ‘next regulatory opportunity’, the changes can be included as part of another appropriate

regulatory procedure under a single scope (e.g. as part of a Type IB variation or Type II variation affecting the RMP without the need for an additional specific variation(s)) (see also Question 5 below). However, in the situation where additional data and significant further assessment is still necessary, this requires a separate Type II variation regardless of whether it is submitted as a stand-alone variation application or part of a grouped application. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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16.4. Which variation classification will apply for my RMP updates? Rev. Mar 2026

16.4.1. Consequential RMP updates

All RMP changes are in principle considered as changes to the MA and therefore require the submission of a specific variation. However, when the RMP updates are consequential to the data provided in an application, the updated RMP should be included as part of the same application. The latter is frequent for Type II variations submitted under categories C.4 or C.6 when the product information is affected, Type II variations under category C.12 when a final study report is provided without any impact on the product information, for line extension applications, renewals of MA and for PSURs when the proposed update is related to the data submitted in the PSUR.

In addition, in case of changes to the Annex II conditions either proposed by the MAH or resulting from the assessment, e.g. safety study in Annex II D or E or additional risk minimisation measures in Annex II D, the MAH should also implement consequential changes to the RMP as part of the same application/procedure.

16.4.2. Variation classification categories for stand-alone RMP updates

Type II under category C.9

• Introduction of a new RMP outside another regulatory procedure.

• Addition, modification or deletion of safety concerns (identified risks, potential risks, missing information) not previously assessed and agreed by the EMA (e.g. with signals, PSURs).

• Changes to agreed post-authorisation studies in the RMP, if there is an impact on the description of the study (objectives as given in the summary table of on-going and planned additional pharmacovigilance activities, excluding changes to due dates) and/or to risk minimisation measures in the RMP not previously assessed and agreed by the EMA;

e.g.:

− Study objective: e.g. no more hypothesis testing.

− Study population: type or number, if it may restrict the objective, e.g. considerable sample size reduction; decrease in centres or geographical spread.

− Study design: e.g. follow-up type; passive versus patient diary.

Type IB under category C.9

• Updates of RMPs not falling within the scope of Type II variations (see above) are in principle Type IB variations.

• Addition, modification or deletion of a safety concern (identified risks, potential risks, missing information) which has already been assessed and requested by the PRAC/CHMP in a previous procedure; i.e. the changes have already been formally assessed and agreed in principle as part of a previous procedure (e.g. assessment of signals, PSURs, variations, PAMs) by the PRAC/CHMP, although the agreement on the exact wording to be implemented in the RMP is still pending and further assessment is therefore required. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Note: In order for the implementation of pre-agreed RMP changes to be handled as a Type IB variation, no additional data should be needed or submitted to support the proposes changes.

• Change to the final due date i.e. the date for the provision of the final study report for category 1, 2 or 3 studies in the RMP and/or the Annex II, as relevant.

• Changes of a due date for protocol submission for an imposed study.

Note: In case the MAH takes the opportunity to propose such changes with an RMP update undertaken for another reason (e.g. as part of a Type II variation), these changes are accepted as minor and do not trigger additional variation scopes (please refer to Question 5 below).

Type IA IN under category C.9.a

• Implementation of changes to the conditions based on an exact wording agreed by PRAC/CHMP without any further changes, provided that no linguistic review of translations is required in case of simultaneous changes to the Annex II (i.e. deletion of information, changes to timelines are acceptable but not the implementation of new wording as such).

• Update of the RMP in response to a request following signal detection provided an exact wording agreed by PRAC/CHMP is implemented without further changes.

• Update of the RMP in response to a request following assessment of a protocol of a category 1,2 or 3 study provided an exact wording agreed by PRAC/CHMP is implemented without further changes.

Note: The changes to be implemented must already have been assessed by the Committee(s) in a previously concluded procedure; only the exact agreed wording is implemented, no additional changes are proposed and no further assessment is required.

However, it should be noted that it is rare that an exact wording is pre-agreed and therefore in most cases a Type IB or Type II variation will be required. Regardless, the MAH should always specify in the submission whether or not the proposed changes have already been assessed, and if so, as part of which procedure.

16.5. Which changes can be included in an RMP update without the need for an additional variation? Rev. Dec 2017

It is in principle acceptable to take the opportunity of a regulatory application (e.g. a Type IB or Type II variation) which warrants an update of the RMP to implement also:

• minor administrative changes to the RMP;

• template-related updates (e.g. from RMP template rev. 1 or rev. 2);

• updates of clinical / post-marketing data (e.g. exposure data and data coming from important clinical trials without impact on key safety information or final due dates);

• changes to category 4 studies listed in table III.4.4 (stated additional pharmacovigilance activities,

also known as ‘REC’= Recommendation) (only from RMPs using rev. 1 of the RMP template);

as long as the proposed changes are not affecting the summary of the safety concerns, the summary table of additional pharmacovigilance activities, the routine risk minimisation activities recommending specific clinical measures to address the risk or additional risk minimisation activities. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Further, in the event that relatively minor RMP changes are requested by PRAC/CHMP for

implementation at the ‘next regulatory opportunity’, i.e. as part of the next application resulting in

more substantial changes to the RMP (e.g. Type IB variation, Type II variation, line extension, renewal), these changes can be included as part of the next upcoming RMP update under a single scope i.e. without any need for an additional specific variation, unless there is a defined timeframe by when the update is requested and there is no other planned major RMP update in the same timeframe.

16.6. Can I group my RMP updates? Rev. Mar 2026

Each proposed ‘major change’ to the RMP triggers in principle its own Type II variation scope. It should be noted that one specific Type II variation is required for each scope even when submitted together with other major changes as part of a grouped variation application. The same rules apply to the grouping of major RMP changes as to the grouping of any other (non)clinical Type II variations:

• changes meaningful to be reviewed simultaneously can be grouped;

• non-clinical and clinical safety changes are not accepted as part of the same grouping;

• and grouping should not delay the implementation of important changes (for instance a proposed extension of indication should not be grouped with safety variations).

With regard to multiple ‘minor changes’ which can be assessed as Type IB variations if submitted on their own, these do not require a grouped application; instead it is acceptable to include these minor changes as part of one single Type IB variation or Type II variation without the triggering of additional Type IB variation scopes i.e. any need for additional variations (see also Question 5 above).

The following cases are meant to illustrate how these rules would be applied for RMP updates:

Example 1

Addition of a new Adverse Drug Reaction and a relevant warning to the SmPC via a Type II variation under category C.4 with consequential update of the list of important identified risks in the RMP and submission of a final study report for a category 3 study in the RMP via a Type II variation under category C.12 with consequential updates of the RMP (i.e. removal of the study from the Pharmacovigilance Plan). This can be submitted as a grouped application of 2 Type II variations.

Example 2

Submission of a final study report for a category 3 study via a Type II variation under category C.12 with consequential updates of the RMP, and:

• Deletion of the category 3 study in the RMP – no need for separate variation since related to the main application;

• Addition of a safety concern in the RMP following a request from PRAC as part of a PSUR assessment – 1 (grouped) Type II variation under category C.9.c if additional data are submitted and/or further significant assessment is required; no need for a separate variation otherwise as the change is implemented as part of a Type II variation affecting the RMP;

• Changes to the due date for the provision of the final study report for a category 3 study in the RMP – no need for a separate variation as the change is implemented as part of a Type II variation affecting the RMP; European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Update of the RMP with significant changes of the clinical trial exposure – can be implemented within the variation without the need for an additional variation.

Example 3

Changes to the due date for the provision of the final study report for two category 3 studies in the RMP.

This can be submitted as a single Type IB variation under category C.9.b.

On the other hand, a grouped application is generally not acceptable if it creates the risk of postponing the implementation of important safety information in the RMP:

Example 4

• In case a Type II variation is submitted under category C.6.a (Extension of Indication), the RMP version submitted as part of this application should include changes that are consequential to the new data provided and the new proposed indication, and it can also include changes that have been previously assessed and agreed. As the procedure for an extension of indication application may take some months to finalise, other non-related changes that require assessment should not be included and/or grouped with an extension of indication application (e.g. the implementation of safety information should not be delayed).

16.7. How should I handle parallel RMP submissions? Rev. Dec 2017

There is only one approved RMP at any time for a medicinal product. Consequently, any time an updated RMP is approved as part of a procedure (e.g. variation, renewal, PSUR), this RMP becomes the approved RMP of the product, and any previous version becomes obsolete. Therefore, MAHs should carefully consider the planning of RMP submission, to make sure that the approved RMP always contains the most up-to-date information on the pharmacovigilance planning and risk minimisation measures.

Given the content-based requirements for RMP submission, it is expected that there will be only few procedures where an RMP update should be included. The MAH should consider whether an RMP is really required with the procedure that is in preparation for submission. Early discussion with the regulators should facilitate the submission, to avoid unnecessary RMP submissions and assessment; parallel procedures warranting RMP updates should be avoided as much as possible.

MAHs are strongly encouraged to streamline RMP amendments and submissions, in co-operation with the EMA for the centrally authorised products, in order to facilitate RMP assessments throughout the product lifecycle.

There are two alternative approaches to the handling of different RMP versions for which the assessment is over-lapping, and the MAH should choose the option that facilitates the assessment taking into account anticipated timelines for the finalisation of the procedures.

Whenever separate applications affecting the RMP are submitted in parallel, in order to facilitate the review, it is generally agreed that the MAH initially and whenever appropriate during the procedure submits one joint draft RMP file as a ‘working document’. This single RMP document should include all data consequential to the concerned procedures running in parallel. To facilitate the assessment, the proposed RMP changes should be marked (e.g. with different colour code), to differentiate changes European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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specific to each procedure (example: new safety concerns derived from an extension of indication in a new population should be marked differently from the changes in the Pharmacovigilance Plan consequential to (early) termination of a study and initiation of another one as a consequence of the limited safety data gathered in the ended study).

If the parallel applications reach the finalisation stage at the same time, the consolidated RMP version will be adopted by the relevant Committee and will become the approved version of the RMP.

If the applications do not reach the finalisation-stage at the same time, at the time of the first opinion for the parallel procedures, the MAH will need to provide for review and approval a final RMP version including only the agreed changes related to the scope of the variation application for which the CHMP is about to adopt an opinion. The joint RMP ‘working document’ will continue to be used in the context of the remaining ongoing procedure(s).

Example: A safety variation is triggered whilst an extension of indication procedure is ongoing, both requiring significant changes in the RMP (new safety concern in the new indication; another safety concern and a new imposed PASS in the safety variation). The RMP for the safety variation can be built upon the RMP document submitted with the extension of indication.

Option A: A joint RMP document including changes relevant to both procedures could be submitted with both the responses to the RSI in the extension procedure, and with the initial submission for the safety variation:

• If both procedures reach the Opinion stage at the same time, than the joint RMP will be adopted and become the approved RMP.

• If however the extension of indication requires a second RSI, and is most likely to be finalised after the parallel safety variation, the MAH will then have to submit before the opinion for the safety variation an RMP including only the safety concern and the new study related to the safety variation data. This version of the RMP will be checked for consistency and approved with the

safety variation opinion. The updated joint RMP ‘working document’, including the changes

consequential to the responses to the second RSI for the extension of indication will continue to be assessed within the extension of indication procedure. This joint RMP will be considered the approved RMP once the extension of indication variation reaches opinion. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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A graphical representation for option A is included below:

Option B: Alternatively, it might be more appropriate when parallel procedures will follow very different assessment timetables to opt for an approach similar to the handling of parallel procedures with product information changes; the RMP submitted with each procedure should only include the changes related to that procedure:

• an updated version of the RMP is submitted as a Type II variation to reflect the changes in the safety profile derived from post-marketing reporting. This RMP version should include only the changes related to the RMP update.

• subsequently or at the same time, another RMP update is submitted as part of a Type II variation for the extension of indication. For this application, the RMP version only includes the changes that are consequential to the extension of indication (i.e. not the changes related to the safety variation.

If both procedures conclude at the same time, the MAH is expected to merge the two RMP documents for approval by the opinion time.

If the RMP update variation is approved before the extension of indication procedure, the RMP submitted will be adopted with the relevant changes and the MAH can submit a consolidated RMP

version as part of the MAH’s responses to an RSI for the extension of indication. This RMP version

includes then the changes approved as part of the recently finalised safety variation (as clean text) as well as the changes related to the extension of indication (with track changes). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The option B can be illustrated as follows:

Regardless of the approach chosen, the MAH should always provide a clear description of the scope(s) of the submission in the cover letter and the changes implemented in the RMP including references to related (previous/parallel) regulatory procedure(s) (see also Question 8 below).

16.8. How shall I present my RMP update? Rev. Oct 2019

Guidance on the format and content of the RMP as outlined in GVP module V and RMP template has

been made available in the Pharmacovigilance section of the Agency’s website. The submitted RMP

should follow the RMP template and guidance.

The RMP should be provided in CTD section 1.8.2. RMP versions submitted for assessment should be version controlled and dated. All parts and modules of the RMP should be submitted in one single PDF-file so that a complete RMP is provided to the Agency.

Only clean versions of documents in PDF format should be managed within the eCTD lifecycle.

However, due to the fact that additional formats are required to facilitate the assessment i.e. ‘tracked changes’ versions for SmPCs, RMPs or other documents as spe cified by the agency, these should be

provided in Word format in the separate folder ‘XXXX -working documents’. Further details in this

regard can be found in section 2.9.9 of the Harmonised Guidance for eCTD Submissions in the EU. It is generally not necessary to include the annexes as part of the RMP ‘working document’ unless any of

the annexes are actually revised. If no tracked changes version can be compiled (e.g. due to template

transition when the tracked changes would be significant throughout the document), a ‘clean’ Word version file of the RMP should still be submitted in the ‘XXXX -working documents’ folder; this will facilitate the preparation of the RMP Summary to be published on the Agency website.

In general, any submitted version of the RMP should be based on the latest approved version (i.e. the latest version agreed by CHMP). However, sometimes it may be more appropriate to base the next

version to be submitted on the latest RMP ‘working document’ version, especially when several

procedures affecting the RMP are ongoing in parallel (see Question 7 above). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Regardless, the submitted RMP version should be seen as a draft, until approved. Details of the RMP approval status should be provided in the Module I of the document. The revised RMP should always get a new version number every time an updated RMP version is submitted for assessment (see recommendations on document versioning in the Guidance on the format of the risk management plan (RMP) in the EU – in integrated format ).

When relevant, a discussion of the proposed RMP changes should be included in the (non-) clinical overview (addendum). It should be noted that the provision of a (non-)clinical overview (addendum) is mandatory as part of a (non-)clinical Type II variation application which includes a revised RMP regardless of the fact that there may be no impact on the product information. In this case the (non-) clinical overview (addendum) should discuss and justify the proposed RMP changes. On the other hand, a (non-) clinical overview (addendum) is never required as part of Type IA and Type IB variation applications.

In the EU application form (AF) and for (non-)clinical variations, the “Present/Proposed” table will in

general only reflect proposed changes to the EN Annexes (SmPC, Annex II, labelling and Package Leaflet). It is not foreseen that the updates to the RMP are reflected in the AF in detail unless quite limited in scope. Instead, when comprehensive changes to the RMP are proposed, it is recommended to provide a comparative table of the RMP (latest agreed version vs. proposed version), summarising –

for all individual RMP parts and modules – the main updates. For example, all changes linked to the

implementation of a new template can be summarised as ‘new RMP template’. Such comparative table

should be provided as an annex to the AF.

16.9. Can I submit a version of the RMP after the Opinion to reflect the last-minute changes made during the CHMP? Rev. Mar 2026

As a matter of principle, the day of the CHMP Opinion/EMA Notification is the last opportunity for the MAH to provide an updated version of the RMP (in word format) for agreement. The same RMP version with the same version number – without any additional changes - can thereafter be submitted as part of a formal eCTD closing sequence post-opinion. However, if additional changes to the RMP are identified post-opinion after receipt of the document, an updated RMP version with a new version number should be provided for review as part of a Type IB variation under category C.9.b.

The same principles apply also in situations when there are different RMP versions undergoing assessment in parallel and concluding the same month (see also Question 7 above). MAHs are requested to provide the final consolidated RMP version (in word format) before the date of the CHMP Opinion/EMA Notification.

16.10. Is the PRAC Rapporteur involved in the assessment of RMP updates?

The PRAC Rapporteur will be involved in the assessment of all variations that include an updated RMP. For Type IB variation including RMP, PRAC Rapporteur will be in the lead of the assessment. For Type II variations, the CHMP or PRAC may take the lead during the assessment depending on the composition of the data provided, and this will be decided on a case-by-case basis at the time of the EMA validation. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Similarly, on a case-by-case basis, the PRAC Rapporteur may also later become involved in the assessment of an application if requested by the CHMP during the procedure.

At the time of validation, the Agency will inform the MAH of the involvement of the PRAC Rapporteur through the assessment timetable which will refer to the relevant assessment reports expected from the PRAC Rapporteur, as appropriate.

16.11. How long after the European Commission decision should Annex 1 of the RMP be submitted to EudraVigilance? Rev. Jun 2023

The maintenance of the Agency’s database for RMP Annex I files (‘Annex I tool’) has been suspended.

Following this decision, as of 4 th December 2020 the Marketing Authorisation Holders for centrally authorised products will no longer be required to create and submit RMP Annex I (.xml) files to the EMA.

Development and integration of a new database for structured electronic representation of the EU risk

management plan to replace Annex I tool is pending the Agency’s digitalisation strategy. Any

announcements about the system replacing the RMP Annex I database, reinitiating the requirements for the submissions, or otherwise instructions about the submissions of RMP in a structured electronic format will be provided (i.e. via the Agency website or directly to MAHs) as appropriate, in due time.

16.12. How and to whom shall I submit my RMP application? Rev. May 2020

As explained in the hereby questions and answers on RMP, the RMP update can be submitted either as part of a procedure driven by another main change defining the procedure classification (e.g. extension of indication, new formulation, etc.) or as a stand-alone variation exclusively including the RMP. In the latter, the variation can be either a Type II, Type IB or T ype IA, see question ‘Which variation classification will apply for my RMP updates?’ for further guidance.

Irrespective whether the RMP update is consequential to another change or a stand-alone update, the RMP document follows the eCTD life-cycle management and should be provided in Module 1.8.2 of the eCTD structure. Submission of the RMP should be made according to the framework of the procedure to which it belongs to and should follow the requirements and technical process for this procedure.

More information is available on ‘Submitting a post -authorisation application’.

The use of the eSubmission Gateway or Web Client is mandatory for all electronic Common Technical Document (eCTD) submissions through the centralised procedure. The European Medicines Agency (EMA) no longer accepts submissions on CD or DVD. This applies to all applications for human medicines.

16.13. What templates should I use for the RMP submission? NEW Dec 2017

Depending on the application submission date, either the Revision 1 or the Revision 2 version of the Guidance on format of the risk-management plan in the European Union should be used including for European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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generics. The Rev. 2 version is also applicable to generics as it includes specific guidance to generics. The transitional arrangements for the RMP submission are presented in the table below.

Acceptable template revisions to be used for RMP submissions:

RMP submission with: 01.10.2017 – 30.03.2018 On and after 31.03.2018

Any post-marketing procedure (initial submission or with responses to a RSI)

Rev.1 or

Rev.2

Only Rev.2

RMPs submitted using Rev. 1 of the template instead of Rev.2 will not be rejected at validation of the submission but will automatically trigger an additional step of assessment and an outstanding issue; applicants and MAHs will be required to update the RMP using the Rev.2 of the template and submit it with the responses to the RSI.

16.14. When and how will the RMP Summary be published on the EMA website? Rev. Dec 2023

All post-authorisation RMP updates assessed and approved in procedures concluding on or after 20 October 2023 will trigger the publication of the full RMP (body and annex 4 & 6).

For RMPs submitted for evaluation with Type IB and IAIN variations, the MAH is asked to include the redacted version for publication (clean and tracked, redacting personal data and commercial confidential information) with the working documents in the variation eCTD sequence, together with the signed RMP Publication Declaration. It is recommended that all necessary changes are implemented via anonymisation and deletion directly in the RMP submitted for evaluation, rather than by redaction in the document for publication.

For RMPs submitted for evaluation in all other types of post-authorisation procedures, post-opinion/recommendation the MAH will be asked to extract the redacted RMP body and Annexes 4 & 6 (as applicable, redacting personal data and commercial confidential information) as one stand-alone PDF document and send it via EudraLink to the EMA, together with a RMP file that can show the content that is proposed for redaction, and the signed RMP Publication Declaration.

The redacted RMP PDF will be published on the EMA website at the time of the EPAR update, on the

product’s page (EPAR summary landing page).

16.15. How should I compile the list of safety concerns in the RMP for generic products when the originator products have an RMP? NEW Apr 2019

When the MAH / Applicant for a generic medicinal product submits an RMP for assessment, the safety concerns should be aligned to those of the originator product that are available either from the

originator’s approved RMP or from the list of safety concern s of the substance published on the CMDh website. Any divergence introduced in the RMP of the generic product (e.g. new safety concerns)

should be thoroughly justified based on either differences in products’ characteristics (e.g. excipients),

or on compelling data generated with this generic product that would warrant a difference in the list of European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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safety concerns in the RMP (e.g. clinical trial or post-marketing epidemiological study data). This justification should be detailed in Module SVII of Part II of the RMP.

This guidance also applies on other types of marketing authorisations with similar RMP requirements: hybrid products and fixed combination products with no new active substance.

References

• Directive 2001/83/EC

• Regulation (EC) No 726/2004

• Commission implementing Regulation No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities

• Guideline on good pharmacovigilance practices – Module V – Risk Management Systems (Rev 1)

• RMP template European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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17. Periodic Safety Update Reports (PSURs)

17.1. How shall I present my PSUR and in which format? Rev. Mar 2025

The format and content of the PSUR, is legally required according to Commission implementing Regulation (EU) No 520/2012 since January 2013 and is further described in the Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report.

In addition, the required format and content of PSURs in the EU are based on those for the Periodic Benefit Risk Evaluation Report (PBRER) described in the ICH-E2C(R2) guideline (see Annex IV ICH-E2C(R2)). To keep the terminology consistent with the one used in the EU legislation, the new PBRER continues to be described as PSUR.

Unless otherwise requested by competent authorities, the marketing authorisation holder shall prepare a single PSUR for all its medicinal products containing the same active substance with information covering all the authorised indications, route of administration, dosage forms and dosing regimens, irrespective of whether authorised under different names and through separate procedures. Of note,

the PSUR section “Worldwide marketing authorisation status" applies irrespectively to centrally

authorised products and nationally authorised products. Regarding centrally authorised products, the marketing status should also be provided as a stand-alone report, which is to be downloaded from IRIS and appended to the PSUR.

Even if a single PSUR is prepared for several products, please note that PSURs should be presented in a new eCTD sequence in the respective eCTD lifecycle of the concerned product.

Where relevant, data relating to a particular indication, dosage form, and route of administration or dosing regimen, shall be presented in a separate section of the PSUR and any safety concerns shall be addressed accordingly.

It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH(s) and is crucial to the overall assessment. The data presented in the individual submissions should be intended exclusively for the purposes of the concerned procedure as it will be assessed and reflected in the single assessment report and will not be redacted prior to sharing with all concerned MAHs. PSUR related data presented in line with GVP module VIIare not considered to be commercially confidential. Of note, MAHs cannot use the information and data contained in the submissions for any other purposes than those related to the concerned procedure. It is recommended to limit the information reported on individual cases to a minimum, i.e. to only include patient level data to the extent necessary for the analysis of the case considering the purposes of the PSUSA procedure.

The marketing authorisation holder is required to consider the impact on the marketing authorisation of the data and evaluations presented within the report. Based on the evaluation of the cumulative safety data and the risk-benefit analysis, the marketing authorisation holder shall draw conclusions as to the need for changes to the product information of the products covered by the PSUR. For the purpose of analysing the impact of the PSUR data, the MAH can establish a so-called reference product informatio n which should include “core safety” and “authorised indications” components, as explained in the GVP module VII on PSURs (section VII.B.4. ‘Reference information’) and be presented in English

language. The changes proposed to the labelling can be based on the reference product information. However, as the reference product information might be different for the various EU product information, it is essential that the MAH considers the proposed changes in the context of those. This should be clearly discussed in both the conclusions and actions section of the body of the PSUR as well European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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as in the EU regional appendix. (see questions “How can I submit the proposed changes to the product information within the PSUR for the products which are part of an EU single assessment” and “How can

I propose changes to the product information within the PSUR for NAPs which are part of an EU single

assessment?”).

Additional clarification on the content of the PSUR can be found in the explanatory note to GVP Module VII and should be used by MAHs for the preparation of PSURs subject to single assessment. As it complements GVP Module VII, both documents should be consulted.

An assessor’s question and answer guidance document has also been developed.

All the entries in the EURD list have been assigned a procedure number presented in the column

“Procedure number of the PSUR single assessment”. The eCTD delivery file should be completed in

accordance with the published EURD list, where the procedure number is the combination of a unique ID and the applicable Data Lock Point (DLP) in YYYYMM format.

In line with article 57(2) of Regulation (EU) No 1235/2010 all holders of marketing authorisations for medicines in the European Union, Northern Ireland and the European Economic Area must submit information to the European Medicines Agency on authorised medicines and keep this information up to date. This is a legally binding requirement from the EU pharmaceutical legislation. The Agency uses this information to support the analysis of data, regulatory activities and communication. In relation to the submission of PSURs, this facilitates the processing of the submissions in the PSUR Repository.

Please see question “ To whom should I submit my PSUR? ” for further details on submission requirements.

References

• Regulation (EC) 726/2004

• Directive 2001/83/EC

• Commission implementing Regulation (EU) No 520/2012 on the performance of pharmacovigilance activities

• Guideline on good pharmacovigilance practices (GVP) – Module VII –Periodic safety update report

• Explanatory Note to GVP Module VII

• ICH guideline E2C (R2) Periodic benefit-risk evaluation report (PBRER)

• Harmonised Guidance for eCTD Submissions in the EU

17.2. What is the European Union reference dates list (EURD list) and frequency of submission of PSURs? Rev. Mar 2025

The list of E U reference dates and frequency of submission of PSURs” (so -called the “EURD list”)

consists of a comprehensive published list of active substances and combinations of active substances, for which PSURs shall be submitted in accordance with the EU reference dates and frequencies determined by the Committee for Medicinal Products for Human Use (CHMP) and the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) following consultation with the Pharmacovigilance and Risk Assessment Committee (PRAC). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The European Union reference date (EURD) corresponds to the date of the first or the earliest known date of the marketing authorisation in the EU of a medicinal product containing the active substance or combination of active substances.

The EURD list facilitates the harmonisation of Data Lock Points (DLPs) and frequency of submission of PSURs for medicinal products containing the same active substance or the same combination of active substances, the optimisation of the management of PSURs and PSURs assessments within the EU allowing a single assessment and reassessment of the risk-benefit balance of an active substance based on all available safety data.

The PSUR frequency as published on the EURD list for a given active substance or combination of active substances overrules the standard submission cycle (i.e. 6-monthly, yearly and thereafter 3-yearly) set out in the legislation and any condition related to the frequency of submission of PSURs included in the Marketing Authorisation. However, competent authorities may still request the submission of a PSUR at any given time.

The EURD list is a living document, meaning that it is updated regularly in response to the emergence of relevant new safety information, newly authorised substances or requests from the marketing authorisation holders. For guidance on submission of requests for amendment of the EURD list, please

refer to the question “ How can I request to amend the EU reference date list s” .

References

• Directive 2001/83/EC

• Guideline on good pharmacovigilance practices – Module VII –Periodic safety update report

• List of European Union reference dates and frequency of submission of Periodic Safety Update Reports Introductory cover note

17.3. When do changes to the EURD list become legally binding? Rev. Mar 2025

The EURD list is updated on a monthly basis and any changes in the EURD list come into force 6 months after its publication. This publication occurs after adoption of the EURD list by the CHMP and CMDh following consultation of the PRAC.

Whilst changes become binding 6 months after publication, there might exceptionally be situations where PSUR submissions are necessary prior to the new frequency taking effect and this will be indicated in the EURD list as well, i.e. in case the PSUR frequency is changed from 6-monthly to yearly as part of a PSUSA outcome, there might be a need for a subsequent 6 monthly PSUR .

It is the responsibility of the marketing authorisation holder to regularly check the EURD and frequency of submission published in the European Medicines Agency website to ensure compliance with the PSUR reporting requirements for their medicinal products.

Reference

• Directive 2001/83/EC European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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17.4. How can I request to amend the EURD? Rev. Mar 2025

Marketing authorisation holders can submit requests to determine the European Union reference dates or to change the frequency of submission of PSURs on one of the following grounds:

• for reasons relating to public health;

• in order to avoid a duplication of the assessment;

• in order to achieve international harmonisation.

The request and its grounds should be considered by the PRAC and the CHMP if it concerns at least one marketing authorisation granted in accordance with the centralised procedure or by the PRAC and the CMDh otherwise, which will either approve or deny the request.

The list will then be amended accordingly when appropriate and published on the European medicines website.

For more details on how to submit amendments to the list, please refer to the EURD list cover note (section 4).

Reference

• Directive 2001/83/EC

• Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report

17.5. Do I have to submit a PSUR if the active substance/combination of active substances of my medicinal product is not in the EURD list? Rev. Mar 2025

If the active substance/combination of active substances contained in the medicinal product is not included in the EURD list, the MAH should submit the PSUR directly to the PSUR repository, using the non-EU single assessment functionality, via the eSubmission Gateway. The PSUR will then be considered delivered to the relevant national competent authority (NCA) where the product is authorized.

The frequency of submission shall be in accordance with the conditions specified in the marketing authorisation (if any), or otherwise according to the standard submission schedule of PSURs (i.e. 6-month intervals, yearly and thereafter 3 yearly).

Marketing authorisation holders for certain medicinal products such a homeopathic simplified registration or a traditional-use registration are not required to submit PSURs, unless there are specific requirements in the MA. For medicinal products authorised under Article 10(1), 10a or 16a of Directive 2001/83/EC, submission of PSURs is only required if indicated in the EURD list column: "Are PSURs required for products referred to in Articles 10(1), 10a, 16a of Directive 2001/83/EC as amended? Yes/No" . PSURs shall also be submitted upon request of the competent authority , please refer also to the question ‘Do I have to submit a PSUR my medicinal product if it is a generic, a product containing a well-established substance, a homeopathic or herbal medicinal product? ’. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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17.6. Do I have to submit a PSUR if the combination of active substances of my product is not in the EURD list, but one or more individual components are listed? Rev. Mar 2025

If the specific fixed dose combination is not listed in the EURD list, PSURs should not be submitted according to the EURD list entry of one or more individual components. However, PSURs should be submitted as specified in the conditions of the marketing authorisation (if any), or otherwise according to the standard submission cycle (i.e. 6-monthly, yearly and thereafter 3-yearly) unless the combination medicinal product falls within the categories of medicinal products exempted from the obligation to submit PSURs.

17.7. Do I have to submit a PSUR if my medicinal product is not marketed? Rev. Mar 2025

MAHs are required to submit PSURs once a medicinal product is authorised in at least 2 Member States in the EU, regardless of its marketing status, for the PSUSA to start. For nationally authorized products authorized in only one Member State, PSURs need to be submitted to the national competent authority for assessment at local level.

17.8. Do I have to submit a PSUR if the marketing authorization for my product has been granted on or after the data lock point (DLP) in the EURD list?

The MAH is not obliged to submit a PSUR if the granting of the Marketing Authorisation (MA) was notified on or after the DLP. The first PSUR will either be due following the subsequent DLP in the EURD list or, depending on the newly approved MA, a first PSUR submission might be considered earlier than the next DLP. However, if the MA was granted before the DLP, the obligation to submit applies.

17.9. My company holds a Parallel Import Authorisation; do we have to submit PSUR for these product(s)? If a PSUR is submitted, will it be assessed? Rev. Mar 2025

As per the provisions of Article 107b of Directive 2001/83/EC and Article 28(2) of Regulation (EC) No 726/2004, only MAHs are required to submit PSURs . Parallel importers do not qualify as MAHs, and therefore they are not subject to the obligation to submit PSURs.

If however, a PSUR has been submitted by a company holding a parallel import authorisation, such PSUR might be taken into account and assessed in terms of its impact on the risk-benefit balance of the medicinal product concerned. If the data contained in the PSUR contribute meaningfully to the scientific assessment, these data should be included in the scope of the PSUR procedure. However, the parallel importer will not become party to the PSUR procedure and will not receive a copy of the assessment report and outcome documentation as a MAH would. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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17.10. Do I have to submit a PSUR for my medicinal product if it is a generic, a product containing a well-established substance, a homeopathic or herbal medicinal product? Rev. Mar 2025

Medicinal products authorised under Articles 10(1), 10a, 14 or 16a of Directive 2001/83/EC or medicinal products which have been authorised through the equivalent legal basis before re-codification are exempted from routine submission of PSURs unless otherwise specified in the marketing authorisation or required through the EURD list (see dedica ted column “Are PSURs required

for products referred to in Articles 10(1), 10a, 16a of Directive 2001/83/EC as amended? Yes/No”).

Competent authorities can also request PSURs for generic medicinal products at any time on the grounds detailed in Article 107c (2) of the Directive.

17.11. Do I have to submit a PSUR for my hybrid medicinal product? Rev. Sep 2014

Medicinal products authorised under Article 10(3) of Directive 2001/83/EC (hybrid application) are not exempted from the obligation to submit PSURs.

17.12. Do I have to submit a PSUR if my medicinal product is authorised in accordance with Article 126(a) of Directive 2001/83/EC? Rev. Mar 2025

As per the provisions of Article 107b of Directive 2001/83/EC and Article 28(2) of Regulation (EC) No 726/2004, only MAHs are required to submit PSURs. Holders of authorisation under Art 126a of Directive 2001/83/EC are not subject to the obligation to submit PSURs with regards to such authorisation.

17.13. Do I have to submit a PSUR if my medicinal product is authorised in accordance with Article 58 of Regulation EC No. 726/2004 (EU-M4all)? Rev. Mar 2026

The obligation to submit PSURs applies also to products that have been given a positive CHMP scientific opinion under Article 58 of Regulation (EC) No 726/2004, since medicinal products and vaccines reviewed under this procedure are assessed as per the same rigorous standards and requirements as medicinal products authorised in the European Union.

However, the obligation to submit to the PSUR Repository does not apply for these medicinal products. For further information on how to submit PSURs for Article 58 products please refer to the guidance on Dossier requirements for Centrally Authorised Products (CAPs). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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17.14. Will the withdrawal/non-renewal/revocation of the marketing authorisation of my product impact on the ongoing EU single PSUR assessment? NEW Aug 2017

In case of withdrawal, non-renewal or revocation of a marketing authorisation (MA) while the EU single PSUR assessment (PSUSA) procedure is ongoing, the impact on the ongoing procedure can be either that:

• the procedure will continue,

− If the PSUSA procedure includes MAs remaining valid, or

− If there are other medicinal products which contain the same active substance or combination of active substances (e.g. generics) as the medicinal product covered by the withdrawn/non-renewed/revoked MA,

OR

• the procedure will be stopped, if the withdrawn/non-renewed/revoked MA is the only MA covered by the ongoing PSUR assessment procedure, unless there are important safety concerns to consider the recall of any remaining medicinal products available on the market or the assessment could inform on public health concerns on long-term safety effects of the concerned product or evaluation of other medicinal products (e.g. same class of products) on the market regarding scientific and technical progress or future risk management or for other public health reasons.

For centrally authorised medicinal products, where the EU single PSUR AR will be completed, the information will be reflected in the EPAR of the concerned medicinal product.

17.15. Will I have to submit PSUR after withdrawal/non-renewal/revocation/suspension of the marketing authorisation of my product? Rev. Mar 2025

Where a marketing authorisation is withdrawn, revoked or not renewed, the former marketing authorisation holder is encouraged to continue to collect spontaneous reports of suspected adverse reactions occurring in the EU (see GVP Module VI) to, for example, facilitate review of delayed onset adverse reactions or of retrospectively notified cases of adverse reactions.

Depending on the date of the EC decision on the revocation or withdrawal, or the date of expiry of the marketing authorization in case of non-renewal, marketing authorisation holders may still be required to submit a PSUR:

• If the date is after the submission deadline specified in the EURD list, submission is mandatory irrespective of whether the date is before or after the start of the procedure.

• If the date is prior to the submission date specified in the EURD list, submission is no longer required except for exceptional cases for centrally authorised medicinal products, whereby the former marketing authorisation holder may be requested to submit a final / ad-hoc periodic safety update report (PSUR). An agreement on the procedural details of the PSUR submission should be reached between the marketing authorisation holder and the Competent Authority, since this PSUR should not be submitted to the PSUR repository. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In the case when the marketing authorisation of a medicinal product is suspended, this would not affect the requirement to submit a PSUR, since this situation corresponds to a temporary marketing cessation which could be lifted. The usual requirements in terms of submission apply. If the product has not been marketed during the whole reporting interval this should be specified in the PSUR.

17.16. Do PSURs need to contain case narratives and line listings? Rev. Mar 2025

The PSUR should focus on summary information, scientific assessment and integrated benefit-risk evaluation.

Marketing authorisation holders are not required to systematically include listings of individual cases, including case narratives, in the PSUR. However, they shall provide case narratives in the relevant risk evaluation section of the PSUR where integral to the scientific analysis of a signal or safety concern in the relevant risk evaluation section.

In this context “case narrative” refers to clinical evaluations of individual cases rather than the CIOMS

narratives included in the individual case safety report (ICSR).

During the assessment of the PSUR, line listings for adverse reactions of special interest may be requested.

Reference

• Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report

17.17. How can I submit the proposed changes to the product information within the PSUR for the procedures which are part of an EU single assessment? Rev. Mar 2025

According to the guidance set out in the GVP module VII on PSURs, proposed changes to the EU labels as a result of the PSUR data should be provided under Section VII.C.5.1. PSUR EU regional appendix, sub-section “Proposed product information” of the PSUR.

It should be presented as a tracked change version of each EU SmPCs and package leaflets of the products concerned and each product information should be translated into English language including the tracked changes proposed, in order to enable the EU single assessment.

This can result in having to submit a large number of sets of tracked change product information with the additional burden of providing translations. Hence MAHs can consider the option to focus on the proposed amendments to SmPC and package leaflet. In such case, only the amended parts of the SmPC and package leaflet should be provided in track changes and in English language under the EU regional appendix.

It is important that changes proposed to the product information which are based on the submitted PSUR data are not submitted in parallel via a separate variation procedure. However, proposed changes that are not based on the data submitted within the PSUR, will not be considered, and a variation will have to be submitted as appropriate to the relevant competent authority. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In case no changes to the product information are being proposed as part of the PSUR, the MAH should not include any product information within the EU regional appendix.

Reference

• Guideline on good pharmacovigilance practices (GVP) – Module VII –Periodic safety update report

17.18. Can I submit a RMP update together with my PSUR? Rev. Mar 2025

A risk management plan (RMP) update can only be submitted with a PSUR for single centrally authorised medicinal product (CAP) or a mixture of CAPs belonging to the same global marketing authorisation (GMA) when the changes to the RMP are a direct result of data presented in the PSUR. In this case no stand-alone RMP variation is necessary, but the MAH should indicate in their cover letter that the RMP update is a direct result of data presented in the PSUR. The MAH should also present clean and tracked changes working versions of the RMP in the submission.

Submission of RMP updates cannot be accepted with PSURs subject to a PSUSA of:

• a mixture of CAPs pertaining to different GMAs;

• a mixture of centrally and nationally authorised medicinal products;

• a mixture of NAPs.

In these cases, MAHs should submit the updated RMPs as part of another procedure affecting the RMP, if one such procedure is foreseen or as a separate variation to update their RMP.

If an RMP is incorrectly submitted with a PSUR, this will be identified during the procedure and the RMP will not be assessed. If the RMP was submitted as an eCTD the MAH will have to delete that version of the RMP in the next sequence to maintain the correct lifecycle of the product.

17.19. Can I submit a clinical study report together with my PSUR? Rev. Mar 2025

The PSUR is not the appropriate procedure for submitting final or interim study reports to the EU regulatory authorities. Final study reports should be submitted and assessed via the appropriate procedure in line with the guidelines on the details of the various categories of variations, on the operations of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008.

However, in case a study report is able to further support the assessment of the PSUR, the MAH may provide the study report (or relevant parts thereof) as an appendix to the PSUR. The inclusion as an appendix does not discharge the MAH from their obligation to submit for assessment the study report via the appropriate procedure in line with the above-mentioned guidelines.

The PSUR should provide comprehensive information on the findings of all PASS, both interventional and non-interventional, in sections 7 and 8 respectively as an integrated summary. Information regarding completed clinical trials provided in the PSUR secti on “Summaries of significant findings from clinical trials during the reporting interval” can be presented in either a narrative format or as a

synopsis. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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17.20. What are the general timelines for the submission of PSURs? Rev. Mar 2025

Marketing authorisation holders should submit PSURs to the Agency as established in GVP Module VII according to the following timelines:

• within 70 calendar days of the data lock point (day 0) for PSURs covering intervals up to 12 months (including intervals of exactly 12 months); and

• within 90 calendar days of the data lock point (day 0) for PSURs covering intervals in excess of 12 months;

• the timeline for the submission of ad hoc PSURs requested by competent authorities will normally be specified in the request, otherwise the ad hoc PSURs should be submitted within 90 calendar days of the data lock point.

The deadline for the submission of PSURs, which is legally binding and must be adhered to, is published in the EURD list. However, the PSUR repository allows for a submission window between the DLP and the submission deadline, there is therefore no technical restriction preventing MAHs from submitting their PSUR in advance of the deadline.

References

• Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report

17.21. What are the timelines for the submission of PSURs after a positive opinion of a centrally approved product? NEW Mar 2025

For the first PSUR submission date after a positive opinion of an initial marketing authorisation for a centralised product, if the substance is not already included in the EURD list, a new EURD list entry will be based on the European Birth Date (EBD) or the International Birth Date (IBD). The applicant will need to indicate whether they wish to align the EBD to the IBD.

If the substance is already included in the EURD list, the PRAC Rapporteur will evaluate whether the existing EURD entry is also valid for the MAA. If the relevant EURD entry could not be valid for the MAA (e.g. a specific entry for a particular indication/pharmaceutical form/legal basis is needed), the PRAC Rapporteur should verify if a separate EURD entry is needed. In this case, a rationale for such addition of an EURD entry will be provided in the relevant CHMP AR and the Applicant will need to clarify whether they wish to align the EBD to IBD before the positive opinion of an initial marketing authorisation.

Post-authorisation, any change to the dates of submission and frequency on PSURs specified in the marketing authorisation shall take effect 6 months after the date of publication.

References

• Guideline on good pharmacovigilance practices (GVP) – Module VII – Periodic safety update report

• Timetable: Periodic Safety Updated Reports (PSUR) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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17.22. What happens if I missed the PSUR submission deadline? Rev. Mar 2025

It is the responsibility of MAHs to ensure that they submit the necessary PSUR by the submission deadline as stated in the EURD list and that they are not in breach of their legal obligations with respect to the submission of PSURs.

If you have missed the submission deadline due to technical issues with the PSUR Repository, please contact EMA as soon as possible via the EMA Service Now in order to request a late submission ID. Please note that late submissions cannot be accepted once the procedure has started.

References

• User Guidance for Marketing Authorisation Holders (MAHs) for PSUR Repository

17.23. To whom should I submit my PSUR? Rev. Mar 2025

The use of the PSUR Repository is mandatory for all PSUR submissions. MAHs are required to submit PSURs directly to the PSUR repository using the eSubmission Gateway; the submission of PSURs directly to national competent authorities is no longer accepted. This affects all PSURs irrespective whether they are for centrally or nationally authorised medicinal products and whether they follow the EU single assessment or purely national PSUR procedure.

The use of the xml delivery file for submissions to the PSUR Repository is mandatory for all PSURs and any related submissions via the eSubmission Gateway and/or the Web Client. For further instructions on creation of the xml delivery file, please refer to the MAH PSUR Repository User Guidance document.

References

• Dossier requirements for Centrally Authorised Products (CAPs)

• SOP on the processing of CMDh PSUR single assessment procedures for nationally authorised

productssubmission guidance document

• PSUR Repository MAH User Guidance document

• eSubmission website

• eSubmission Gateway / Web Client website

• Common Repository website

• PSUR Repository website

• Harmonised Guidance for eCTD Submissions in the EU

17.24. How to identify the official contact person for the PSUR? NEW Mar 2017

The official contact person for the PSUR procedure is the one provided in the xml delivery file. This person will be the sole recipient of any communication from EMA throughout this procedure, including the PRAC Recommendation, CHMP/CMDh output, and Commission Decision, as applicable. The contact European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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information provided in the xml delivery file will always override any information provided in the cover letter.

17.25. How will my PSUR submission be handled? Rev. Mar 2025

The PSUR assessment under an EU-PSUSA procedure is as follows, regardless whether it refers to one or more centrally authorised medicinal products, a mix of centrally authorised medicinal products and nationally authorised products, or nationally authorised products only. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

EMEA-H-19984/03 Page 247/305 Receipt of PSUR(s) from MAH(s) Technical validation by the Agency Start Rapporteur/Member State preliminary assessment report 60 days Comments from MAH(s) and PRAC members/Member States 30 days Rapporteur/Member States updated assessment report 15 days PRAC recommendation At the next PRAC meeting PRAC recommendation received by CHMP/ CMDh If variation, suspension or revocation of the marketing authorisation is recommended 30 days CAP/NAPs CHMP Opinion sent to EC, marketing authorisation holder(s) and NCAs EC decision to update centralised marketing authorisation

CAP

EC decision addressed to Member States for implementation at national level

NAP

CMDh majority position sent to EC, marketing authorisation holder(s) and NCAs CMDh position CMDh consensus position sent to marketing authorisation holder(s) and NCAs 30 days NAPs only Implementation at national level European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

EMEA-H-19984/03 Page 248/305 Receipt of PSUR(s) from MAH(s) Technical validation by the Agency Start Rapporteur/Member State preliminary assessment report 60 days Comments from MAH(s) and PRAC members/Member States 30 days Rapporteur/Member States updated assessment report 15 days PRAC recommendation At the next PRAC meeting PRAC recommendation received by CHMP/ CMDh If variation, suspension or revocation of the marketing authorisation is recommended 30 days CAP/NAPs CHMP Opinion sent to EC, marketing authorisation holder(s) and NCAs EC decision to update centralised marketing authorisation

CAP

EC decision addressed to Member States for implementation at national level

NAP

CMDh majority position sent to EC, marketing authorisation holder(s) and NCAs CMDh position CMDh consensus position sent to marketing authorisation holder(s) and NCAs 30 days NAPs only Implementation at national level European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The assessment of a PSUR or several PSURs for the same active substance(s) is undergone by the PRAC Rapporteur or in case of nationally authorised products only by the appointed Lead Member State, respectively. The timelines for assessment are for up to 134 days followed by 67 days of Commission decision making process (if applicable). Upon technical* validation by the EMA of the submitted PSUR(s), the following timetable shall apply:

Day Action

Day 0 Start of the procedure according to the published timetable

Day 60 PRAC Rapporteur’s / Lead Member State preliminary assessment report

Day 90 MAH and PRAC members’ / Member States

comments

Day 105 PRAC Rapporteur’s / Lead Member State updated assessment report (if necessary)

Day 120 PRAC recommendation adoption with the PRAC assessment report

Day 134 CHMP opinion / CMDh position (in case PRAC recommends a variation, suspension or revocation of the MA)

• There is no validation of the content of the PSUR.

The MAH is expected to provide, as applicable, by Day 90:

• responses to the “request for supplementary information” as outlined in the relevant section of the

PRAC Rapporteur / Lead Member State PSUR preliminary assessment report,

• comment on the proposed wording (in case the recommendation is a variation),

• propose product information wording in case the recommendation is a variation, but no exact wording is proposed by the PRAC Rapporteur / Lead Member State,

• provide a justification in case the MAH does not agree with the PRAC Rapporteur / Lead Member State recommendation to vary, suspend or revoke the MA; and/or

• include additional comments or clarification deemed necessary by the MAH

The MAH’s comments should be submitted as per the PSUR dossier submission requirements detailed in the question “ How shall I submit the response to a request for supplementary information during a PSUSA procedure? ”.

In case of major disagreement with the PRAC Rapporteur’s/Lead Member State’s proposed

Recommendation as stated in the updated assessment report, the MAH should contact the EMA Procedure Manager no later than two working days following receipt of the report and provide in

writing a rationale for the major disagreement for the PRAC Rapporteur’s/Lead Member State’s

consideration. In this communication the MAH should indicate whether they would wish to make use of the opportunity of an oral explanation to defend their position before the PRAC. In the absence of a European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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reply within two days following receipt of the report, the EMA will assume that no oral explanation is requested.

The MAH of centrally authorised medicinal products should submit a clean and a tracked version of the agreed amended product information prior to the adoption of the PRAC recommendation on the PSUSA.

In case the PRAC adopts a recommendation on the maintenance of the marketing authorisation, such recommendation is not transmitted to the CHMP or CMDh and the procedure ends with the adoption of the PRAC recommendation.

In case the PRAC recommends any regulatory action i.e. variation, suspension or revocation of the marketing authorisation, the PRAC recommendation will be transmitted to the CHMP if it includes at least one CAP or to the CMDh if it includes only NAPs. At its next meeting following the PRAC recommendation, the CHMP or the CMDh, as applicable, will adopt an opinion or a position, respectively. Subsequently, where the procedure includes at least one CAP, the Commission will adopt a decision to the MAHs for the centrally authorised products and, as applicable, to the competent authorities of the Member States for nationally authorised products. Where the procedure includes only NAPs, the procedure ends with the CMDh position in case of consensus and in case of a majority vote, the CMDh position will be followed by a Commission decision (CD) to the Member States, which respectively have to be implemented according to the timetable indicated in the CMDh position or within 30 days of the CD receipt by the Member States . For further details on the procedural aspects of the EU PSUSA for NAPs only, please refer to the relevant CMDh SOP on the processing of PSUR single assessment for nationally authorised products.

The outcome of the PSUR assessment results in a legally binding decision or CMDh position and any action to vary, suspend or revoke the marketing authorisations must be implemented in a harmonised and timely manner for all products within the scope of the procedure across the EU.

References

• Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report

• CMDh SOP on the processing of PSUR single assessment for nationally authorized products

• Guidance to applicants /marketing authorisation holders (MAHs) on oral explanations at EMA

17.26. How shall I submit the response to a request for supplementary information during a PSUSA procedure? Rev. Mar 2025

No specific template needs to be followed for the responses to the request for supplementary information (RSI). The responses to the RSI should be accompanied by a cover letter within the deadline, which cannot be extended at the request of the MAH.

The submission requirements for responses to requests for supplementary information are the same as those for the submission of the PSURs. For the submission of responses to the PSUR Repository, the xml delivery file is filled in the same way as the original PSUR submission apart from the selection of

‘response ’ as a regulatory activity (submission unit). This xml delivery file should be attached to the relevant eCTD sequence submitted via the eSubmission Gateway/Web Client. The regulatory activity

‘PSUR’ can only be used for the ‘initial’ PSUR submission due to the built -in business rules linking to the submission deadline. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Please refer to the eSubmission: Projects and the PSUR Repository MAH user guide for more information on the creation of the delivery file.

17.27. How is the CHMP opinion/CMDh position structured? How does the translation process work, and which annexes need to be translated? Rev. Mar 2025

The preparation of the translation process

In view of the short timeframe for finalisation of the translations and in order to optimise the quality of the translations, the MAHs are strongly advised to prepare for the translation process well in advance in the pre-opinion / position stage, i.e. just following adoption of the PRAC recommendation for variation.

In case of a PSUSA procedure where several MAHs are involved, the EMA will coordinate the translation process by approaching the MAHs individually and provide the timelines accordingly. MAHs should translate all relevant Annexes for each procedure, respectively.

Procedures that contain centrally authorised products (CAP(s))

• Annex B: Annexes I, II, IIIA, IIIB, IV 1 (scientific conclusions and grounds for the variation of the marketing authorisation) and 127a (risk minimisation measures addressed to Member States)

Procedures that contain a mix of centrally authorised products (CAP(s)) and nationally

authorised products (NAP(s))

For the CAP(s):

• Annex B: Annexes I, II, IIIA, IIIB, IV 8 (scientific conclusions and grounds for the variation of the marketing authorisation) and 127a (risk minimisation measures addressed to Member States)

For the NAP(s):

• Annex C: it is the CAP MAHs responsibility to provide NAP Annex C translations

• Annex I (scientific conclusions and grounds for variation to the terms of the marketing authorisations)

• Annex II (amendments to the product information of the nationally authorised medicinal products)

• Annex III (conditions to the marketing authorisations), as applicable

Procedures that contain only nationally authorised products (NAP(s))

• Annex C:

• Annex I (scientific conclusions and grounds for variation to the terms of the marketing authorisations) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Annex II (amendments to the product information of the nationally authorised medicinal products)

• Annex III (conditions to the marketing authorisations)

• Annex III or IV (timetable for implementation 9)

During the translation process

Depending on the type of outcome and whether a Commission Decision is required , the timelines for the translation process vary depending on the need for a linguistic review as illustrated below: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Is there a CD? MAH will have 3 working days (5 calendar days) for translation Yes MAH will have 10 working days (14 calendar days) for translation No D05: MAH initiates linguistic review as per adopted TT D14: MAH initiates voluntary linguistic review as per provided TT D19-25: MAH integrates all comments and sends compiled PDF of all languages to EMA D28-34: MAH integrates all comments and sends compiled PDF of all languages to EMA D27: PA sends linguistic package to EC, and finalises EPAR folder D35-45: EMA sends linguistic package to CMDh inbox, prepares EPAR folder and publishes outcome on dedicated webpage PA sends email to web-team requesting EPAR publication CD

a) In case of CHMP opinion or CMDh position by majority i.e. followed a Commission Decision, the MAH has to provide the translations of the adopted Annexes in all EU languages (including Icelandic and Norwegian – if applicable as detailed below) according to the following timelines:

Day 5 (5 days after opinion/ position) Translations of the adopted Annexes in EN and in all other EU languages (including Icelandic and Norwegian) are to be provided electronically (in one Eudralink package if applicable) to the Member European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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States (MS) Contact Points for Translations and to

the EMA’s procedure assistant and the PSUSA

Mailbox.

Day 19 (19 days after opinion/ position) Member States will send linguistic comments on the Annexes to the MAH by e-mail with a copy to the PSUSA Mailbox.

Day 25 (25 days after opinion / position) The MAH(s) will implement the required changes, compile the translations and send it back to the EMA.

In case of disagreement between a Member State and the MAH, the EMA will not interfere in the translation process at this stage. Disagreements should be solved directly with the concerned MS.

In order to facilitate and accelerate the check of the

implementation of the’ comments, the MAH should indicate in “ QRD Form 2 ” for each language if all

comments have been implemented or not. In the latter case, a justification should be provided for the appropriate language(s) stating why certain comments are not reflected in the final texts.

b) In case of CMDh position by consensus, Member States may perform a voluntary linguistic review in the translation process, therefore the following timelines apply:

Day 1 – 14 (1 to 14 days after position): MAH translates the adopted Annexes in all other EU languages based on the EN provided version. MAHs with marketing authorisations in Iceland and/or Norway will provide these languages as well.

Day 15 (15 days after the position): Translations of the adopted Annexes in EN and all other EU languages (incl. Icelandic and Norwegian if applicable) are to be provided electronically (in one Eudralink package if applicable) to the Member States (MS) Contact

Points for Translations and to the EMA’s

procedure assistant and the PSUSA Mailbox for voluntary linguistic check.

Day 28-34 (28-34 days after position) The MAH(s) will implement the required changes.

Translation of the adopted Annexes in EN and in all other EU languages (including Icelandic and Norwegian) are to be compiled and provided electronically (in one Eudralink package if European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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applicable) to the EMA’s procedure assistant and

the PSUSA Mailbox.

Day 35-45 (35-45 days after position) The EMA will send the package to the CMDh and prepare the translations for publication.

In case of an adoption of a European Commission decision addressed to the EU Member States, translation into Irish language is also required since January 2022 but the translation into Gaelic language will be performed by the Translation Centre (CDT) in Luxembourg and reviewed by the Ireland Member State: Product-information requirements.

After the translation process

Once the translations are received from the MAH, the Agency will check if all Member States’

comments have been implemented.

a) In case of a CHMP opinion or a CMDh majority position the Agency will compile the Annexes in all languages and send the final copies to the Commission, members of the Standing Committee and the MAH(s) at Day 27 (27 days after opinion). Following receipt of the final compiled translations, the Commission will start the 22-day Standing Committee consultation, addressing only legal and public health matters (which means in principle no further linguistic review).

b) In case of a CMDh position (by consensus), the Agency will compile the Annexes in all languages, send the final copies to the Member States and, where applicable, the full set of Annexes will be published on the EMA website.

Standards of translation of Annexes

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated PIs. This applies to the English version submitted at the time of opinion, the draft translations submitted at D+5 and the final translations submitted at D+25. Please submit annotated PIs in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated PI submitted by the marketing authorisation holder.

• The structure of the English Annexes has to be strictly followed and should be exactly translated as per the adopted English version (i.e. full product information or only amendments to the relevant sections of the product information).

• For translations of Annexes QRD templates for each language should be used

• Make sure that the title pages are adjusted and all brackets (i.e. <>) are deleted from the title.

• Do not leave sections out, do not update the Annex III, e.g. the sections [to be completed on a

national level] simply to be translated as ‘to be completed on a national level’. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Good quality of the translations and compliance with the Member States’ comments is required to

facilitate the process.

If a translation is considered not to be of an acceptable quality, the Member State concerned will inform the MAH and the Agency within 3 days of receipt of the translation. The Agency will inform the MAH of the insufficient quality of the translations and the transmission to the Commission will be delayed until receipt of the amended translation (which would be expected within 1 week). A revised timetable will then be prepared.

The MAHs are also strongly advised to liaise directly with the Member States in case of disagreement with any of the comments made or in case further clarification on some comments is required, and to

reflect the outcome in “ QRD Form 2 ”.

In addition, the MAHs are reminded that in case the complete product information is part of the Annex III, it should be presented in strict compliance with the QRD Convention (e.g. format, layout and margins).

The Agency will monitor the quality of the translations, the review by the Member States and industry’s compliance with the Member States’ comments as part of the Performance Indicators.

References

• QRD convention to be followed for the EMA-QRD templates

• Product Information Templates

• List of the Member States (MS) Contact Points for Translations

17.28. To whom should I submit follow-up data requested as part of the conclusion of a PSUSA procedure? Rev. Mar 2025

Requests for follow-up data made as part of the conclusion of a EU-PSUSA procedure are expected to be submitted as post-authorisation measures (LEG) for CAPs and PSUFU for NAPs.

The submission of a LEG for CAPs must be done in eCTD format via the eSubmission Gateway/Web Client. LEGs must not be submitted to the PSUR Repository. For more information on the submission of a LEG, please refer to the existing Post-authorisation measures: questions and answers.

PSUFUs for NAPs must not be submitted in the PSUR Repository and neither to EMA. The submission and assessment are expected to take place at national level and be coordinated across the Member States. For more information on the submission of a PSUFU, please refer to the existing CMDh PSUFU guidance document.

References

• CMDh Guidance on the Informal Work-Sharing procedure for PSUSA for NAPs (PSUFU procedure)

• Post-authorisation measures: questions and answers European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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17.29. How can I know about the outcome of a PSUSA procedure? Rev. Mar 2025

Information on the outcome of PSUSA involving centrally authorised medicinal products only is made available in the European Public Assessment Report (EPAR) page of the relevant medicine.

Information regarding the variation of NAPs that are part of a mixed CAP/NAP procedure is available in the Union Register for nationally authorised products.

Information on the outcome of the EU single assessment of PSURs involving nationally authorised medicinal products only is made available on the EMA web page under 'Download medicine data

section’ .

Additionally, the MAHs are reminded to routinely check the minutes of the relevant Committee/Coordination group, where the outcomes of PSUSA procedures and of the respective plenary discussions are also published.

17.30. How shall I implement the outcome of a PSUSA procedure? Rev. Mar Oct 2026

For PSUSA involving CAPs the product information is varied as part of the Commission Decision issued to the MAHs, without the need for a variation. For CAPs outside the procedure (e.g. generics), if the

wording is implemented exactly as agreed and harmonised national translations are available, the

changes should be introduced as a Type IA IN variation under category C.3.a. Should these conditions

not be met, implementation requires through a Type IB variation under category C.3.b.

For the NAPs included in the PSUSA procedure, the Commission decision (when applicable) is addressed to the Member States and therefore, it should be implemented by the NCAs within 30 days of its notification. The respective variations for the NAPs have to be submitted to the relevant NCA within 10 days after publication of the Commission Decision on the EC website.

For NAPs included in a PSUSAs procedure, for which a CMDh position was adopted by consensus, a timetable for submission of the variations is applicable to all affected products, including those that are not listed in the annex to the position, is published on the EMA website. In case of a majority position, the deadlines foreseen in the legislation for implementation after the Commission Decision apply.

Changes to the product information resulting from a single PSUR assessment may be implemented through the submission of an Type IA IN variation under category C.3.a if harmonised national translations are available, irrespective of the medicinal product being part of the PSUSA procedure or

not and no further adaptation of the currently approved wording is necessary. In cases where the

wording has to be adapted, a Type IB variation under category C.3.b has to be submitted. In case the MAH wants to submit new data for assessment, a Type II variation should be submitted.

For other products not directly involved in the PSUSA procedure, the changes have to be submitted via a variation procedure according to the timelines indicated in the table below.

For NAPs, further guidance on the implementing variation can be found on the CMDh website (Question & Answers, Pharmacovigilance legislation). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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CAP products NAP products

Product involved in procedure

Yes No Yes No

Implementing variation needed, type and classification

Not applicable; the variation is directly implemented through Commission Decision to MAH involved in the PSUSA procedure

Yes

IA IN C.3.a if

harmonised national

translations are

available and no

adaptation to the

wording is required

IB C.3.b if additional

minor assessment is

required

Yes

Please refer to answer to

Question 3.3 of the CMDh Variations Q&A.

Heads of Medicines Agencies: Questions & Answers (hma.eu)

Yes

Please refer to answer to

Question 3.3 of the CMDh Variations Q&A.

Heads of Medicines Agencies: Questions & Answers (hma.eu)

Timeframe for submission of variation

Not applicable MAHs to submit variations within two months after receipt of the EMA communication encompassing the safety updates referred to in the relevant PSUSA procedure

For CMDh position by consensus: as per the date

indicated in the translation timetable i.e.

105 10 calendar days after adoption of the CMDh position.

For CMDh position by majority vote:

10 days after publication 11 of CD on EC website.

For CHMP Opinion: 10 days after publication

For CMDh position by consensus: as per the date indicated in the translation timetable i.e.

105 3 calendar days after adoption of the CMDh position.

For CMDh position by majority vote:

60 days after publication of CD on EC website.

For CHMP Opinion: 60 days after publication of CD on EC website.

10 45 calendar days for translation publication + 60 calendar days from publication of translations 11 See also Q 3.3 of the Q/A-LIST FOR THE SUBMISSION OF VARIATIONS ACCORDING TO COMMISSION REGULATION (EC) 1234/2008 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure EMEA-H-19984/03 Page 259/305

of CD on EC website.

17.31. Can I extrapolate the PRAC recommendation on a PSUSA to medicinal products not included in the procedure? NEW Mar 2026

The PRAC recommendation resulting from a PSUSA is directly applicable to the medicinal products within scope of the single assessment for the concerned EURD entry.

Marketing authorisation holders whose medicinal products are not included in the scope of the single assessment are reminded of their obligation to keep the product information up to date, in line with current scientific knowledge.

They should therefore consider whether a PRAC recommendation arising from a PSUSA is also relevant to their products and, where applicable, submit the appropriate variation with the corresponding data package, even when PRAC has not explicitly requested the extrapolation of the recommendation.

In exceptional cases, upon completion of the procedure, the PRAC Assessment Report may, consider that the PRAC recommendation can be extrapolated to medicinal products not included within the scope of the single assessment. In such case, PRAC may support that a request for product information amendments to medicinal products containing a single active substance is extended to fixed-dose combinations containing this active substance, or vice versa, when supported by the evidence reviewed in the PSUSA.

• If centrally authorised products (CAPs) are affected by extrapolation, the EMA will contact the concerned MAHs to enable them to take the necessary regulatory actions to implement the PRAC recommendation in their marketing authorisations.

• If nationally authorised products (NAPs) are affected, the request will be made public through the CMDh meeting minutes to enable the concerned MAHs to take the necessary regulatory actions on the marketing authorisations. Further information is available in the CMDh Q&A on the Pharmacovigilance Legislation: Heads of Medicines Agencies: Questions & Answers.

17.32. Who should I contact if I have a question regarding the preparation of a PSUR submission and during the procedure? Rev. Mar 2025

For centrally authorised products (CAPs), if you cannot find the answer to your question in the Q&A when preparing your application or during the procedure, please contact the Product Lead responsible for your product.

For nationally authorised products (NAPs), the assigned EMA Procedure Manager should be contacted during the procedure in case of questions. If you encounter issues while preparing for the PSUR submission and before the EMA Procedure Manager has been assigned, and cannot find the answer to your question in the Q&A, please submit your query using the Ask EMA feature. The use of the key word 'PSUR' as a minimum in the subject line will help the Agency allocate your query to the correct person. Please give as much detail as possible when completing your request (the procedure number of the PSUR single assessment as per the EURD list, the name of the product and the name of the active substance/combination of active substances) and be sure to include your correct and complete European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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contact details. You should type the full details of your query in the appropriate space. If the contact details you provide are incomplete or inaccurate this may prevent the Agency from communicating with you. In case of incomplete or incorrect data in the web form, the request may not be processed.

17.33. Who should I contact if I have a technical issue with the submission of the PSUR? Rev. Mar 2025

For PSUR repository interface, eSubmission Gateway and/or the Web Client questions, issues and requests for services, please contact us through the EMA Service Now .

Within the portal, to report an issue with the PSUR Repository or other related eSubmission tool,

please select option ‘Report an issue with eSubmission’ and select the relevant system from the menu under ‘Service Offering’ .

To help us deal with your enquiry, please provide as much information as possible including whether your query refers to a NAP or a CAP, the procedure number of the PSUR single assessment as per the EURD list, the name of the product and the name of the active substance/combination of active substances in your correspondence. Please also include screenshots or attachments with further information where relevant. In case of incomplete or incorrect data, the request may not be processed.

Please refer to the e submission webpage and the PSUR Repository MAH user guide for additional information.

17.34. Who should I contact if I have an issue related to the EURD list? Rev. Mar 2025

For details on how to submit requests for amendments of the EURD list or any other questions related

to the EURD list, please refer to the ‘ Introductory cover note to the List of European Union reference dates and frequency of submission of Periodic Safety Update Reports ’.

MAHs and other stakeholders can request amendments to the EURD list by emailing [email protected] with the following information:

Template for a request for amendments of or addition of active substances or combinations of active substances to the European Union reference-date list (DOCX/103.03 KB)

Reference

• Introductory cover note to the List of European Union reference dates and frequency of submission of Periodic Safety Update Reports

17.35. What fee should I pay and whom to contact if I have an issue related to the payment of fee and QPPV advice notes? Rev. Mar Oct 20265

For more information on fees to be paid, applicable fee reductions and payment process, please refer to the Fee Q&As in Annex I, Section 14, onand the Fees payable to the European Medicines Agency:

page. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Reference

• Regulation (EU) 2024/568 of the European Parliament and of the Council of 7 February 2024 on fees and charges payable to the European Medicines Agency European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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18. Article 46 paediatric study submission

18.1. What is the “Article 46 paediatric study submission”? Rev. Oct 2023

Article 46 of Regulation (EC) No 1901/2006 (t he ‘Paediatric Regulation’) sets out the obligation for the

Marketing Authorisation Holder to submit to the competent authority any MAH-sponsored studies involving the use in the paediatric population of an authorised medicinal product, whether or not they are part of a PIP. For centrally authorised medicinal products, the studies should be submitted to the European Medicines Agency.

This includes clinical studies that are:

• completed or discontinued;

• published or not.

Studies should be submitted regardless of the region where they were performed, the aim, outcome, design/methodology, population studied and indication.

Reference

• Article 46 of Regulation (EC) No 1901/2006

18.2. When shall I submit my article 46 paediatric study application? Rev. Dec 2014

The MAH should submit the paediatric study(ies) within 6 months of its completion and irrespective whether or not it is part of a PIP (completed/or not yet completed) of whether or not it is intended for submission later on as part of a variation, extension or new standalone Marketing Authorisation Application.

Completion of a study is defined in the Commission Guideline on the format and content of paediatric investigation plans. Clinical studies are deemed to have been completed on the date of the last visit of the last subject in the study or at a later point in time as defined in the protocol.

Reference

• ICH Topic E3, Note for Guidance on Structure and Content of Clinical Study Reports, CPMP/ICH/137/95

• Commission Communication, Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies

18.3. How shall I present my article 46 paediatric study application at submission? Rev. Mar 2026

A paediatric study is to be submitted pursuant to article 46 as a post-authorisation measure (‘stand -

alone’ submission). However, if amendments to be introduced to Product Information are identified by European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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the MAH, a variation (e.g. category C.4 or C.6) should be submitted directly containing the article 46 paediatric study.

The submission of an application under article 46 should include the following documents, preferably presented in accordance with appropriate headings and numbering of the EU-CTD format:

• Cover Letter including information on the context in which the article 46 paediatric study submission is made (e.g. stand-alone study or study included in a development program) and statement that there are no regulatory consequences identified by the MAH.

• In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file UI.

• A completed PAM submission form with the full description of the PAM. The description should mention the due date (6 months from the completion of study). This form will ensure the correct classification of the submission, involvement of designated Committees(s) and timetable to be applied.

• A short critical expert overview clarifying the context of the data, including information on the pharmaceutical formulation used in the study, the existence of a suitable paediatric formulation and if relevant, conditions for an extemporaneous formulation

• Final clinical study report

• For a paediatric study that is part of a development program, a line listing (see template) of all the concerned studies

In case of submission of a variation including study relevant to article 46, the application should be presented in EU-CTD format accordingly to the guidance for variation (see also in guidance on variations). The following box should be ticked in the vari ation application form: “ THIS APPLICATION RELATES TO PAEDIATRIC STUDIES SUBMITTED ACCORDING TO ARTICLE 45 OR 46 OF THE PAEDIATRIC REGULATION ”.

References

• ICH Topic E3, Note for Guidance on Structure and Content of Clinical Study Reports, CPMP/ICH/137/95

18.4. How and to whom shall I present my article 46 paediatric study application? Rev. Feb 2019

Information is available on ‘Submitting a post -authorisation application’.

18.5. How shall the evaluation of my article 46 paediatric study application be handled (timetable), and what could be the outcome of the evaluation? NEW Feb 2014

The following 60-day timetable shall apply to the assessment of the paediatric study submitted by the MAH: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

EMEA-H-19984/03 Page 264/305

Day Action

Day 1 Start of the procedure as per published timetable (see below)

Day 30 Receipt of Rapporteur’s Assessment Report

Day 45 CHMP Members’ comments

Day 50 Receipt of Rapporteur’s updated Assessment

Report (if necessary)

Day 60 (CHMP meeting)

(up to Day 90 if a Request for Clarification is needed)

CHMP adoption of conclusion or Request for Clarifications

The submission deadlines and full procedural detailed timetables are published as a generic calendar on the EMA website (see submission deadlines and full procedural timetables).

The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

The EMA will inform the MAH of the outcome of CHMP evaluation. The following may be envisaged

depending on CHMP’s conclusion at D60:

• No amendment to the product information is required at this point of time.

• Further clarifications are required. The CHMP will request additional clarifications (directly linked to the paediatric study submitted) and a 30-day extension of the timeframe will normally apply.

• A variation is needed to amend the product information in accordance with the CHMP conclusion. The variation submission is normally requested within 60 days after adoption of the CHMP conclusion. If the MAH is unable to submit the variation within this timeframe, he must justify the delay and inform the EMA/Rapporteur and propose a new submission date.

At the time of finalising an opinion, it may be needed that the MAH generate additional data (see also guidance on post-authorisation measures).

18.6. Do I have to pay fees for the article 46 paediatric study submission? NEW Feb 2014

There is no fee payable for article 46 paediatric studies. However, the normal fees are applied to any variations containing Article 46 paediatric data or variations resulting from the assessment of such article 46 paediatric study submission.

18.7. Will there be any publication on the outcome of my article 46 paediatric study? Rev. Feb 2014

The assessment report of the procedure will be published on the European Medicines Agency website under the EPAR tab of the product after removal of commercially confidential information.

References

• EPARs European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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19. Transfer of Marketing Authorisation

19.1. What is a Transfer of Marketing Authorisation? Rev. Mar 2026

A Transfer of Marketing Authorisation (MA) is the procedure by which the MA is transferred from the currently approved Marketing Authorisation Holder (MAH) to a new MAH which is a different person/legal entity.

Such a Transfer may result from the MAH’s commercial decision to divest the MA or be needed in

anticipation of the MAH ceasing to exist as a legal entity and MA being taken over by another legal entity.

In case a MA Transfer is sought for several medicinal products, a common data package may be prepared but an application must be submitted for each MA (i.e. 1 application per product).

A change of name and/or address of the MAH is not a MA Transfer if the holder remains the same person/legal entity. Such change should be notified through a Type IA/E.4.a variation application.

A Transfer of MA does not include a Transfer of Orphan designation since this is subject to a different procedure (s ee also “Do I also have to transfer the Orphan designation when my medicinal product has been granted such a designation?”).

A Transfer of a MA can only be initiated once a MA has been granted. In case there is a need to change the proposed MAH during the initial Marketing Authorisation Application procedure, please see the question and answers in the EMA pre-authorisation guidance “How can I change the applicant for an ongoing marketing authorisation application?” .

From this point onward:

• The MAH of the MA to be transferred is termed the Transferor.

• The person/legal entity to whom the Transfer is to be granted is termed the Transferee.

References

• Commission Regulation (EC) No 2141/96 of 7 November 1996 concerning the examination of an application for the Transfer of a marketing authorisation for a medicinal product falling within the scope of Council Regulation (EC) No 2309/93

• Commission Regulation (EC) No 1234/2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures

19.2. How shall I present my application for the Transfer of Marketing Authorisation? Rev. Jul 2026

Transfer applications should be presented as follows, in accordance with the appropriate headings and numbering of the EU-CTD format.

Module 1: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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1.0 Cover letter (signed by the Transferor) with the following documents attached (Cover letter):

All documents to be submitted from the Transferee and/or the Transferor, as appropriate, must be legible and preferably shall be printed on a headed paper. A template for each document is attached to provide guidance on the information that should be included in each document.

1. Information about the Transferor, Transferee and concerned product(s) (Attachment 1)

A document is required that contains information about the Transferor, Transferee (name, address, contact person at MAH address, telephone number, and email address) and concerned product(s), including the authorisation number(s) and date(s) of initial marketing authorisation(s) – see 'Authorisation details' tab of the product-specific website on the European Medicines Agency website or respective information in the Union product database.

The document should also include declarations stating that all necessary information has been made available to the Transferee. This includes confirmation that the complete and up-to-date file concerning the medicinal product or a copy of this file, including any data/documents related to the paediatric obligations, has been made available to or transferred to the Transferee.

If appropriate, a declaration of undertaking signed by the Transferee listing any remaining recommendations or post-authorisation measures should be provided with the referred attachment

1. See also “Transfer of Marketing Authorisation – How to handle remaining follow-up measures

and specific obligations when transferring a marketing authorisation?”

Furthermore, a signed statement should confirm that no other changes have been made to the product information other than those to the details of the MAH and, if appropriate, the details of the local representatives.

The document should also include a declaration confirming that, following adoption of the Commission Decision, the Transferee will update the product contact details in IRIS in line with the information provided in the MA Transfer application.

1. Transitional organisational arrangements (Attachment 2)

A document stating the date on which the Transferor and the Transferee finalise the transitional organisational arrangements and the Transferee takes over all responsibilities. This is referred to as the implementation date. The transitional period between the notification of the Commission decision on the transfer of a marketing authorisation and the implementation date should be proportionate to the organisational activities that need to be performed by the Transferor and Transferee and this date should not exceed 6 months (see also Transfer of Marketing Authorisation - “How to choose the implementation date?”) .

If applicable, this document should include a “Statement of activities performed by the Transferor during the transitional period”. This statement should briefly provide the Agency with an overview

of the organisational activities which will be performed by the Transferor - as agreed with the Transferee - during the transitional period. The transitional period is the period between the date of notification of the Commission Decision on the Transfer and the implementation date.

Moreover, a statement should confirm the status of the product in the market. If the medicinal product concerned has not yet been marketed in the EU/EEA in any of its presentations or has been marketed in the EU/EEA in any of its presentations this should be specified in a signed statement. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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1. A proof of establishment of the Transferee within the European Economic Area (EEA) issued in accordance with national provisions (e.g. Chamber of Commerce). This document should be no older than 6 months.

2. A document showing the capacity of Transferee to perform all the responsibilities required of a MAH under Union Pharmaceutical legislation.

Please provide an updated summary of the Pharmacovigilance System Master File (PSMF)

under the Transferee’s name in Module 1.8.1 of the application, and ensure to include the following elements:

• proof that the applicant has at his disposal a qualified person responsible for pharmacovigilance,

• the Member States in which the qualified person resides and carries out his/her tasks, the contact details of the qualified person,

• a statement signed by the applicant to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX of Directive 2001/83/EC,

• a reference to the location where the pharmacovigilance system master file (PSMF) for the medicinal product is kept

When the name of a product is composed of ‘INN + company name ’ please see Transfer of Marketing Authorisation - “Can I change the name of a medicinal product as part of a transfer application? ”.

When the product information includes a URL and/or QR code that directs to information, website, etc. of the current marketing authorisation holder (transferor), the new marketing authorisation holder (transferee) must update these details. Following adoption of the Commission Decision for the transfer procedure, the transferee is required to submit an Art. 61(3) Notification within the agreed transitional period to update the labelling and/or package leaflet accordingly.

1.3 Product Information

1.3.1 SmPC, Annex II, Labelling and Package Leaflet:

The revised product information (SmPC, Annex II, labelling, and package leaflet) in all EU languages including Iceland and Norway must be provided electronically in Word format (highlighted using track changes) and in PDF format (clean).

The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU language. Page numbering should start with "1" (bottom, centre) on the title page of Annex I. The Annexes should be presented in strict compliance with the QRD Convention published on the EMA website. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed ‘Checklist for the submission of product information annexes and Annex A (if applicable) for minor procedures without linguistic review ’, and MAHs should follow/pay attention to the User guide on how to generate PDF versions of the product information - human.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version and all the translations. The annotated product information files must include the statement containing the procedure number(s) and may be published on the EMA website as part of the product EPAR page. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA, the publication on the EMA website and its further sharing by EMA with third parties such as other applicants, marketing authorisation holders (MAH) and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated PI submitted by the MAH.

1.3.2 Mock-up

English and multi-lingual (‘worst -case’) colour mock -up of outer and immediate packaging for each pharmaceutical form in each container type (e.g. blister and bottle, vial and pen) in the smallest pack-size ( see also “Transfer of Marketing Authorisation – Do I have to submit mock-ups and specimens?”).

Reference

• Commission Regulation (EC) No 2141/96 of 7 November 1996 concerning the examination of an application for the Transfer of a marketing authorisation for a medicinal product falling within the scope of Council Regulation (EC) No 2309/93

• Checking process of mock-ups and specimens of outer/immediate labelling and package leaflets of human medicinal products in the centralised procedure

• Guideline on Pharmacovigilance for Medicinal Products for Human Use, Volume 9A of the Rules governing Medicinal Products in the European Union

19.3. How and to whom shall I submit my Transfer of Marketing Authorisation application? Rev. Feb 2019

Information is available on ‘Submitting a post -authorisation application’.

19.4. How shall my Transfer of Marketing Authorisation application be handled (timetable)? Rev. Jul 2021

A Transfer application follows a 30-day procedure following receipt of the application. There are no set submission dates. In order to choose the best submission date, especially in case of any other ongoing/expected procedures, the transferor should contact the EMA at least 1 month prior to the submission of the application (see also ‘Transfer of Marketing Authorisation – Who should I contact if I

have a question when preparing my application or during the procedure?’ .

Within 7 days upon receipt of the Transfer application, the EMA will check whether the Transfer application is correct and complete. In case the application is correct and complete the Agency aims to finalise the procedure by Day 10. In case of an incorrect or incomplete application the applicant will be notified and required to provide the amended and/or additional documentation via eCTD submission within 10 calendar days from the date of the EMA notification. The EMA will not be able to issue a favourable opinion on the Transfer in case the documentation is incomplete. Upon receipt of the applicant responses the Agency aims to finalise the procedure by Day 20. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In any case finalisation of the opinion should be within 30 days upon receipt of the Transfer application.

The Transfer opinion will be sent to the Transferor, Transferee, European Commission and the competent authorities of Iceland and Norway. Subsequently, the European Commission will issue a decision on the Transfer of the MA. The transfer of the marketing authorisation is authorised from the date of the notification of the Commission decision on the Transfer.

However, the Agency by mutual agreement with the Transferor and the Transferee can set an implementation date for the Transfer (see also “How to choose the implementation date?”).

Reference

• Commission Regulation (EC) No 2141/96 of 7 November 1996 concerning the examination of an application for the Transfer of a marketing authorisation for a medicinal product falling within the scope of Council Regulation (EC) No 2309/93

19.5. How to choose the implementation date? Rev. Jun 2024

The implementation date is the date on which the Transferee takes over ALL responsibilities as the Holder of the MA. This date is proposed by the Transferor and Transferee in the Transfer application, attachment 2, and will be subject to agreement by the EMA. This date is stated on the opinion adopted by the Agency and also on the European Commission decision.

For the Transfer of a Marketing Authorisation covering medicinal products already marketed in the EU/EEA by the Transferor , the proposed date should be set taking into account the following timelines (s ee also “ Transfer of Marketing Authorisation - How shall my Transfer of Marketing

Authorisation application be handled (timetable)?”):

• The EMA timeframe for finalisation of the opinion is 30 days from the receipt of an application (Day A).

• The Commission will subsequently issue a Commission Decision on the Transfer of the marketing authorisation. As of the date of notification of the Commission Decision on the Transfer of the marketing authorisation (Day B), the Transfer is effective, and the Transferee becomes the new MAH of the medicinal product.

• Between Day B and Day C (implementation day) there is a transitional period during which the previous MAH and the new MAH have to finalise their organisational arrangements, as defined in the Transfer application (e.g. contractual agreements as regards to batch release). The Transfer application should include information as to the date on which the Transferor will release the last produced batch in the distribution chain, duly justifying why that particular date has been chosen. The transitional period between the notification of the Commission decision on the transfer of a marketing authorisation (Day B) and the implementation date (Day C) should be proportionate to the organisational activities that need to be performed by the Transferor and Transferee. Nevertheless, it should be noted that as of Day B, the Transferee becomes the new MAH of the medicinal product and the EMA will only deal with the new MAH for any further regulatory activity (e.g. variations applications).

• Before Day B the Transferor is responsible for released batches. As of Day B, the new MAH can start releasing batches. The batches released by the new MAH should be in accordance with the European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Annexes of the Commission Decision on the Transfer and therefore, these batches should have the name of the new MAH in the Product Information. During this transitional period and on the basis of the arrangements agreed between Transferor and Transferee, batches bearing the name of the previous MAH can be placed on the market as well. Nevertheless, it should be noted that as of Day B, the responsibility on all released batches lies with the new MAH.

• After day C only the new MAH (Transferee) can release batches and place them on the market. The batches that have been placed on the market before Day C and that bear the name of the previous MAH can remain on the market.

For the Transfer of a Marketing Authorisation covering medicinal products not yet marketed in the EU/EEA by the Transferor , the proposed date should always refer to the day on which the Commission Decision on the Transfer will be issued.

Reception of a valid application [Day A]

Notification of EC Decision [Day B]

The Transferee becomes the new MAH and the product contact of EMA for further regulatory activity.

Implementation day [Day C]

The Transferee takes over all

organisation activities as MAH.

MA TRANSFER PROCEDURE TRANSITIONAL PERIOD (6 months maximum ) IMPLEMENTATION

The transferor is responsible for the

released batches.

The new MAH ( transferee) is responsible for all released

batches .

The transferee can release batches.

Upon agreement with the transferee, the transferor can still release batches bearing its name.

Only batches under the

name of the transferee can be released on the market.

19.6. What fee do I have to pay for my Transfer of Marketing Authorisation application? Rev. Dec 2024

For more information on fees to be paid, applicable fee reductions and payment process, please refer to the Fee Q&A in Annex IV, Section 2, on the Fees payable to the European Medicines Agency page.

References

• Fees payable to the European Medicines Agency European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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19.7. How to handle planned/ongoing variations procedures during the Transfer of Marketing Authorisation? Rev. Mar 2026

MAHs should avoid submitting variation procedures in parallel to a Transfer of MA application.

MAHs are strongly advised to contact the EMA in advance of the submission of the Transfer of application, in order to discuss how to handle any planned/ongoing procedures (especially in case the product information is affected) or in case there are variations linked to the Transfer procedure (see

also “ Transfer of Marketing Authorisation – Who should I contact if I have a question when preparing my application or during the procedure ?”) .

Where a regulatory deadline coincides with an on-going transfer (defined as the interval between the submission date and the notification of the adoption of the Commission Decision on the transfer), the procedure should be submitted by the current marketing authorisation holder (transferor).

Following the adoption of the Commission Decision on the transfer, the responsibility for the on-going concomitant procedure will rest with the new marketing authorisation holder (transferee). At this point, the transferee should contact the EMA product team to ensure continuity of the on-going concomitant procedure.

19.8. How to handle remaining Post-authorisation Measures and recommendations when transferring a Marketing Authorisation? Rev. Mar 2024

Enforceable post-authorisation measures (PAMs) may have been agreed for the medicinal product at the time of the granting of the marketing authorisation or subsequent modifications. If such PAMs are still remaining for the medicinal product concerned, it is the responsibility of the Transferee to fulfil them within the timeframe previously agreed.

In case of remaining PAM a declaration of undertaking signed by the Transferee listing them should be provided with the referred attachment 1.

Reference

• Commission Regulation (EC) No 2141/96 of 7 November 1996 concerning the examination of an application for the Transfer of a marketing authorisation for a medicinal product falling within the scope of Council Regulation (EC) No 2309/93

19.9. Do I have to submit mock-ups and specimens? Rev. Mar 2026

Mock-ups

According to point 6 in the Annex to Regulation (EC) No 2141/96 on transfers of centrally authorised medicinal products, mock-ups are to be included in the transfer application. Ideally, applicants must provide at submission an English and multi-lingual (‘ worst-case’) colour mock -up of outer and immediate packaging for each pharmaceutical form in each container type (e.g. blister and bottle, vial and pen) in the smallest pack-size. If not available, relevant example mock-ups of the marketed presentation may be submitted instead. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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If the transfer only affects the MAH details on the packaging and package leaflet without any impact on the overall design, in addition to the submission of the mock-ups, a declaration stating that only the details of the MAH have been modified and that such changes will be introduced in all product presentations should be included in module 1.3.2 of the application dossier.

EMA will review the mock-ups in parallel to the handling of the transfer procedure. If EMA has any comments on the mock-ups, these will be sent to the MAH within 15 working days from the start of the procedure.

In case of comments on the mock-ups, the MAH should submit responses and/or updated mock-ups, as applicable, to the EMA ([email protected]) prior to the specimen printing. EMA will discuss the best and feasible corrective action with the MAH, taking into account the nature and number of issues identified. EMA will endeavour to provide such feedback as soon as possible and taking into consideration the production plan of the medicinal product, as applicable.

Specimens

Only in case the transfer has an impact on the overall design, relevant revised example specimens should be provided to the EMA by the new MAH, in line with the requirements for new applications and extensions.

If the transfer only affects the MAH details on the packaging and package leaflet without any impact on overall design, specimens are not required.

The EMA will perform a general check within 15 working days and will check if any previous comments on specimens have been duly implemented. The applicant will be informed about the outcome of the check.

In case of comments on the specimens, the MAH should submit responses and/or updated mock-ups, as applicable, to the EMA ([email protected]) prior to the launch of the medicinal product. EMA will discuss the best and feasible corrective action with the MAH, taking into account the nature and number of issues identified. EMA will endeavour to provide such feedback as soon as possible and taking into consideration the launch plan of the medicinal product, as applicable.

The above principles also apply to mock-ups for Iceland. The mock-ups should be sent by e-mail to [email protected]. See also http://www.ima.is/.

No mock-ups and specimens are required for Norway.

References

• Checking Process of mock-ups and specimens of outer/immediate labelling and package leaflets of human medicinal products in the Centralised Procedure (EMA/305821/2006)

19.10. Do I also have to transfer the Orphan designation when my medicinal product has been granted such a designation? Rev. Dec 2007

When transferring the MA of a designated Orphan medicinal product, the MAH must also transfer the Orphan designation of the product concerned in accordance with Article 5(11) of Regulation (EC) No 141/2000 in order to maintain the orphan status.

Transfers of orphan designation and transfers of MA are different procedures and must be handled as such. The applications for transfer of the orphan designation and transfer of the MA should preferably European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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be submitted to the Agency at the same time. The cover letter accompanying each of the applications should make reference to the two applications, as the two procedures will be handled in parallel by the Agency.

Fee waivers can only apply to the transferred medicinal product once the transfer of the orphan designation is completed.

In preparing an application to transfer an orphan designation, sponsors should follow the guidance

given in the European Commission’s “Guideline on the format and content of applications for

designation as orphan medicinal products and on the transfer of designation from one sponsor to

another” and in the “Checklist for sponsors applying for the transfer of orphan medicinal product designation”.

References

• Article 5(11) of Regulation (EC) No 141/2000 of 16 December 1999 on orphan medicinal products

• Guideline on the format and content of applications for designation as orphan medicinal products and on the Transfer of designation from one sponsor to another

• Checklist for sponsors applying for the transfer of Orphan Medicinal P roduct (OMP) designation”

(EMA/41277/2007)

19.11. Can I include changes to manufacturing sites in my Transfer of Marketing Authorisation application? Rev. Jul 2021

Changes to a manufacturer(s) resulting from the transfer of the MA are not considered part of the transfer procedure. Therefore, the appropriate variations should be submitted separately. These variations will be handled separately from the transfer procedure. In such case, the MAH is advised to contact the EMA prior to submitting a transfer application in order to discuss the appropriate timeframe of such variations.

In addition, when the need for good-manufacturing practice inspections is anticipated by the MAH, it is advisable to contact the Agency in advance of the variation and transfer submission ( see also “Transfer

of Marketing Authorisation – Who should I contact if I have a question when preparing my application

or during the procedure?”) .

19.12. Can I change the Qualified Person for Pharmacovigilance and what

information on the summary of the transferee’s pharmacovigilance system

should I submit as part of my Transfer of Marketing Authorisation application? Rev. May 2018

A change to element(s) to the summary of the pharmacovigilance system master file (PSMF), e.g. the Qualified Person for Pharmacovigilance (QPPV) or of the PSMF location resulting from the transfer of the marketing authorisation (MA) can be notified as part of the transfer application without the need

for a separate variation (see also “ How shall I present my application for the transfer of marketing authorisation ”). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The summary of the transferor’s pharmacovigilance system in the MA dossier needs to be replaced in the transfer application with an updated summary of the transferee’s pharmacovigilance system

including:

• a proof that the transferee has at his disposal a QPPV, the Member State(s) in which the QPPV resides and carries out his/her tasks and its contact details,

• a statement signed by the transferee to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX of Directive 2001/83/EC,

• a reference to the location where the PSMF for the medicinal product is kept.

It is nevertheless required to update accordingly the information in the Article 57 database after the conclusion of the procedure for the MA transfer.

References

• Good pharmacovigilance practices

• Guidelines on Good Pharmacovigilance Practices (GVP) : Module I – Pharmacovigilance systems and their quality systems

• Guideline on Good Pharmacovigilance Practices (GVP): Module II – Pharmacovigilance system master file

19.13. Can I change the name of a medicinal product as part of a transfer application? Rev. Mar 2026

In order to change the name of a medicinal product, a variation is required and should be submitted separately and concurrently with the transfer procedure.

In the case the transfer procedure concerns a medicinal product whose name is constructed as [INN / common name + name of the MAH], the name of the medicinal product needs to be changed to reflect the name of the new MAH (transferee) through a Type IA IN variation E.1)

(see also “Changing the (invented) name of a centrally authorised medicine: questions and answers”

and the Generic and hybrid applications “How will I know if the proposed (invented) name of my

generic/hybrid medicinal product is acceptable from a public health point of view?” ).

The acceptance by the Name Review Group (NRG) of the new name has to be finalised prior to the submission of the variation for changing the name of the medicinal product, including where the transferee wishes to use the common or scientific name, together with a trademark or the name of the MAH.

Reference

• Commission Regulation (EC) No 1234/2008 of 24 November 2008

• Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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19.14. Will there be any publication on the Transfer of Marketing Authorisation? Rev. Mar 2024

The Commission decision on the transfer of Marketing Authorization is published in the Union register of medicinal products for human use on the European Commission website.

The European public assessment report (EPAR) will also be revised to implement the change in the MAH.

Reference

• Union register of medicinal products (centrally-authorised products for human use)

• EPARs

19.15. Who should I contact if I have a question when preparing my application or during the procedure? Rev. Mar 2024

If you cannot find the answer to your question in the Q&A when preparing your application, please contact us by raising a ticket via EMA ServiceNow, selecting the sub-option: “MAH transfer queries”.

If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance on creating an EMA Account, please refer to the guidance "Create an EMA Account".

The Agency aims to respond to your query within 10 working days. To help us deal with your enquiry, please provide as much information as possible including the name of the product in your correspondence.

Transfers will be handled by a dedicated team of Procedure Managers (PM). A PM will be nominated upon receipt of the application. This allocated PM will be the contact point for this procedure. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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20. Transparency

Since the establishment of EMA, transparency has been an important feature of the Agency’s

operation. This resulted in the introduction of the European Public Assessment Reports (EPARs) in line with the requirements of the Union legislation. European Union (EU) law sets the minimum level of transparency that the Agency must apply. However, in many areas, the Agency has decided to go beyond what law requires, so that it can provide as much information to the public as possible. In all cases, it takes care to balance this with the protection of commercially confidential information and personal data.

An overview of the EMA transparency measures are presented on the Transparency page on EMA’s

website.

The Agency has also published a guide to information on human medicines evaluated by EMA which describes the different types of information the Agency currently publishes for both centrally and non-centrally authorised medicines, as well as publication tim es and location on EMA’s website. The guide

aims to help stakeholders know what kind of information to expect on medicines undergoing evaluations and other regulatory procedures.

In addition, the public has the right to request information and documents from the Agency in accordance with its rules on access to documents.

20.1. Which EMA transparency measures apply for on-going marketing authorization application procedures? Rev. Aug 2016

Information on on-going medicine evaluations is published on EMA’s website under Find Medicine -Medicines under evaluation. Information published relates to the INNs and therapeutic areas for each medicine under evaluation.

For more detailed information please refer to the guide to information on human medicines evaluated by EMA which describes all the information publicly available for on-going procedures.

20.2. Which transparency measure applies for the publication of assessment reports? Rev. Aug 2016

For information on the publication of assessment reports including a description of the documents that the EPAR comprises, all the circumstances that require an update of the EPAR and the information available before an EC decision is issued, please refer to the Guide to information on human medicines evaluated by EMA. This guide also includes tabulated overviews of EMA documents, including their location and publication time.

20.3. Which transparency measures apply with regard to the clinical data submitted by applicants/MAHs to support their regulatory applications? NEW May 2017

Clinical data submitted by applicants/MAHs to support their marketing authorisation applications or

applications for extension or modification of indication and line extensions is published on the Agency’s European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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clinical data publication website. This is a result of the implementation of the Agency policy on the publication of clinical data (Policy 0070).

For more detailed information on the clinical data published by the Agency, please refer to the clinical

data publication page on the EMA’s website.

Access to unpublished clinical data can be requested by completing the online form. For further information, see the guide on access to unpublished documents. This is in accordance with Regulation (EC) No 1049/2001.

20.4. Which transparency measures apply with regard to EMA’s scientific

committees? NEW Aug 2016

For transparency measures regarding the publishing of agendas, minutes and meeting

highlights/reports for the different EMA’s committees, please refer to the Guide to information on

human medicines evaluated by EMA.

20.5. Which specialised databases are publicly available? Rev. Aug 2016

• Side effects of medicines

Information on suspected side effect reports is available in the European database of suspected adverse drug reaction reports. This website allows users to view the total number of individual suspected side effect reports submitted to the EudraVigilance database for each centrally authorised medicine and also for some active substances contained in nationally authorised medicines. Users can sort the suspected side effect reports by age group, sex, type of suspected side effect and outcome.

• Clinical trials

The EU Clinical Trials Register contains information on interventional clinical trials on medicines conducted in the European Union (EU), or the European Economic Area (EEA), including therefore also Iceland, Liechtenstein and Norway, which started after 1 May 2004.

Clinical trials conducted outside the EU/EEA are included if:

− they form part of a paediatric investigation plan (PIP), or

− they are sponsored by a marketing authorisation holder and involve the use of a medicine in the paediatric population as part of an EU marketing authorisation.

The EU Clinical Trials Register also displays information on more than 18000 older paediatric trials, which were completed by 26 January 2007 (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

• GMP and GDP inspections

Information on inspections of manufacturers, importers and distributors as well as their authorisations and registrations issued by regulatory authorities are available in a public database called EudraGMDP. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• ENCePP database

The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) is a network coordinated by the European Medicines Agency (EMA). The members of this network (the ENCePP partners) are public institutions and contract and research organisations (CRO) involved in research in pharmacoepidemiology and pharmacovigilance. Research interests are not restricted to the safety of medicines but may include the benefits and risks of medicines, disease epidemiology and drug utilisation. Participation to ENCePP is voluntary.

ENCePP aims to strengthen the monitoring of the benefit-risk balance of medicinal products in Europe by:

− Facilitating the conduct of high quality, multi-centre, independent post-authorisation safety studies (PASS) with a focus on observational research;

− Bringing together expertise and resources in pharmacoepidemiology and pharmacovigilance across Europe and providing a platform for collaborations;

− Developing and maintaining methodological standards and governance principles for research in pharmacovigilance and pharmacoepidemiology.

The ENCePP website hosts the EU PAS Register which is a publicly available register of non-interventional post-authorisation safety studies (PASS). The Register has a focus on observational research, and its purpose is to increase transparency, reduce publication bias, promote the exchange of information and facilitate collaboration among stakeholders, including academia, sponsors and regulatory bodies, and ensure compliance with EU pharmacovigilance legislation requirements. Information on post-authorisation efficacy studies (PAES) that are not clinical trials (i.e. outside the scope of Directive 2001/20/EC ) should also be entered in the EU PAS Register to support transparency on post-authorisation efficacy studies (PAES), whether they are initiated, managed or financed by a marketing authorisation holder voluntarily or pursuant to an obligation.

• Parallel distribution notices

The public register of parallel distribution notices, launched in July 2015, provides up-to- date information on parallel distribution notices currently held by EMA.

20.6. Does EMA provide monthly figures on centralised procedures for human medicines? Rev. Aug 2016

Monthly Statistics reports on medicinal products for human use (with latest cumulative figures for the

current year) are published on EMA’s website. These documents provide current information related to

the volume and outcomes of evaluations of marketing authorisation and post-authorisation applications received by EMA. The purpose is only to provide on-going factual information. Commentaries and analysis are provided in the EMA’s annual reports .

The published Monthly Statistics reports can be found on the EMA’s website under News and events-Statistics.

References

• Guide to information on human medicines evaluated by EMA European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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21. Pharmacovigilance system summary

21.1. Requirements regarding the summary of the pharmacovigilance system Rev. Jan 2016

Applicants for marketing authorisation are required to provide a summary of their pharmacovigilance system, in accordance with Article 8(3)(ia) of Directive 2001/83/EC, which they will introduce once the authorisation is granted .

The requirement for the summary of the pharmacovigilance system was introduced by the new pharmacovigilance legislation (Directive 2010/84/EU amending, as regards pharmacovigilance, Directive 2001/83/EC).

The summary of the pharmacovigilance system should be provided in Module 1.8.1 of the application for marketing authorisation and includes the following elements:

• proof that the applicant has at his disposal a qualified person responsible for pharmacovigilance,

• the Member States in which the qualified person resides and carries out his/her tasks,

• the contact details of the qualified person,

• a statement signed by the applicant to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX of Directive 2001/83/EC,

• a reference to the location where the pharmacovigilance system master file (PSMF) for the medicinal product is kept.

The MAH may combine this information in one single statement using the required statement as per Article 8(3)(ia) of Directive 2001/83/EC regarding the obligation to have the necessary means to fulfil the tasks and responsibilities listed in Title IX (Pharmacovigilance). Such statement should be signed by an individual who can act on behalf of the legal entity of the applicant/MAH and by the qualified person responsible for pharmacovigilance (QPPV). The title, role and responsibility of each individual signing the statement should be clearly specified in the document.

The summary of the pharmacovigilance system is specific to each application/marketing authorisation as per the legislation and therefore should be signed by the relevant applicant/MAH.The requirement for the summary of the pharmacovigilance system is the same for any marketing authorisation application, independent of the legal basis for the application.

References

• Directive 2001/83/EC

• Directive 2010/84/EU

• Commission implementing Regulation (EU) No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 of the European Parliament and of the Council and Directive 2001/83/EC of the European Parliament and of the Council

• European Commission Question and answers on transitional arrangements concerning the entering into force of the new pharmacovigilance rules provided by Directive 2010/84/EU amending European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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Directive 2001/83/EC and Regulation (EU) No 1235/2010 amending Regulation (EC) No 726/2004 (SANCO/D5/FS/(2012)1014848)

• HMA-EMA Questions and answers on practical transitional measures for the implementation of the pharmacovigilance legislation (EMA/228816/2012 – v.3)

• Guideline on good pharmacovigilance practices - Module I – Pharmacovigilance systems and their quality systems (EMA/541760/2011)

• Guideline on good pharmacovigilance practices - Module II – Pharmacovigilance system master file (EMA/816573/2011)

21.2. Requirements regarding the pharmacovigilance system and pharmacovigilance system master file NEW March 2013

The MAH has to operate a pharmacovigilance system for the fulfilment of his pharmacovigilance tasks.

The pharmacovigilance system master file (PSMF) is a detailed description of the pharmacovigilance system used by the MAH with respect to one or more authorised medicinal products.

The PSMF is not part of the marketing authorisation (MA) dossier and is maintained independently from the MA. It should be permanently available for inspection and should be provided within 7 days to the Competent Authorities if requested. The PSMF must be located either at the site in the Union where the main pharmacovigilance activities of the marketing authorisation holder are performed or at the site in the Union where the QPPV operates. The QPPV has to both reside and operate in the Union.

Applicants are required, at the time of initial MA application (MAA), to have in place a description of the pharmacovigilance system that records the system that will be in place and functioning at the time of granting of the MA and placing of the product on the market. During the evaluation of a MAA the applicant may be requested to provide a copy of the PSMF for review.

The PSMF has to describe the pharmacovigilance system in place at the current time. Information about elements of the system to be implemented in future may be included, but these should be clearly described as planned rather than established or current.

The pharmacovigilance system will have to be in place and functioning at the time of granting of the MA and placing of the product on the market.

References

• Directive 2001/83/EC

• Guideline on good pharmacovigilance practices - Module II – Pharmacovigilance system master file (EMA/816573/2011)

21.3. Subcontracting pharmacovigilance activities NEW March 2013

The MAH may subcontract certain activities of the pharmacovigilance system to third parties. It shall nevertheless retain full responsibility for the completeness and accuracy of the pharmacovigilance system master file (PSMF). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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The MAH will have to draw up a list of its existing subcontracts between himself and the third parties, specifying the product(s) and territory(ies) concerned.

When delegating any activities concerning the pharmacovigilance system and its master file, the MAH retains ultimate responsibility for the pharmacovigilance system, submission of information about the PSMF location, maintenance of the PSMF and its provision to competent authorities upon request. Detailed written agreements describing the roles and responsibilities for PSMF content, submissions and management, as well as to govern the conduct of pharmacovigilance in accordance with the legal requirements, should be in place.

For more guidance on the requirements for pharmacovigilance system and PSMF, please refer to the relevant Good Pharmacovigilance Practice (GVP) Modules.

References

• Guideline on good pharmacovigilance practices - Module I – Pharmacovigilance systems and their quality systems (EMA/541760/2011)

• Guideline on good pharmacovigilance practices - Module II – Pharmacovigilance system master file (EMA/816573/2011)

21.4. How to inform the authorities of a change in the summary of the pharmacovigilance system? Rev. Jan 2016

As of 1 February 2016, changes to the summary of the pharmacovigilance system – changes in QPPV (including contact details) and/or changes in the Pharmacovigilance Master File (PSMF) location are to be notified to the authorities through the Art 57 database only without the need for any further variation. From that date MAHs are not required to notify EMA or national competent authorities (as applicable) of changes to the QPPV or PSMF data by submitting a Type IA IN variation.

Upon a change in the QPPV or location of the PMSF, the Art 57 database should be updated by the MAH immediately to allow continuous supervision by the Competent Authorities.

References

• News item: Regulatory information – Green light for reliance on Article 57 database for key pharmacovigilance information on medicines for human use in Europe

• Art. 57 Reporting requirements for Marketing Authorisation Holders

• Detailed Guidance on electronic submission of information on medicines

21.5. Is it mandatory to enter and maintain the location of the Pharmacovigilance System Master File in the XEVMPD? If so, how do we enter this information in the XEVMPD? NEW Jan 2016

Please refer to question “Is it mandatory to enter and maintain the Location of the Pharmacovigilance System Master File in the XEVMPD? If so, how do we enter this information in the XEVMPD?” in the

pre-authorisation guidance. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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21.6. Is the information on the Deputy QPPV required as part of the summary of the pharmacovigilance system? Rev. Jan 2016

Please refer to question “ Is the information on the Deputy QPPV required as part of the summary of the pharmacovigilance system? ” in the pre -authorisation guidance.

21.7. Is there a PSMF template? NEW Jan 2016

Please refer to question “ Is there a PSMF template? ” in the pre -authorisation guidance.

21.8. Pharmacovigilance System Master File location: can the server of the Pharmacovigilance System Master File be physically located and administered outside EU if it is validated and operational/accessible 24/7 for EU markets and EU QPPV? New Jan 2016

Please refer to question “Pharmacovigilance System Master File location: can the server of the

Pharmacovigilance System Master File be physically located and administered outside EU if it is validated and operational/accessible 24/7 for EU markets and EU QPPV? ” in the pre -authorisation guidance.

21.9. What information will be made public on the EU web-portal regarding pharmacovigilance contact details and PSMF locations? Will details of the QPPV be made public? New Jan 2016

Please refer to question “ What information will be made public on the EU web-portal regarding pharmacovigilance contact details and PSMF locations? Will details of the QPPV be made public? ” in the

pre-authorisation guidance. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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22. Article 61(3) Notifications

22.1. What is an Article 61(3) Notification? Rev. Jul Oct 2026

A so-called “61(3) Notification” is defined as a change to an aspect of the Labelling and/or Package

Leaflet (PL) text not connected with the Summary of Product Characteristics (SmPC) and is laid down

in Article 61(3) of Directive 2001/83/EC.

In order for a 61(3) Notification to be valid:

• the change must affect only the Annexes IIIA (labelling) and/or IIIB (PL), with no changes to the SmPC and/or the Annex II. In addition,

• the changes must affect the English labelling and/or PL text, with consequential amendments to all other language versions.

Examples of changes falling within the scope of 61(3) Notification:

• Changes in the local representatives

• Minor changes to the labelling and/or PL

− Labelling: e.g. changes of abbreviation for the batch number

− PL: Harmonisation of wording used in the PL

• Introduction of mobile scanning and other technologies in the labelling and/or PL, such as quick response (QR) codes, when not included in a regulatory procedure which affects the Annexes (e.g. initial marketing authorisation application, type II variation). Please refer to question on ‘How to

present mobile scanning and other technologies in the labelling and/or package leaflet of centrally

authorised medicinal products submitted via a 61(3) Notification?’.

• Introduction of combined PL (after prior consultation with QRD)

• Change in Braille (inclusion/deletion/change)

• Change in instruction for use in the PL

• Change in the local representatives. Please refer to question ‘When can I submit my 61(3)

Notification?’

The following examples do not fall within the scope of 61(3) Notification:

• Changes to SmPC or Annex II,

• Changes that only affect some languages but not all,

• Changes in overall lay-out, design, readability of labelling and/or PL with no changes to the text. In such case, the need for an EMA review of the proposed changes by means of the provision of specimens, should be discussed with EMA ([email protected]), as outlined in

“Checking Process of Mock -Ups and Specimens of outer/immediate labelling and package leaflets of

human medicinal products in the Centralised Procedure” on the EMA website.

• Updated PL after User Testing when the User Testing report and amended leaflet cannot be included in an upcoming regulatory procedure which affects the Annexes (e.g. Type II variation). In the absence thereof, the marketing authorisation holder should apply for this change by European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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submitting a variation type IB scope C.11. Please refer to question on ‘When is the submission of

assessments carried out on target patient groups in order to comply with Article 59(3) of Directive 2001/83/EC and any resulting change(s) to the Package Leaflet a stand-alone variation?’ It is possible to introduce within a single 61(3) Notification, several changes to the labelling and/or the package leaflet, which do not affect the SmPC or the Annex II (e.g. submission of a change in the local representative and harmonisation of the wording used in the PL).

The Agency strongly recommends, that whenever possible, the marketing authorisation holder (MAH) includes minor changes to the labelling and/or PL as part of another on-going or upcoming regulatory procedure amending the Product Information (e.g. Type IA*, Type IB or II variation affecting the product information, etc.).

Where this concerns changes related only to local representatives, including their addition, removal or changes to their contact details, a standalone Art. 61(3) Notification will not be required prior to the

implementation of the change. tThe MAH may implement such changes prior to informing the Agency

and notify them at a later stage through the next variation impacting the product information or if

none is foreseen through an Article 61(3) Notification. Consequently, a standalone Art. 61(3)

Notification will not be required.

Should the MAH have a query on changes that may fall under the scope of 61(3) Notification they should contact the EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post -authorisation - Human”, followed by the sub -

option: “Article 61(3) Notification queries”.

If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".

However, if submitted stand-alone, changes only affecting Annex III have to be submitted as a 61(3) Notification (i.e. not possible to submit as a variation).

Upon submission, the Agency will inform the marketing authorisation holder (MAH) within 90 days whether the proposed changes are accepted or not. The Agency will inform concomitantly the Commission in cases where the changes have been accepted (for information on the update of the Commission Decision see: How and when will the updated Annexes become part of the Marketing Authorisation?).

*Only changes for which no rapporteur involvement, nor linguistic review is needed (e.g. change to local representatives).

References

• Directive 2001/83/EC

• The Revised Checking Process of Mock-Ups and Specimens of outer/immediate labelling and package leaflets of human medicinal products in the Centralised Procedure (EMEA/305821/2006)

22.2. Is the Rapporteur involved in 61(3) Notifications? Rev. Jul 2026

The Rapporteur is normally not involved in the review of a 61(3) Notification. However, the Rapporteur may be involved on a case-by-case basis depending on the changes requested (e.g. extensive changes in the instructions for use in the PL). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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22.3. When can I submit my 61(3) Notification? Rev. Jul Oct 2026

There are no recommended submission dates for 61(3) Notifications. Hence, the MAH can submit a 61(3) Notification at any time.

The Agency strongly recommends that whenever possible the marketing authorisation holder (MAH) includes these minor changes to the labelling and/or PL as part of another on-going or upcoming regulatory procedure amending the Product Information (e.g. Type IA*, Type IB or II variation affecting the product information, etc.).

Where this concerns changes related only to local representatives, including their addition, removal or changes to their contact details, a standalone Art. 61(3) Notification will not be required prior to the

implementation of the change. tThe MAH may implement such changes prior to informing the Agency

and notify them at a later stage through the next variation impacting the product information or if

none is foreseen through an Article 61(3) Notification. Consequently, a standalone Art. 61(3)

Notification will not be required.

Should the MAH have a query on changes that may fall under the scope of 61(3) Notification they should contact the EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post -authorisation - Human”, followed by the sub -

option: “Article 61(3) Notification queries”.

If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".

• Only changes for which no rapporteur involvement, nor linguistic review is needed (e.g. change to local representatives).

22.4. How shall I present my 61(3) Notification? Rev. Jul 2026

The submission of a 61(3) Notification should include:

22.4.1. Cover Letter indicating the product name

• including a summary and / or explanation of the proposed changes

• including a list of on-going/upcoming regulatory procedures affecting the Annexes and including a confirmation that the proposed changes only affect Annex III).

• including a confirmation from the MAH that there are no other changes than those identified in the cover letter (except for those addressed in other variations submitted in parallel),

• present/proposed table of the changes (this can be a separate annex).

Use the cover letter template:

• cover letter – Art. 61(3) Notification

22.4.2. Product information

• The revised product information (‘complete set of Annexes’ includes Annex I, II, IIIA and IIIB i.e.

all SmPC, labelling and PL texts for all approved strengths and pharmaceutical forms of the product concerned), with or without linguistic review, in all EU languages (incl. IS+NO) European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• in Word format (highlighted) indicated via ‘Tools – Track changes’

• in PDF format (clean) with all changes ‘accepted’

• Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version and all the translations. The annotated product information files must include the statement containing the procedure number(s) and may be published on the EMA website as part of the product EPAR page. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA, the publication on the EMA website and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU language. Page numbering should start with "1" (bottom, centre) on the title page of Annex I. The Annexes should be presented in strict compliance with the QRD Convention published on the EMA website. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed ’Checklist for the submission of product information annexes and Annex A (if applicable) for minor procedures without linguistic review ’, and MAHs should follow/pay attention to the guidance on how to correctly prepare the PDF versions.

The Annexes should be presented on the latest CHMP approved version.

The Annexes provided should only reflect the changes introduced by the 61(3) Notification. However, it is possible for the MAHs to take the opportunity to introduce minor linguistic amendments in the labelling and/or the PL for all or some EU languages. These changes should be clearly mentioned in the cover letter. Any changes not listed in the Notification cover letter will not be considered as part of the 61(3) Notification. In addition, it is not possible for the MAHs to introduce minor linguistic amendments in the SmPC and/or the Annex II.

22.4.3. If applicable

• Any supportive relevant documentation, such as the request/declaration form for the provision of information via mobile scanning and other technologies in the centralised procedure, reference correspondence, mock-ups of labelling and/or package leaflet clearly illustrating the location of the mobile technology feature, script of a video for instructions for use, etc., to the 61(3) Notification, presented under the appropriate headings and numbering of the EU-CTD format.

22.5. How and to whom shall I submit my 61(3) Notification? Rev. Feb 2019

Information is available on ‘Submitting a post -authorisation application’. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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22.6. How shall my 61(3) Notification be handled (timetable), and what could be the outcome? Rev. Jul 2026

A dedicated Procedure Manager (PM) will be assigned to the procedure once your notification has been submitted.

22.6.1. Timelines

The length of the procedure will vary depending on the need for Rapporteur’s involvement, linguistic

review and the submission of revised information by the MAH when required. If the EMA 61(3) Notification is not issued within 90 days following the introduction of the request, the applicant may put the change into effect.

22.6.2. Process

• Upon submission of your 61(3) Notification, the PM will review the content of the documentation.

• When the documentation submitted by the MAH does not meet the requirements, the PM will contact the MAH. The MAH should then provide revised documentation within 5 days. Upon receipt of the revised documentation, the PM will review the information. Should the information provided by the MAH be incomplete or does not fall under the scope of 61(3) Notification, the PM will inform the MAH that the proposed change cannot be implemented.

• Upon receipt of satisfactory documentation and in cases where the Rapporteur’s input is needed

(e.g. introduction of mobile scanning or other technologies leading to additional (non-statutory) information ), the Rapporteur will assess the MAH’s proposal within 15 working days. Should the outcome of the Rapporteur’s assessment be not satisfactory, the MAH will be requested to provide revised documentation within 5 days. Upon assessment of the MAH’s responses , should the

Rapporteur involved?

Linguistic review?

61(3) Notification that the changes are accepted

61(3) Notification that the changes are not accepted

Outcome of the assessment satisfactory?

61(3) Notification that the changes are not accepted

No No No Yes No Yes No (after 1st RSI)

Submission satisfactory?

Revised Submission satisfactory?

Yes

Linguistic review

Yes European Medicines Agency post-authorisation procedural advice for users of the centralised procedure EMEA-H-19984/03 Page 288/305

outcome of the Rapporteur’s assessment remain unsatisfactory, the PM will inform the MAH that

the proposed change cannot be implemented.

• Once the proposed changes have been agreed and the linguistic review is complete (when applicable), the MAH will receive a 61(3) Notification via email that the changes have been accepted.

22.6.3. Possible outcomes

In summary, the following outcomes may be envisaged for 61(3) Notification:

• Changes are acceptable and an EMA 61(3) Notification is issued within a maximum of 90 days.

• Changes are not acceptable (even after receipt of additional/revised information if required). The PM will inform the MAH that the proposed change cannot be implemented.

• The proposed changes do not fall under the scope of a 61(3) Notification (even after receipt of additional/revised information if required). The PM will inform the MAH that the change does not fall under the scope of Article 61(3) and cannot be processed. The proposed change cannot be implemented.

22.7. What fee do I have to pay for a 61(3) Notification?

There is no fee payable for 61(3) Notifications.

22.8. Do I have to submit mock-ups and specimens? Rev. Mar 2026

22.8.1. Mock-ups

In principle, no mock-ups are to be provided with 61(3) Notifications, however, where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected as part of the 61(3) Notification, the need for the provision of mock-ups should be discussed with the EMA ([email protected]) on a case-by-case basis (e.g. mock-ups would be required when proposing a new corporate design of packs, use of different colours, major changes in layout, introduction of new text in the labelling in line with the SmPC).

In case the submission of mock-ups is required, the relevant example mock-ups would need to be included in the module 1.3.2 of the application dossier.

In case of comments on the mock-ups, the MAH should submit responses and/or updated mock-ups, as applicable, to the EMA ([email protected]) prior to the specimens printing. EMA will discuss the best and feasible corrective action with the MAH, taking into account the nature and number of issues identified. EMA will endeavour to provide such feedback as soon as possible and taking into consideration the production plan of the medicinal product, as applicable.

22.8.2. Specimens

Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected as part of the 61(3) Notification, the need for the provision of specimens should be European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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discussed with the EMA ([email protected]) on a case-by-case basis (e.g. specimens would be required when proposing major changes in lay-out, use of different colours as part of the 61(3) Notification, but not e.g. when only limited text is added/revised in a PL section).

In case specimens are required, in principle only one relevant example (multi-lingual if possible) would need to be sent to the EMA at the latest 15 working days before marketing. However, depending on the nature and extent of the change(s) concerned, additional specimens may be required by the EMA. The EMA will perform a general check from the viewpoint of readability within 15 working days and will check if any previous comments on specimens have been duly implemented. The MAH will be informed about the outcome of the check.

22.8.3. Note

In case the MAH wishes to receive EMA feedback on their proposed new packaging in advance of the specimen review, the EMA could agree with the MAH on a case-by-case basis, to review draft mock-ups before specimen submission.

The above principles also apply to mock-ups for Iceland. The mock-ups should be sent to [email protected]. See also http://www.ima.is/.

No mock-ups and specimens are required for Norway.

References

• Checking Process of Mock-Ups and Specimens of outer/immediate labelling and package leaflets of human medicinal products in the Centralised Procedure (EMEA/305821/2006)

22.9. How and when will the updated Annexes become part of the Marketing Authorisation? Rev. Aug 2014

Upon finalisation of a 61(3) Notification, the changes to the product information Annexes will be reflected in the framework of the next regulatory procedure for which a Commission Decision will be issued. For example, the changes could be included with the Commission Decision of a subsequent Type II variation.

However, the agreed changes can be implemented upon receipt of the EMA 61(3) Notification without awaiting the update of the Marketing Authorisation through a Commission Decision, and the agreed changes should be included in the Annexes of any regulatory procedure subsequent to the 61(3) Notification. Additionally, if the EMA 61(3) Notification is not issued within 90 days following the introduction of the request, the applicant may put the change into effect.

22.10. Will there be any publication on the outcome of my 61(3) Notification? Rev. Apr 2012

The EPAR (published on the EMA website) will be revised to implement the outcome of the 61(3) Notification, after issuance of the EMA 61(3) Notification.

References

• EPARs European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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22.11. Who is my contact at the European Medicines Agency during post-authorisation procedures? Rev. Feb 2019

Information is available on ‘Contacting EMA: post -authorisation’.

22.12. How to present mobile scanning and other technologies in the labelling and/or package leaflet of centrally authorized medicinal products submitted via a 61(3) Notification? NEW Mar 2026

As described in the guidance on ‘Mobile scanning and other technologies in the labelling and/or package leaflet of centrally authorised medicinal products’, marketing authorisation holders may use

mobile technologies to provide statutory information or additional information that is compliant with Article 62 of Directive 2001/83/EC approved by the Agency. This entails:

• Statutory information: readily available information extracted from the approved package leaflet, the approved summary of products characteristics (SmPC) and/or the approved additional risk minimisation measures as outlined in the Risk Management Plan (e.g. educational material).

• Additional information: any other information or content (e.g. videos) that is not included in the product information annexes but is useful to the intended users and is not connected with any promotional elements.

Marketing authorisation holders should inform the EMA as early as possible of their intention to use mobile technologies on the packaging materials and/or package leaflet. The request for use of mobile technologies should be applied for in the context of an evaluation procedure, as appropriate, and applicants/MAHs should make use of the pre-submission phase to present their strategy and address any potential issues before the procedure starts. Such information will be reviewed by the Agency that will conclude whether the application is acceptable or not.

References

• Mobile scanning and other technologies in the labelling and package leaflet of centrally authorised medicinal products European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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23. Marketing status updates and withdrawals

23.1. What is the meaning of “actual marketing” / “placing on the market”? Rev. Jul 2021

• In accordance with Article 13(4) of Regulation (EC) No 726/2004, Marketing Authorisation Holders are required to inform EMA of the date(s) of actual marketing of their centrally authorised product on the Union Market.

• The actual marketing corresponds to the “placing on the market” which is defined in Chapter 1 of

volume 2A of the Notice to Applicants as the date of release into the distribution chain i.e. out of the direct control of the Marketing Authorisation Holder. This also applies to the placing on the market following a marketing cessation.

For centrally authorised medicinal products “marketed” means that at least one presentation of the

medicinal product is at least marketed in one Member State of the Union.

References

• Article 13(4) of Regulation (EC) No 726/2004

• Article 23a of Directive 2001/83/EC, as amended

• Chapter 1 (section 2.4.2), The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2A

23.2. What is the meaning of “cessation of placing on the market”? Rev. Jul 2021

In accordance with Article 13(4) of Regulation (EC) No 726/2004, Marketing Authorisation Holders are required to inform EMA if their centrally authorised product ceases to be placed on the market of a Member State, either temporarily or permanently.

By analogy to the placing on the market, t he “cessation of placing on the market” or “marketing cessation” is defined in the general general principles outlined in the Chapter 1 of volume 2A of the Notice to Applicants , as the “cessation of release into the distribution chain” with the consequence that

the concerned product may no longer be available for the supply to the patients.

The date of marketing cessation shall be the date of the last release into the distribution chain.

References

• Article 13(4) of Regulation (EC) No 726/2004

• Article 23a of Directive 2001/83/EC, as amended

• Chapter 1 (section 2.4.2), The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2A European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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23.3. What is the aim of monitoring the marketing status of medicinal products? Rev. Jul 2021

Monitoring the marketing status of medicinal products in the EU allow for the application of Article 24(4) to (6) of Directive 2001/83/EC and Article 14(4) to (6) of Regulation (EC) No 726/2004

(“monitoring of the sunset clause” (See also Q&A on Sunset clause monitoring).

This marketing status reporting also aims to increase transparency on availability of medicinal products across the Union and to enable EMA and National Competent Authorities to consider the need for action in different Member States or at EU level to protect Public Health.

23.4. What information should be reported to the Agency on the marketing status of CAPs? Rev. Dec 2022

• The actual marketing of a centrally authorised medicinal product (CAP) shall be reported to the Agency per presentation and per Member State (see question What is the meaning of “actual marketing” / “placing on the market”? ). Of note, for centrally authorised medicinal products, presentation corresponds to pack-size.

• MAHs shall also report to the Agency any marketing cessation (temporary/permanent) of their medicinal product per presentation and per Member State. This also includes the withdrawal of a medicinal product from the EU market, or any decision to withdraw or suspend the marketing authorisation or not to apply for the renewal of a marketing authorisation. The MAH should specify the reasons for such action and particularly if this is solely based on a commercial decision or related to any of the reasons listed in Articles 116 and 117 of Directive 2001/83/EC (e.g. quality, efficacy, safety reasons). When the marketing cessation or withdrawal is due to reasons listed in Articles 116 and 117 (e.g. due to the presence of nitrosamine impurities), MAHs should also notify the EMA of actions undertaken in third countries.

In case of a temporary marketing cessation, t he anticipated reintroduction date needs to be provided.

MAHs are advised that when cessation/suspension/withdrawal is due to efficacy, safety and/or quality related issues for which already particular procedures are established, reporting of such cessation in IRIS is without prejudice to applying the other specific related procedures (e.g. quality defect, pharmacovigilance reporting, etc.), in parallel, as appropriate:

• In case of an emerging safety issue (ESI), should the MAH decide to take any action with regards to the marketing of the medicinal product or to the marketing authorisation of this medicinal product, the notification of such action to the Agency should be done in parallel to the notification to the ESI mailbox ([email protected]).

• In case of a quality defect, should the MAH decide to take any action with regards to the marketing of the medicinal products or to the marketing authorisation of this medicinal products, the MAH should complete the published Defective Product Report Form, specifying in which countrie(s) the action(s) is/are taken and the anticipated date(s) as to when the medicinal product is no longer available on the market of the concerned countrie(s). The form should be sent to [email protected] as detailed in Notifying quality defects or products recalls.

• When reporting a marketing cessation, MAHs will be asked to clarify whether they anticipate a risk of shortage. MAHs should provide such information to the best of their knowledge at time of European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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reporting a marketing cessation. This information will not replace existing processes to report shortages to EMA. This is only intended to facilitate dissemination of the information within EMA and EU Network.

• In case of a voluntarily request from the MAH to withdraw a marketing authorisation, the MAH should send a letter to the European Commission to request a withdrawal of the marketing authorisation and provide a copy of the letter to the Product Lead, Product mailbox, Withdrawn product mailbox, Rapporteurs and CHMP Chair. (See question How should I request the withdrawal of my central marketing authorisation?)

• For medicinal products authorised in a paediatric indication and for which the MAH has benefited from rewards or incentives under the Paediatric Regulation, the MAH should inform the Product Lead, Product mailbox, Rapporteurs of its intention to discontinue the placing on the market of the product (see question When to report the marketing status overview of centrally-authorised products to the Agency?) explaining the actions they are undertaking to ensure the medicinal product remains available to EU paediatric patients (e.g. transfer of a marketing authorisation, informed consent), in accordance with Article 35 of Regulation (EC) No 1901/2006. See question Is there an obligation to market a medicine which is authorised for a paediatric indication, following completion of an agreed paediatric investigation plan, and the product has already been marketed with other indications?

References

• Article 13(4) of Regulation (EC) No 726/2004

• Articles 116 and 117 of Directive 2001/83/EC

• Article 35 of Regulation (EC) No 1901/2006

• Chapter 1 (section 2.4.2), The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2A.

23.5. When to report the marketing status overview of centrally authorised products to the Agency? Rev. Jul 2021

The so-called marketing status overview refers to the picture of the marketing situation of a specific medicinal product, at one time point of the product lifecycle, per presentation and per Member State.

As of July 2021, the EMA is using the IRIS database to collect the marketing status notifications for centrally authorised products and to provide an up-to-date overview to the EU Member States. (see question How to report marketing status updates to the Agency for CAPs? )

MAHs should inform the Agency of the marketing status of their centrally authorised medicinal product(s), at the time of the initial placing on the market and for any subsequent changes in marketing status (i.e. temporary marketing cessation, reintroduction on the EU market or permanent cessation), for each presentation and in each Member State, according to the timelines given hereafter:

• The MAH should notify the Agency within 30 days of the placing on the market, including the reintroduction on the market (i.e. placing on the market following a marketing cessation) of a medicinal product within the Union (i.e. per presentation and per Member State). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• The MAH should notify the Agency at least 60 days in advance, of a marketing cessation (temporary or permanent) at Member State level - unless the marketing cessation/suspension/withdrawal is related to the grounds listed in Articles 116 and 117 of Directive 2001/83/EC (e.g. quality, efficacy, safety issues) in that case the Agency should be notified immediately. MAHs should also inform the Agency immediately of marketing cessations undertaken in third countries due to reasons covered in Articles 116 and 117 of Directive 2001/83/EC (e.g. quality, efficacy, safety issues).

• The MAH should notify the Agency of their request to withdraw their central marketing authorisation at least 2 months in advance unless unforeseeable circumstances which may require an immediate notification (e.g. safety reasons). The update in IRIS would not replace the formal request to address to the European Commission (see question How should I request the withdrawal of my central marketing authorisation?). Of note, for medicinal products authorised in a paediatric indication and for which the MAH has benefited from rewards or incentives under the paediatric regulations, the MAH should inform the EMA of its intention to discontinue the placing on the market of the product at least 6 months before discontinuation. See question Is there an obligation to market a medicine which is authorised for a paediatric indication, following completion of an agreed paediatric investigation plan, and the product has already been marketed with other indications?

• The MAH should notify the Agency of their intent not to apply for a renewal of their central marketing authorisation at time of expected submission (i.e. at least 9 months prior to MA expiry). Notification in IRIS would not replace the need to inform the Product Lead in parallel (cc product mailbox).

Since the IRIS database is intended to be kept up to date with the marketing status of centrally authorised medicinal products, it is no longer needed to provide an annual update to the Agency at the time of anniversary of the Commission Decision on the central marketing authorisation. However, an overview of the marketing status of medicinal products is still expected to be provided within PSUR and renewal applications

References

• Article 13(4) of Regulation (EC) No 726/2004

• Article 23a of Directive 2001/83/EC, as amended

• Articles 116 and 117 of Directive 2001/83/EC

• Article 35 of Regulation (EC) No 1901/2006

23.6. How to report marketing status updates to the Agency for CAPs? Rev. Feb 2022

EMA used to receive notifications of placing on the market, marketing cessations and withdrawn product notifications by email.

As of end of July 2021, EMA requests MAHs of centrally authorised products (CAPs) to submit their marketing status notifications via the IRIS platform.

• Newly authorised CAPS will be added progressively to IRIS with a status “Never marketed” by

default. The MAH will be required to notify all changes to marketing status using the platform. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• CAPs that were authorised prior to the launch of IRIS Marketing Status, will have their marketing

status in IRIS as ‘No data provided’:

• For authorised CAPs not yet marketed in any EU/EEA MS, MAHs should report the initial placing on the market of relevant presentations and any subsequent marketing status updates directly via the IRIS platform.

• For authorised CAPS already marketed in at least one EU/EEA MS, MAHs will progressively upload the marketing status of their CAPs in IRIS during a 9-months transition period (baseline data). Whilst it is allowed to report changes to the marketing status of their CAPs via the existing process (e-mails) during the transition period, once the baseline data have been submitted in IRIS, reporting of changes to the marketing status should continue in IRIS.

How to report marketing status updates via IRIS (new process that can be used as of end of

July 2021)

There are 3 possibilities to report updates on marketing status for a medicinal product:

• Marketing Status Notification (Single)

This function allows to report the same change in marketing status affecting one or more presentations of a CAP in one or more MS (e.g. placing on the market of 3 presentations in 5 Member States on the same day).

• Marketing Status notification (bulk upload)

This function enables to report several different changes in marketing status affecting one or multiple presentations in one or multiple MS, by uploading an excel spreadsheet (e.g. placing on the market of presentation B in CZ, AT and NL + marketing cessation of presentation A in IT on different dates).

• Withdrawn product notifications (affecting all presentations in all MS):

This function allows to report

• A request for withdrawal of the central marketing authorisation of your product (This would not replace the formal request to send to the European Commission, see question How should I request the withdrawal of my central marketing authorisation?)

• a decision not to apply for the renewal of the marketing authorisation

• a permanent marketing cessation affecting all presentations of a medicinal product in all MS. Of note, if the marketing authorisation is not withdrawn, it will automatically expire after 3 years of non-marketing under the sunset clause provision (see Q&A on sunset clause provision ).

How do I submit baseline data for already authorized CAPs in IRIS?

For CAPs already marketed in at least one EU/EEA MS, MAHs should progressively upload the marketing status of their CAPs in IRIS during a 9-months transition period (baseline data). To upload the baseline data, the same options available to report marketing status updates can be used, i.e. single or bulk upload. For detailed information on how to perform the submission, see IRIS technical guidance (sections 6.1 and 6.2).

When submitting the baseline for the first time, the marketing status will appear in IRIS as ‘No data provided’. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Presentations already on the market: status should be reported as ‘Marketed’ with the date of the initial placing in the market as ‘Date of Marketing Status change’. This will become the ‘Date of initial placing in the market’ once the submission is processed.

Example: For product X, presentation 001 is currently in the market in ES and PT. Presentation

001 was first launched in ES on 01/01/1999 and in PT on 03/02/1999. By default, the IRIS database reflects: “No data provided ” for all presentations in all EU/EEA MS.

Report for 001 Status: Marketed. ”Date of Marketing Status change ” 01/01/1999 for ES and 03/02/1999 for PT. This will result in 01/01/1999 becoming the” Date of initial placing in the market ” in ES and 03/02/1999 becoming the ”Date of initial placing in the market ” in PT.

In the exceptional situation where the launch date is unknown “01/01/1900” should be used.

• Presentations that have never been marketed in at least one Member State A specific Marketing Status category has been added for products that have never been on the market.

‘Never marketed’ should be chosen from the list of Marketing Status options. Reason for Cessation

and the Date of Marketing Status change can be left blank. For newly authorised products, the

default status will already be ‘Never marketed’.

Example: Presentation 002 of Product X was never marketed in any MS and is currently showing as

‘No data provided’. A Marketing Status change from ‘No data provided’ to ‘Never marketed’ should

be submitted for presentation 002 for all MS. Date of Marketing Status change and Reason for Cessation can be left blank.

• Presentations that were previously marketed and for which the MAH would like to report a (temporary or permanent) marketing cessation as the current marketing status report through IRIS: this needs to be done in two steps: the initial placing on the market needs to be reported first before the marketing cessation can be reported.

Example: Presentation 003 of Product X was first placed in the market in Austria on 01.03.1995 and is permanently ceased from 01.03.2021. The MAH should report as a single or bulk upload a change in Marketing status to ”Marketed ” with ”Date of Marketing Status change ” as 01.03.1995. Once this case is processed, the MAH should report a change of marketing status as ”Not Marketed ” with ”Date of Marketing Status change ” as 01.03.2021.

EMA has prepared a technical guidance to help MAHs to submit their marketing status updates via IRIS.

For any question regarding your IRIS submission please contact EMA Service Desk.

How to report marketing status updates via email (existing process to be discontinued from

May 2022 for EU/EEA/UK (Northern Ireland)).

During the 6-month transition period where IRIS is progressively being populated with marketing status data of CAPs, MAHs can continue to report the marketing status updates of their already marketed CAP via emails as per the existing process until the baseline data are submitted into IRIS:

initial placing on the market in EU/EEA/UK (Northern Ireland) to be notified within 30 days to the mailbox [email protected] with the EMA Product Lead with the product mailbox in copy.

marketing cessations or withdrawn product notifications (in EU/EEA/UK (Northern Ireland) to be notified to the Agency via the dedicated mailbox [email protected] using the European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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template cover letter and notification report table “Notification of withdrawn products” with the Product Lead, Product mailbox and the Rapporteur of the product in copy.

Particular cases of Withdrawn product notifications related to Art 116 117 reasons (e.g. quality, efficacy, safety) in 3rd countries – please see question on “When and how to report to the Agency actions taken in 3rd countries? ”

References

• Article 13(4) of Regulation (EC) No 726/2004, as amended

• Article 14b of Regulation (EC) No 726/2004, as amended

• Article 16(2) of Regulation (EC) No 726/2004, as amended

• Article 35 of Regulation (EC) No 1901/2006, as amended

• Chapter 1 (section 2.4.2), The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2A

23.7. When and how to notify marketing cessations for nationally authorised products to the Agency? NEW Jul 2021

MAHs of nationally authorised products (NAPs) are required to inform the relevant National Competent Authorities of the marketing status of their medicinal products as per the requirements of Articles 23a and 123 of Directive 2001/83/EC, as amended. Notification to the competent authorities of the Member State(s) concerned should be submitted in accordance with the practices established at national level if applicable. Where national competent authorities have not provided particular instructions, the template cover letter and notification report table “Notification of withdrawn products”

should be used.

MAHs of NAPs are also required to inform forthwith the EMA of any action taken by the holder, in a

EU/EEA Member State or in a 3rd country ,

• to suspend the marketing of a medicinal product,

• to withdraw a medicinal product from the market

• to request the withdrawal of a marketing authorisation

• or not to apply for the renewal of a marketing authorisation,

when the reasons for such action are based on any of the grounds set out in Article 116 or Article

117(1) of Directive 2001/83/EC, as amended (e.g. related to efficacy, safety, quality and/or

compliance issues ).

Such notification should be made to the Agency through the dedicated mailbox [email protected] using the template cover letter and notification report table

“Notification of withdrawn products” , and to the Member State(s) concerned as applicable.

In case of an emerging safety issue (ESI), should the MAH decide to take any action with regards to the marketing of the medicinal product or to the marketing authorisation of this medicinal product, the notification of such action to the Agency should be done in parallel to the notification to the ESI mailbox ([email protected]). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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References

• Article 23a of Directive 2001/83/EC, as amended

• Article 123 of Directive 2001/83/EC, as amended MAH intends to take action to withdraw* a product from the market Start What is the marketing authorisation procedure? Where is the action to take place? Centralised Authorisation Procedure National Authorisation Procedure (incl. MRP, DCP) Is action based on grounds set out in Art. 116 and 117 of DIR 2001/83/EC? En dWhere is the action to take place?

Notify concerned Member States no less than 2 months before the interruption in the placing on the market of the product (unless exceptional circumstances)

EU Notify forthwith EMA Is action based on grounds set out in Art. 116 and 117 of DIR 2001/83/EC? Third Country NO NO YES YES Is action based on grounds set out in Art. 116 and 117 of DIR 2001/83/EC? Notify forthwith concerned Member States and EMA Is action based on grounds set out in Art. 116 and 117 of DIR 2001/83/EC? EU Third Country NO YES YES NO END END

Actions to withdraw * : - cease temporarily or permanently the marketing of the product - suspend the marketing of a medicinal product; - withdraw a medicinal product from the market; - request the withdrawal of a marketing authorisation; - not to apply for the renewal of a marketing authorisation Notify EMA no less than 2 months before the interruption in the placing on the market of the product (unless exceptional circumstances)

23.8. How will the Agency inform the Member States? Rev. Jul 2021

As per the existing process, once the Agency receives a notification of a “withdrawn product” via email

from a MAH whether this is for a centrally or nationally authorised medicinal product, the Agency forwards such notification to all Competent Authorities in the EEA without undue delay.

As of end of July 2021, EMA uses the IRIS database to collect marketing status updates in the different EU/EEA Member States including withdrawn product notifications for centrally-authorised products and this information will be accessible to the National Competent Authorities and the European Commission. Notifications of withdrawn products received by email for NAPs will continue to be forwarded to EEA Competent Authorities as per the existing process.

References

• Article 14b of regulation (EC) No 726/2004, as amended European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• Article 123 of Directive 2001/83/EC, as amended

23.9. How should I request the withdrawal of my central marketing authorisation? Rev. Oct 2023

The MAH should send by email a request for withdrawal of the marketing authorisation to the European Commission ([email protected] and [email protected]) keeping in copy the EMA Product Lead, the CHMP/PRAC/CAT Rapporteurs (as applicable), Chairs and Vice chairs of relevant committees and the EMA withdrawn products mailbox ([email protected]).

The letter to the European Commission should cover the following points:

• Medicinal product concerned (name, EU number(s)…);

• The reason for the withdrawal of the marketing authorisation and whether or not it is based on the grounds provided in Articles 116 and 117 of Directive 2001/83/EC;

• The Member States where the product is currently marketed;

• The proposed effective date for the withdrawal of the MA. The withdrawal of the MA will become effective on the EC notification date by default (e.g. usually within two months of the MAH request), or by any date agreed with the European Commission and specified in the Commission decision withdrawing the marketing authorisation. The MAH is therefore invited to clarify in their request if they would like to suggest a withdrawal date more than the two-month after their request to withdraw the marketing authorisation.

• How the MAH will approach the continued use of any remaining product, as they will continue to be responsible for any remaining product on the market(s); The MAH should therefore ensure that any product remaining on the market has been produced according to current GMP standards and that the QP responsible for batch release remains fully responsible for any remaining product that may still be in the market, including continuous monitoring of any product defects. Further, the MAH should ensure that the Pharmacovigilance System is still fully active in monitoring any safety signals that may arise from the usage of the withdrawn product and that the QP responsible for Pharmacovigilance is still maintaining all responsibilities for the product (whilst stock remains).

• How and when the company plans to inform the public, doctors and pharmacists, as applicable;

• The therapeutic alternative available, if appropriate, and whether the planned withdrawal will allow physicians and patients adequate time to consider and transition to alternative therapies.

• For medicinal products authorised in a paediatric indication, the MAH should confirm whether Article 35 of Regulation (EC) No 1901/2006 would apply in their case and what actions they are undertaking to comply with the requirements of the Paediatric Regulation to ensure the medicinal product remains available to EU paediatric patients.

Provided that the withdrawal is solely based on commercial reasons (i.e. the withdrawal of the marketing authorisation is not linked to underlying quality, safety, efficacy or benefit/risk issues), it is agreed at EU level that there is no need for batch recalls for CAPs, the medicinal product can remain on the EU market until expiry date. The MAH remains responsible for the batches on the market and for pharmacovigilance activities. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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In parallel to the formal request made to the Commission, IRIS needs to be updated via the withdrawn

product notification (see question “How to report marketing status updates to the Agency for CAPs?”).

References

• Article 13(4) of Regulation (EC) No 726/2004, as amended

• Article 14b of Regulation (EC) No 726/2004, as amended

• Article 16(2) of Regulation (EC) No 726/2004, as amended

• Article 35 of Regulation (EC) No 1901/2006, as amended

23.10. When and how to report to the Agency actions taken in 3 rd

countries? NEW Feb 2022

MAHs are also required to notify the EMA of any action taken outside the EEA to suspend the marketing of a medicinal product, to withdraw a medicinal product from the market, to request the withdrawal of a marketing authorisation or not to apply for the renewal of a marketing authorisation, when such action is based on any of the grounds set out in Article 116 or Article 117(1) (e.g. quality, safety or efficacy issue).

Such notification should continue to be made by email to [email protected] using the

template cover letter and notification report table “Notification of withdrawn products” and with the

Product mailbox and EMA Product lead in copy.

It is planned that these notifications regarding non-EEA countries will be included into IRIS and the EMA will communicate when such function is developed.

References

• Article 123 (2b) of Directive 2001/83/EC

• Articles 116 and Article 117(1) of Directive 2001/83/EC

23.11. Which information does the Agency publish about the marketing status of EU medicinal products? Rev. Dec 2022

Currently only information on withdrawn medicinal products are made public on the EMA website:

• The list of human medicinal products which have been withdrawn from the EU market (also

referred as “list of withdrawn products”) is published every year on the EMA website. The list includes both centrally and nationally authorised medicinal products for which marketing authorisations have been refused, revoked or suspended in the Union, or whose supply has been prohibited or which have been withdrawn from the market due to grounds related to Article 116 and 117 (e.g. quality, efficacy or safety reasons). The list specifies whether the action has been initiated by the Marketing Authorisation Holder or whether it was imposed by the Competent Authorities (e.g. following a referral procedure at European level). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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• For centrally-authorised products, the withdrawal or the expiry of the marketing authorisation is also made publicly available on the EPAR webpage of the medicinal product on the EMA website, together with the reason(s) for such action.

As of July 2021, EMA uses the IRIS database to collect an overview of the marketing status of centrally-authorised products in the EU/EEA/UK(Northern Ireland) (at presentation level). Currently these marketing status data are only shared with the National Competent Authorities and the European Commission.

In the future, information on the availability of EU medicinal products might be made publicly available. The Agency will communicate in due course when such functionality becomes available.

References

• List of withdrawn medicinal products in accordance with Art. 123(4) of the Directive

• Article 123(4) of Directive 2001/83/EC, as amended

23.12. Is there an obligation to market a medicine which is authorised for a paediatric indication, following completion of an agreed paediatric investigation plan, and the product has already been marketed with other indications? Rev. Mar 2025

For further information, please see the webpage: Paediatric investigation plans: questions and answers, section 'Articles 33 and 35: Marketing a medicine authorised for a paediatric indication'

(Paediatric investigation plans: questions and answers on the European Medicines Agency ’s website). European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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24. Sunset clause monitoring

24.1. What is the sunset clause? Rev. Jul 2021

The so-called “sunset clause” is a provision leading to the cessation of the validity of the marketing

authorisation if:

• the medicinal product is not placed on the market within three years of the authorisation being granted or,

• where a medicinal product previously placed on the market is no longer actually present on the market for three consecutive years.

• This provision applies to nationally-authorised products and centrally-authorised products.

For centrally-authorised products, the European Commission may grant exemptions on public health grounds and in exceptional circumstances if duly justified (see question How to request an exemption to the sunset clause provision for centrally-authorised products?).

References

• Article 14(4-6) of Regulation (EC) No 726/2004

• Article 24(4-6) of Directive 2001/83/EC, as amended

• Chapter 1 (section 2.4.2), The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2A

24.2. Does the sunset clause apply to existing medicinal products? Rev. Jul 2021

This provision applies prospectively to all centrally authorised medicinal products from the date of entry into force of the Regulation i.e. 20 November 2005.

Therefore, for centrally-authorised medicinal products for which a MA has been granted before 20 November 2005 and for which no presentation are marketed in the Union at this date, the three-year period which leads to cessation of the MA will start as of 20 November 2005.

References

• Document published by the Commission on 10 October 2005 - Application of the “Sunset Clause” in

the Review of the Pharmaceutical Legislation to Medicinal Products Authorised before Directives 2004/27/EC and 2004/28/EC and Regulation (EC) No 726/2004 start to apply

• Chapter 1 (section 2.4.2), The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2A European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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24.3. What are the requirements to maintain a marketing authorisation for a centrally authorised medicinal product? Rev. Jul 2021

The marketing authorisation of a medicinal product will remain valid if at least one authorised presentation/pack-size is placed on the market in the Union (in at least one EU/EEA Member State).

The marketing authorisation of a centrally authorised medicinal product includes the initial marketing authorisation and all variations (e.g. additional presentations) and extensions (e.g. new strengths, new pharmaceutical forms) authorised for this specific medicinal product. This notion has been applied since the beginning of the centralised procedure and is reflected in the way the EU numbers are allocated to a specific centrally authorised medicinal product and all its presentations.

References

• Chapter 1 (section 2.4.2), The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2A

24.4. How the sunset clause is monitored by the EMA? Rev. Jul 2021

A three-year period without marketing of a medicinal product in the EEA can be encountered further to the granting of the marketing authorisation: when a medicinal product has never been marketed or, after marketing of a medicinal product has been completely stopped.

The term “no longer actually present on the market” should be understood in the same way as “ceases to be placed on the market”. Therefore, the sunset clause period in case of a complete marketing

cessation of the product shall start from the last date of release into the distribution chain of the medicinal product. For definition and modalities of reporting of cessation, details are given in Marketing and cessation notification.

As of end of July 2021, the EMA uses the IRIS database to collect marketing status updates and monitor the sunset clause provision for centrally authorised medicinal products. This is done in view to notify the Commission when a three consecutive year period without marketing has elapsed and that the sunset clause provision should take effect.

The MAH should be aware of the timing with regard to the sunset clause period for their product in order to take any action, should they wish to retain their central marketing authorisation.

Please refer to the Q&A on marketing status updates and withdrawals for more information on the IRIS database and the reporting of actual marketing and marketing cessation.

References

• Article 13(4) and Article 14(4-6) of Regulation (EC) No 726/2004

24.5. When is the sunset timer ON/OFF? Rev. Jul 2021

The following situations can lead to the start of the sunset clause period (“ON”):

• Granting of the Marketing authorisation European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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At the time of the granting of the marketing authorisation, the medicinal product may not be immediately placed on the Union market. As a consequence, the sunset timer will start running from the granting of the marketing authorisation by the Commission or from the timepoint when the MAH can legally place the medicinal product on the market. (See also question ‘ In case of a protection period to be respected before placing the medicinal product on the market, when will the sunset clause period start counting? ’)

• A temporary or permanent cessation of placing on the market the medicinal product

The MAH is obliged to inform the Agency of any product cessation (see Q&A on Marketing and cessations and withdrawals). When there is no longer any presentation of the medicinal product placed on the Union market, the sunset timer will start running from the last date of release into the distribution chain of the medicinal product.

The following situations lead to the stop of the sunset clause period (“OFF”):

• Initial placing on the Union market

The sunset timer will stop running at the time of the first placing on the market of one presentation in one Member State.

• At the re-placing on the market after a temporary marketing cessation affecting all the authorised presentations of the medicinal product

As soon as a medicinal product is again placed on the Union market after a temporary cessation, the sunset timer will stop running at this date.

• Exemption

As soon as an exemption is granted by the Commission for a medicinal product, the sunset timer will be stopped.

24.6. In case of a protection period to be respected before placing the medicinal product on the market, when will the sunset clause period start? Rev. Jul 2021

The determination of the start of the 3-year period from granting of the marketing authorisation should be the date when the medicinal product can be marketed by the marketing authorisation holder, taking into account, e.g. marketing protection and other protection rules which have to be respected.

For a medicinal product authorised after 20 November 2005, under the centralised procedure, the Commission Decision will, in most cases, initiate the monitoring of the sunset clause and trigger the 3-year period.

However, where data protection rules apply to reference products, the 3-year period for generic, hybrids and similar biological medicinal products will start as of the end of the 10 or 11-year of marketing protection period of the concerned reference medicinal product.

Furthermore, other protection rules might need to be respected. Such information is not known by the Agency. MAHs are therefore advised to inform the EMA Product Lead of the existence and if known, the expiry date of the other protection period(s) to be respected as appropriate. This should be notified within 60 days from the date of the granting of the MA. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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References

• Chapter 1 (section 2.4.2), The Rules governing Medicinal Products in the European Union, Notice to Applicants, Volume 2A

• Summary record of the 58th meeting of the Pharmaceutical Committee (1st June 2005) –

published on the Commission website on 10 October 2005,

• Article 14(11) of Regulation (EC) No 726/2004

• Article 10(1) of Directive 2001/83/EC, as amended

24.7. How to request an exemption to sunset clause provision for centrally authorised products? Rev. Dec 2022

The Commission may grant exemptions from the application of the sunset clause on public health grounds and in exceptional circumstances.

Exemptions can apply at any time of the central marketing authorisation life cycle (i.e. at the time of the marketing authorisation, during the marketing authorisation life, or approaching the expiry of the sunset clause period) depending on the type of exemptions.

At submission stage the following exemptions might be applicable:

• Medicinal products to be used in emergency situations, in response to public health threats duly recognised either by the WHO or by the Union (Decision No 2119/98/EC).

• Antimicrobial medicinal products such as antibiotics, antivirals and immunologicals (for active and passive immunisation) aimed at the prevention and/or treatment of disease caused by bio-terror agents in response to an emergency public health need.

It will be up to the MAH to justify why an exemption should apply based on public health grounds and in exceptional circumstances.

A request for an exemption including a justification should be notified to the European Commission, Health and Food Safety Directorate-General, Unit B5 ([email protected]) with the EMA product lead, product mailbox and [email protected] in copy. Each justification will be considered on a case-by-case basis.

References

• Article 14(6) of Regulation (EC) No 726/2004