FDA 发布 Phase 1 IND 常见问题解答，梳理适用、提交与安全报告要求

Find answers to questions sponsors commonly have about Phase 1 INDs.

Throughout this FAQ, "IND" refers to Investigational New Drug application.

1. What is the scope of Phase 1 clinical trials, and what are their primary objectives, study designs, and typical subject population size?

Phase 1 includes the initial introduction of an investigational new drug into humans, often referred to as "first-in-human" studies. These studies are closely monitored and may be conducted in patients or healthy volunteers.

Phase 1 studies are designed to:

Determine the metabolism and pharmacologic actions of the drug in humans
Assess the side effects associated with increasing doses
Gain early evidence on effectiveness, when possible

During Phase 1, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The number of subjects and patients enrolled in Phase 1 studies generally ranges from 20 to 80, though this can differ depending on the specific drug being studied.

Phase 1 studies also include studies of structure-activity relationships and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes.

For additional information, see 21 CFR 312.21(a) and Step 3: Clinical Research.

2. What nonclinical studies are required to support an IND for a Phase 1 study?

The nonclinical data supporting a Phase 1 IND should adequately characterize the drug's safety profile and provide a sound basis for the proposed starting dose and study design. FDA’s Regulations outline a range of pharmacological and toxicological information that must be addressed in an IND submission, see IND Applications for Clinical Investigations: Pharmacology and Toxicology (PT) Information.

For general scientific considerations around types of nonclinical studies and timing of conduct during clinical development, see the ICH guidances M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals and S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.

However, the type and extent of nonclinical information needed to support a phase 1 first-in-human clinical protocol depends on risk-based characteristics such as the intended clinical population, product modality, and mechanism of action.

FDA supports strategies to reduce use of animals in drug development, and sponsors should use all relevant and publicly available information to optimize safety evaluation of the investigational product in a scientifically justified manner while reducing unnecessary use of animals. CDER maintains a web page summarizing additional guidance documents and accepted practices that successfully facilitate streamlined nonclinical programs and integration of New Approach Methodologies into regulatory decision-making, see: CDER Streamlined Nonclinical Studies and Acceptable New Approach Methodologies (NAMs).

In March 2026, CDER issued a draft guidance, General Considerations for the Use of New Approach Methodologies in Drug Development, which provides drug developers with a validation framework for New Approach Methodologies (NAMs) based upon context of use, human biological relevance, technical characterization, and fit-for-purpose considerations. When finalized, this guidance will reflect FDA’s current thinking on the topic.

3. Can a Phase 1 study be skipped, or can Phase 1 and Phase 2 be combined?

FDA recognizes that clinical development programs may not always follow a traditional sequential phase structure. Although clinical investigations are generally divided into three phases, the phases may overlap and may not need to be conducted sequentially (21 CFR 312.21).

While the regulations do not provide for skipping Phase 1 entirely, each proposed development program is reviewed on a case-by-case basis. Early engagement with FDA is encouraged when a sponsor is considering a nontraditional approach, such as combining phase 1 and phase 2 studies.

For combined study designs that incorporate adaptive elements, sponsors may also review the guidance for industry Adaptive Design Clinical Trials for Drugs and Biologic s and the draft guidance for industry E20 Adaptive Designs for Clinical Trials for additional information.

A formal meeting may be requested prior to IND submission to discuss the proposed program. For information on meeting types and how to submit a meeting request, see the draft guidance Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

4. What are the different categories of INDs?

INDs generally fall into two categories:

Commercial IND: An IND in which the sponsor (typically a corporate entity) intends to market the drug product by eventually submitting a marketing application.
Research (non-commercial IND): An IND in which the sponsor (generally an individual investigator, academic institution, or non-profit entity) does not intend to market the drug product.

For additional information, see Investigational New Drug (IND) Application for CDER-Regulated Products and Investigational New Drug Applications (INDs) for CBER-Regulated Products.

5. When is an IND required?

Under 21 CFR 312.20, an IND is required when a sponsor intends to administer an investigational drug or biological product to humans for the purpose of conducting a clinical study, unless the study meets specific criteria for exemption (for information on exemptions from IND requirements, see Q6 below). The requirement for an IND typically applies when the drug or biological product is not yet approved by the FDA, or when an approved drug is being studied for a new indication, dosage, route of administration, or patient population in a way that could significantly increase risk or alter its labeling. An IND is also needed when the study results are intended to support a marketing application.

6. Would my clinical study be exempt from IND requirements?

Not all investigator-initiated clinical investigations require an IND. Before contacting FDA or submitting an IND for an investigator-initiated clinical investigation, investigators should review the exemption criteria in the Code of Federal Regulations (CFR) at 21 CFR 312.2 and refer to the Guidance for Clinical Investigators, Sponsors, and IRBs: Investigational New Drug Applications (INDs)—Determining Whether Human Research Studies Can Be Conducted Without an IND to determine whether their clinical investigation requires submission of an IND.

Generally, a clinical investigation of a marketed drug is exempt from the IND requirements if all of the criteria for an exemption under 21 CFR 312.2(b)(1) apply:

The drug product is lawfully marketed in the United States
The clinical investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication (new FDA-approved use) for the drug and there is no intent to use the clinical investigation to support any other significant change in the labeling of the drug
In the case of a prescription drug, the clinical investigation is not intended to support a significant change in the advertising for the drug
The clinical investigation does not involve a route of administration, dose, patient population, or other factors that significantly increase the risk (or decreases the acceptability of the risk) associated with the use of the drug
The clinical investigation is conducted in compliance with Institutional Review Board (IRB) requirements (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50)
The investigation is conducted in compliance with 21 CFR 312.7 (generally prohibiting the commercial marketing or promotion of investigational drugs)

Investigators may use the IND Application Procedures: Exemptions from IND Requirements as an educational tool for help in determining whether a proposed clinical investigation is IND exempt or requires an IND.

7. Does a clinical study that uses real-world data (RWD) require an IND?

The applicability of IND requirements to studies using RWD depends on whether the study meets the definition of a clinical investigation under 21 CFR 312.3. This is discussed in the Guidance for Industry Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and Biological Products.

Non-interventional (observational) studies that use RWD, such as studies using electronic health records (EHRs), medical claims data, or disease registries, are generally not considered clinical investigations under 21 CFR 312.3 and therefore do not require an IND. In these studies, any drugs involved are administered based on a medical provider's clinical judgment as part of routine care, rather than pursuant to a research protocol.

Interventional studies that incorporate RWD as part of the study design remain subject to IND requirements under 21 CFR Part 312. For example, an externally controlled trial - in which one arm receives an investigational drug under a protocol and another arm uses RWD as the comparator - is considered an interventional study and will generally be subject to Part 312 regardless of the data source used for the external control.

FDA encourages sponsors to engage early with FDA if their study uses RWD and the applicability of the IND regulations is unclear.

For additional information on RWD, see Real-World Evidence.

8. Does a clinical investigation involving a marketed product require Institutional Review Board (IRB) review and approval?

Yes, if the investigation is governed by FDA regulations (see 21 CFR 56.101, 56.102(c), 312.2(b),361.1, 601.2, and 812.2).

Importantly, IRB review and approval are required regardless of whether the study requires an IND. As noted in Q6, a clinical investigation of a marketed drug may qualify for an exemption from IND requirements, but IND-exempt studies that are otherwise subject to FDA regulations must still comply with the IRB requirements under 21 CFR Part 56 and the informed consent requirements under 21 CFR Part 50.

IRB review generally encompasses evaluation of the study protocol, informed consent documents, investigator qualifications, and the overall risk-benefit profile of the proposed investigation to ensure the protection of human subjects.

For comprehensive information on IRB requirements and responsibilities, see Institutional Review Boards Frequently Asked Questions.

9. When can I start drug administration after I submit an IND?

The IND may go into effect 30 days after FDA receives the application, unless FDA notifies the sponsor that the investigations described in the application are subject to a clinical hold. FDA may also notify the sponsor earlier that clinical investigations may begin, in which case the IND takes effect upon that notification (see 21 CFR 312.40(b)).

Once an IND is in effect, the investigational new drug may be shipped to the investigator(s) named in the application. An investigator may not administer an investigational new drug to human subjects until the IND goes into effect (see 21 CFR 312.40(c)).

10. I want to meet with FDA before I submit an IND. Is that possible?

Yes. Meetings can be a valuable tool in planning a drug development program. Early interactions with FDA staff can help prevent clinical hold issues and support preparation of a complete IND. Pre-IND meetings are classified as Type B meetings and can cover topics such as study design, safety data requirements, CMC expectations, and regulatory pathway questions. Sponsors developing novel products or programs that present unique challenges in early development may also consider requesting an INTERACT meeting, which is available before IND submission or before a pre-IND meeting has been held.

To request a meeting, sponsors must submit a formal meeting request. For more information on how to request and prepare for a meeting, see:

11. When can I expect a response to my pre-IND meeting request?

Pre-IND meetings are classified as Type B meetings. FDA's goals for Type B meetings are to respond to a meeting/written response only (WRO) request within 21 calendar days and to hold the meeting or issue written responses within 60 calendar days from receipt of the request.

For complete information on timelines, including tables summarizing meeting request and WRO goals across all meeting types, refer to Section IV, Assessing and Responding to Meeting Requests, of the guidance, Formal Meetings with Sponsors and Applicants for PDUFA Products.

12. How do I submit an IND?

How you submit depends on the type of IND.

Sponsors of all (CDER and CBER) commercial INDs must submit electronically in the Electronic Common Technical Document (eCTD) format through the FDA’s Electronic Submissions Gateway (ESG).

Sponsors of CDER regulated research (non-commercial) INDs are encouraged to submit electronically whenever possible. Consider submitting electronically via the CDER NextGen Portal, a web-based system that allows submission of initial INDs and subsequent amendments without eCTD capability.

To learn more about the submission process for CDER regulated INDs, see Electronic Regulatory Submission and Review and Information for Sponsor-Investigators Submitting Investigational New Drug Applications (INDs).

Sponsors of CBER regulated research (non-commercial) INDs are encouraged to submit electronically through the Electronic Submissions Gateway (ESG). You may also submit via email (150MB max) to [email protected].

To learn more about the submission process for CBER regulated INDs, see Investigational New Drug Applications (INDs) for CBER-Regulated Products and Submission of an Investigational New Drug Application (IND) to CBER.

13. What if I have technical difficulties submitting the IND electronically?

For Electronic Submissions Gateway (ESG) related questions, contact [email protected]. For technical issues with the CDER NextGen Portal, visit the Help Center for resources and to contact technical support.

14. What is a clinical hold?

A clinical hold (21 CFR 312.42) is an order issued by FDA to the sponsor of an IND to delay a proposed clinical investigation or to suspend an ongoing investigation. All or some of the investigations conducted under an IND may be placed on clinical hold.

A full clinical hold is imposed when all clinical trials operating under an IND are delayed or suspended from proceeding.

A partial clinical hold applies when only certain trials, protocols, or parts of a protocol are restricted from proceeding while others may continue. It may also apply when currently proposed trials under the IND are permitted to proceed, but future submissions may not until FDA-identified deficiencies are resolved.

To learn more, see SOPP 8201: Administrative Processing of Clinical Holds for Investigational New Drug Applications and MAPP 6030.1 Rev.3 - IND Clinical Holds.

15. What are some common reasons for a clinical hold for a Phase 1 Investigation?

The grounds for imposition of a clinical hold for a proposed or ongoing Phase 1 investigation include the following:

Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury; or
The clinical investigators named in the IND are not qualified by reason of their scientific training and experience to conduct the investigation described in the IND; or
The investigator brochure is misleading, erroneous, or materially incomplete; or
The IND does not contain sufficient information needed to assess the risks to subjects of the proposed studies; or
The IND is for the study of an investigational drug intended to treat a life-threatening disease or condition that affects both sexes, and men or women with reproductive potential who have the disease or condition being studied are excluded from eligibility because of a risk of reproductive toxicity (i.e., affecting reproductive organs) or developmental toxicity (i.e., affecting potential offspring).

For additional information, see IND Application Procedures: Clinical Hold and 21 CFR 312.42.

16. How do I amend my IND?

Once an IND is in effect, the sponsor of the application may amend the application as needed to ensure that the clinical investigations are conducted according to protocols included in the IND.

Sponsors are expected to submit a type of IND amendment called a protocol amendment (see 21 CFR 312.30) for new protocols or changes to existing protocols before implementation of the respective changes. New studies may begin when the sponsor submits the change to FDA for its review and the new protocol or changes to the existing protocol have been approved by the Institutional Review Board (IRB) with the responsibility for review and approval of the studies. If the IND sponsor desires FDA to comment on a submission, they should submit a request for such comment and the specific questions that FDA's response should address. For additional information, see IND Application Reporting: Protocol Amendments.

In addition to IND protocol amendments with new or revised protocols, sponsors may also need to submit other information amendments (see 21 CFR 312.31). An information amendment is any amendment to an IND with information essential to the investigational product that is not within the scope of protocol amendments, safety reports, or annual reports. For example, information amendments to INDs may include new toxicology, chemistry, or other technical information or a report regarding discontinuance of a clinical or nonclinical investigation.

Information amendments to an IND should be submitted as necessary but, to the extent feasible, not more than every 30 days. For additional information, see IND Application Reporting: Information Amendments.

17. What IND safety reporting is expected?

FDA regulations establish several IND safety reporting requirements for sponsors conducting clinical trials, including expedited safety reports, follow-up reports, and annual safety reports.

Expedited Safety Reporting

Under FDA regulations (21 CFR 312.32), sponsors are required to promptly review all safety information and submit IND safety reports for serious and unexpected suspected adverse reactions, which are adverse events that are serious, unexpected, and for which there is a reasonable possibility that the drug caused the event (21 CFR 312.32(a)). This type of report is sometimes referred to as a Suspected Unexpected Serious Adverse Reaction (SUSAR).

Expedited IND safety reports must be submitted to FDA and all participating investigators as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting (21 CFR 312.32(c)(1)). For unexpected fatal or life-threatening suspected adverse reactions, the safety reports must be submitted to FDA as soon as possible but in no case later than 7 calendar days after the sponsor’s initial receipt of the information (21 CFR 312.32(c)(2)).

For more information on IND safety reporting, see FDA Adverse Event Monitoring System (AEMS) Electronic Submissions.

Follow-Up Safety Reports

Any relevant additional information obtained by the sponsor related to a previously submitted IND safety report must be submitted as a Follow-up IND Safety Report. This follow-up report should be submitted promptly upon receipt of the new information, and no later than 15 calendar days after the sponsor becomes aware of it.

Annual Safety Reports

In addition to expedited safety reporting, sponsors are expected to submit an annual IND report within 60 days of the anniversary date of the IND going into effect (21 CFR 312.33). This report includes a summary of all significant safety information collected during the reporting period.

For more information on IND safety reporting requirements, see:

IND Application Reporting: IND Safety Reports
Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies
Guidance for Industry: Sponsor Responsibilities - Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies