AveXis对FDA 2019年483的初次回复涉Zolgensma数据操纵整改计划

刚刷了一个最近的警告信，大意是某公司大量的违反DI行为，但认为风险较小，FDA给其发了警告信。

正巧这周在看一份古早的DI整改，这份是 AveXis（Zolgensma 基因疗法生产商，该公司2018年被诺华收购，次年前员工爆料数据造假，诺华对其进行了DI整改，并获FDA认可）对 2019 年 8 月 FDA 483 的初始书面回复（59 页，2019-08-23 提交）。背景是两名高管曾篡改小鼠效力试验（IVRPA）原始数据，公司于 6 月 28 日主动上报。回复含三部分：Ⅰ 数据操纵调查过程；Ⅱ 公司级合规行动计划（质量整合计划 + 数据完整性整改计划）；Ⅲ 对 5 项观察项逐条回应——未彻底调查数据差异（NCR-1922/409/965）、实验室记录不完整（天平无审计追踪）、质量部门职责未落实（动物房人员归 R&D 管理）、参照品未经放行标准检验（两批次参照品）、未遵循既定检验规程（体重称量频率与死亡判定），各项均附整改措施与完成时限（2019-11 至 2020-03）。

AveXis, Inc. 对 FDA 483 检查缺陷项的初步回复（双语文档）

AveXis, Inc.'s Initial Response to the Form FDA 483 (Bilingual)

August 23, 2019

2019 年 8 月 23 日

Via Electronic Mail Confidential

通过电子邮件发送保密

Office of Regulatory Affairs Office of Biological Products Operations (OBPO) US Food and Drug Administration [email protected]

美国食品药品监督管理局生物制品运营办公室（OBPO）监管事务办公室 [email protected]

Re: AveXis, lnc.'s Initial Response to the Form FDA 483 Issued on August 2, 2019 to the San Diego, CA Quality Control Laboratory FEI: 3014617030 Investigators: Scott T. Ballard and Mihaly S. Ligmond

事由：AveXis, Inc. 对 2019 年 8 月 2 日签发给加州圣迭戈质量控制实验室的 FDA 483 表的初次回复 FEI：3014617030 检查员：Scott T. Ballard 与 Mihaly S. Ligmond

Dear Sir or Madam:

尊敬的先生/女士：

Enclosed please find AveXis, lnc.'s (AveXis or the company) initial response to the Form FDA 483 (483) issued at the conclusion of FDA's July 24 - August 2, 2019 inspection (the July/August 2019 Inspection) of the company's quality control laboratory located in San Diego, California (FEI: 3014617030).

随函附上 AveXis, Inc.（以下简称“AveXis”或“公司”）对 FDA 483 表（483）的初次回复。该 483 表系 FDA 于 2019 年 7 月 24 日至 8 月 2 日对公司位于加利福尼亚州圣迭戈的质量控制实验室（FEI：3014617030）进行现场检查（2019 年 7/8 月检查）结束后签发。

As FDA is aware, the July/August 2019 Inspection followed AveXis's June 28, 2019 self reporting to the agency of data manipulation issues involving a mouse potency assay- known as the in vivo relative potency assay (IVRPA)-used as a product release test during the early clinical phase of Zolgensma® (onasemnogene abeparvovec-xioi). 1 Specifically, it was alleged that two AveXis senior executives altered or instructed others to alter a small amount of raw data used to run the IVRP A. Such conduct is unacceptable, and the two A veXis senior executives have been tenninated.

如 FDA 所知，2019 年 7/8 月检查系在 AveXis 于 2019 年 6 月 28 日向该机构自我报告数据操纵问题之后进行。该问题涉及一项小鼠效力试验——即体内相对效力试验（IVRPA）——该试验在 Zolgensma®（onasemnogene abeparvovec-xioi）早期临床阶段被用作产品放行检验。1 具体而言，据指控，AveXis 的两名高级管理人员篡改或指示他人篡改了用于运行 IVRPA 的少量原始数据。此类行为不可接受，这两名高级管理人员已被解雇。

1 Zolgensma~. Biologics License Application (BLA), STN 125694, is the first gene therapy approved to treat children less than two years of age with spinal muscular atrophy (SMA), the most severe form of SMA and the leading genetic cause of infant mortality.

1 Zolgensma®（生物制品许可申请（BLA），STN 125694）是首个获批用于治疗两岁以下脊髓性肌萎缩症（SMA）患儿的基因治疗药物；SMA 是最严重的 SMA 类型，也是导致婴儿死亡的首要遗传原因。

A veXis would like to make clear that it is committed to transparency with FDA, and to ensuring that data it generates is attributable, legible, contemporaneous, original and accurate. Please note that the investigation into the data manipulation allegations was conducted with focus and diligence. Details regarding the various steps of the investigation into the data manipulation issues are provided in Section I (pp. 1-9) of the enclosed response. Please also note that the investigation has not shown an impact on patient safety or product efficacy or quality. Indeed, FDA has stated that the data manipulation issues self-reported by AveXis do "not change the agency's positive assessment of the information from the human clinical trials that were conducted as part of the development program. The totality of the evidence demonstrating the product's effectiveness and its safety profile continues to provide compelling evidence supporting an overall favorable benefit-risk profile:'2

AveXis 谨此明确表示，公司致力于对 FDA 保持透明，并确保其生成的数据具有可归属性、清晰可读性、同步记录性、原始性和准确性。请注意，对数据操纵指控的调查是满怀专注、勤勉尽责地开展的。关于数据操纵问题调查各步骤的详情见随附回复的第一部分（第 1-9 页）。还请注意，调查未显示对患者安全或产品疗效或质量产生影响。事实上，FDA 已表示，AveXis 自我报告的数据操纵问题“不会改变该机构对作为开发计划一部分开展的人体临床试验信息的积极评价。证明产品有效性及其安全性特征的证据总体继续提供令人信服的证据，支持总体获益-风险特征良好。”2

The company recognizes that the agency has raised concerns regarding the timing of AveXis's June 28, 2019 self-disclosure. AveXis notes that there were 39 working days from the first interview with the reporter to the conclusion of the investigation's first phase determining the veracity of the allegations. There were 36 working days from the start of the quality investigation to the submission of the June 28, 2019 self-disclosure. As more fully detailed in Section I (pp. 1-9) of the enclosed response, this was a complex investigation into data integrity allegations, and took significant resources and time. That being said, AveXis understands FDA's concerns and fully appreciates that the circumstances presented by a new gene therapy is something that should be taken into account with regard to the timing of notifying FDA. Although AveXis is confident that the actions detailed in this response will prevent such daca manipulation issues from occurring in the future, the company will going forward notify the agency within 5 business days of receipt by our quality organization of any credibJe allegation related to data integrity impacting a submitted Biologics License Application (BLA).

公司认识到，该机构对 AveXis 于 2019 年 6 月 28 日自我披露的时机提出了关切。AveXis 指出，从首次约谈举报人到调查第一阶段结束（确定指控的真实性），共用了 39 个工作日。从质量调查启动到提交 2019 年 6 月 28 日自我披露，共用了 36 个工作日。如随附回复第一部分（第 1-9 页）更详细所述，这是一项针对数据完整性指控的复杂调查，耗费了大量资源和时间。尽管如此，AveXis 理解 FDA 的关切，并充分认识到，就通知 FDA 的时机而言，应考虑新型基因治疗药物所处的具体情况。虽然 AveXis 相信本回复中详述的措施将防止此类数据操纵问题再次发生，但公司今后将在质量组织收到任何与数据完整性相关、可能影响已提交生物制品许可申请（BLA）的可信指控后的 5 个工作日内通知该机构。

AveXis takes the feedback contained in the 483 seriously and is committed to comprehensively addressing the noted observations. The company's goal moving forward is to ensure a robust culture of quality and sustainable GxP compliance across AveXis. In light of the data integrity issues mentioned above, and the 483, AveXis, with significant input and oversight from the Novartis Group of companies (Novartis), has developed- and is in the process of implementing- a company-wide Compliance Action Plan (the CAP). As detailed in Section II (pp. 10-20) of the enclosed response, the core elements of the CAP are (A) the Quality Integration Plan and (B) the Data Integrity Remediation Plan.

AveXis 严肃对待 483 中所载的反馈意见，并致力于全面解决所列出的检查发现项。公司今后的目标是在整个 AveXis 确保建立强大的质量文化和可持续的 GxP 合规。鉴于上述数据完整性问题及 483，AveXis 在诺华集团（Novartis）的大力意见输入和监督下，已制定并正在实施一项全公司范围的合规行动计划（CAP）。如随附回复第二部分（第 10-20 页）所述，CAP 的核心要素为（A）质量整合计划和（B）数据完整性整改计划。

The specific responses to the 483 observations are provided in Section III (pp. 21-56) of the enclosed response. For ease of reference, the responses are formatted as follows: each response

对 483 检查发现项的具体回复见随附回复第三部分（第 21-56 页）。为便于查阅，回复格式如下：每条回复

2 Statement on data accuracy issues with recently approved gene therapy (Aug. 6, 20l9)t https://www.fda,govlnews-events(m;ess-announcementslstatement-data-accuracy-issues-recently approved-gene-therapy.

2 《关于近日获批基因治疗药物数据准确性问题的声明》（2019 年 8 月 6 日），https://www.fda.gov/news-events/press-announcements/statement-data-accuracy-issues-recently-approved-gene-therapy。

begins with a restatement of FDA's observation in italic text. This is followed by the site's response to the observation(s). At the conclusion of each observation response, planned corrective and preventive actions are detailed with preliminary target completion dates, as appropriate.

以斜体文字复述 FDA 的检查发现项开始，随后是现场对该（各）检查发现项的回复。每条检查发现项回复的结尾，酌情详述计划采取的纠正和预防措施及初步目标完成日期。

AveXis is confident the CAP, together with the actions discussed in the company's specific 483 responses, will be successful and ensure sustainable GxP compliance. To ensure AveXis and FDA are in alignment on the approaches detailed in this response, AveXis respectfully requests a meeting with FDA to update the agency on the investigation into the data manipulation issues, the company's CAP, and the specific actions addressing the 483 observations.

AveXis 相信，CAP 连同公司对各 483 检查发现项的具体回复中所讨论的措施，将取得成功，并确保可持续的 GxP 合规。为确保 AveXis 与 FDA 就本回复中详述的方法达成一致，AveXis 谨请求与 FDA 举行会议，向该机构通报数据操纵问题调查的进展、公司的 CAP 以及针对 483 检查发现项的具体措施。

Please do not hesitate to contact me if you have any questions or need further information. I can be contacted by phone ator by email atAveXis with provide periodic updates to FDA on the status of its ongoing actions and investigations, and will also keep FDA apprised of any new actions undenaken. AveXis's first update will be provided to FDA at the end of September 2019.

如您有任何疑问或需要进一步信息，请随时与我联系。可通过电话或电子邮件联系我。AveXis 将定期向 FDA 通报其正在开展的措施和调查的最新进展，并将随时告知 FDA 任何新采取的措施。AveXis 将于 2019 年 9 月底向 FDA 提交首次进展更新。

This document and attachments contain confidential commercial and trade secret information that is protected from public disclosure under the Federal Food, Drug, and Cosmetic Act, the Freedom of Information Act, FDA's implementing regulations, and the Trade Secrets Act. ln accordance with FDA 's implementing regulations, if a request for disclosure is received, the company asks that it be notified and provided an opportunity to address why the information or materials should not be released.

本文件及附件载有受《联邦食品、药品和化妆品法》《信息自由法》、FDA 实施细则及《商业秘密法》保护、免于公开披露的机密商业信息和商业秘密。根据 FDA 实施细则，如收到披露请求，公司请求得到通知，并获得机会说明该等信息或材料不应公开的理由。

Sincerely,

此致，

Mark Roache

Mark P. Roache Senior Vice President, Chief Quality Officer AveXis, Inc. Digitally Signed by Dave Lennon Date: 2019.08,23 14:54:30

Mark P. Roache 高级副总裁、首席质量官 AveXis, Inc. 由 Dave Lennon 数字签名日期：2019.08.23 14:54:30

David Lennon President AveXis, Inc .

David Lennon 总裁 AveXis, Inc.

I. AveXis’s Investigation Into Data Manipulation Allegations

一、AveXis 对数据操纵指控的调查

A. AveXis and Zolgensma®

A. AveXis 与 Zolgensma®

By way of background, AveXis is a biotechnology company focused on developing novel treatments for patients suffering from rare and life-threatening genetic diseases. On May 15, 2018, AveXis was acquired by Novartis.3 At the time of the acquisition, AveXis’s lead gene therapy candidate, AVXS-101, had demonstrated highly c ompelling clinical data in the treatment of spinal muscular atrophy (SMA). SMA is a rare genetic disease caused by a mutation in the survival motor neuron 1 (SMN1) gene. The gene encodes the survival motor neuron (SMN) protein—a protein found throughout the body, which is critical for the maintenance and function of specialized nerve cells, called motor neurons. Motor neurons in the brain and spinal cord control muscle movement throughout the body. If there is not enough functional SMN protein, then the motor neurons die, leading to debilitating and often fatal muscle weakness. SMA caused by mutations in the SMN1 gene is generally c lassified into several subtypes, based on the age of onset and severity; infantile-onset SMA Type 1 is the most severe and most common subtype. Children with this condition have problems holding their head up, swallowing and breathing. These symptoms may be present at birth or may present by the age of 6 months. SMA is the leading g enetic cause of infant death. If left untreated, SMA Type 1 leads to death or the need for permanent ventilation by the age of two in more than 90% of cases.

作为背景说明，AveXis 是一家生物技术公司，专注于为患有罕见且危及生命的遗传疾病的患者开发新型治疗方法。2018 年 5 月 15 日，AveXis 被诺华收购。3 收购之时，AveXis 的领先基因治疗候选药物 AVXS-101 在治疗脊髓性肌萎缩症（SMA）方面已展现出极具说服力的临床数据。SMA 是一种由运动神经元存活 1（SMN1）基因突变引起的罕见遗传病。该基因编码运动神经元存活（SMN）蛋白——一种遍布全身的蛋白质，对称为运动神经元的特化神经细胞的维持和功能至关重要。大脑和脊髓中的运动神经元控制全身的肌肉运动。如果功能性 SMN 蛋白不足，运动神经元便会死亡，导致使人衰弱且往往致命的肌无力。由 SMN1 基因突变引起的 SMA 通常根据发病年龄和严重程度分为若干亚型；婴儿型 SMA 1 型是最严重、最常见的亚型。患有该疾病的儿童存在抬头、吞咽和呼吸困难。这些症状可能在出生时即出现，也可能在 6 个月大时出现。SMA 是导致婴儿死亡的首要遗传原因。如不加治疗，SMA 1 型在 90% 以上的病例中会导致患者在两岁前死亡或需要永久性通气支持。

On October 1, 2018, AveXis submitted its Biologics License Application (BLA), STN 125694, for Zolgensma® (onasemnogene abeparvovec-xioi) for the treatment of pediatric patients less than 2 years of age with SMA with bi-allelic mutations in the SMN1 gene.4 The Zolgensma® BLA was approved on May 24, 2019. This was AveXis’s first FDA approval.

2018 年 10 月 1 日，AveXis 为 Zolgensma®（onasemnogene abeparvovec-xioi）提交了生物制品许可申请（BLA），STN 125694，用于治疗 SMN1 基因双等位基因突变、年龄小于 2 岁的 SMA 儿科患者。4 Zolgensma® BLA 于 2019 年 5 月 24 日获批。这是 AveXis 首次获得 FDA 批准。

B. The In Vivo Relative Potency Assay

B. 体内相对效力试验

Between approximately March 2017 and June 2018, AveXis used a mouse potency assay— known as the in vivo relative potency a ssay ( IVRPA)—for release and stability testing of clinical product. The IVRPA used SMNΔ7 mice to determine the relative potency of lots of AVXS-101 for release and stability testing. SMNΔ7 mice have a genetic mutation that models SMA disease, resulting in a greatly reduced life expectancy compared to mice without the mutation. Untreated, SMNΔ7 mice will die of SMA-like disease approximately 15 days after birth. As part of the IVRPA, the date that each mouse died was recorded, and these dates of death were used to assess the median number of days of survival for each of the groups of mice. The information for each mouse used in the IVRPA was first manually recorded on “cage cards” affixed to each mouse

约在 2017 年 3 月至 2018 年 6 月期间，AveXis 使用一种小鼠效力试验——即体内相对效力试验（IVRPA）——对临床产品进行放行和稳定性试验。IVRPA 使用 SMNΔ7 小鼠来确定 AVXS-101 各批次用于放行和稳定性试验的相对效力。SMNΔ7 小鼠带有模拟 SMA 疾病的基因突变，与无突变小鼠相比寿命大幅缩短。如不加治疗，SMNΔ7 小鼠将在出生后约 15 天死于 SMA 样疾病。作为 IVRPA 的一部分，每只小鼠的死亡日期均被记录，这些死亡日期用于评估每组小鼠的生存天数中位数。IVRPA 中使用的每只小鼠的信息首先人工记录在贴于每个小鼠

3 Novartis successfully completes acquisition of AveXis, Inc. (May 15, 2018), https://www.novartis.com/news/media-releases/novartis-successfully-completes-acquisition-avexis-inc. 4 See BLA 125694, Summary Basis for Regulatory Action at 4.

3 诺华成功完成对 AveXis, Inc. 的收购（2018 年 5 月 15 日），https://www.novartis.com/news/media-releases/novartis-successfully-completes-acquisition-avexis-inc。 4 参见 BLA 125694《监管行动依据摘要》第 4 页。

cage, and then transcribed onto an individual raw data sheet for each mouse. The data from the individual mouse sheets were used to calculate the median dates of survival, and the response was expressed as a relative potency percentage, with reference to a pre-selected reference standard lot of AVXS-101.

笼的“笼卡”上，然后转录到每只小鼠单独的原始数据单上。来自各小鼠单独数据单的数据用于计算生存中位数日期，结果以相对效力百分比表示，参照预先选定的 AVXS-101 参考标准品批次。

Although adequate for its intended purpose of supporting AVXS-101 development, the IVRPA was known to have a large degree of variability. At FDA’s request, AveXis developed and validated an in vitro relative potency assay that, together with a confirmatory in vivo functionality a ssay, replaced the IVRPA for product release and stability testing. IVRPA has not been used for clinical product release purposes since June 2018, nearly a year before Zolgensma® was approved, and was never used for the release of commercial product. The IVRPA was a small part of the overall testing of AVXS-101.

尽管 IVRPA 足以满足其支持 AVXS-101 开发的预期目的，但业内已知其存在较大程度的变异性。应 FDA 的要求，AveXis 开发并验证了一种体外相对效力试验，该试验连同一种确认性体内功能试验，取代了 IVRPA 用于产品放行和稳定性试验。自 2018 年 6 月起，IVRPA 不再用于临床产品放行目的——这比 Zolgensma® 获批早了近一年——且从未用于商业产品的放行。IVRPA 只是 AVXS-101 整体检验的一小部分。

Both the in vitro cell-based assay and the new in vivo functionality assay were validated and included in the Zolgensma® BLA as the tests to be used to assess potency for both release and stability purposes. Together, the assays are considered to be a significant improvement over the IVRPA, including by reducing testing variability. The IVRPA was not included in the BLA as a commercial final product release test or as a currently-used stability test.

体外基于细胞的试验和新的体内功能试验均已验证，并被纳入 Zolgensma® BLA，作为用于放行和稳定性目的的效力评估检验。总体而言，这些试验被认为较 IVRPA 有显著改进，包括降低了检验变异性。IVRPA 未被纳入 BLA，既未作为商业最终产品放行检验，也未作为现用的稳定性试验。

AveXis takes the integrity of all clinical and GxP data extremely seriously. The allegations made in March 2019 concerned a small portion of the clinical product testing data, and as already mentioned involved a test that has not been used for clinical product release purposes since June 2018 and is not identified in the BLA as a commercial final product release test or as a currently-used stability test. Further, none of the data discrepancies identified during the investigation was determined to impact original lot release determinations. Notably, reassessment of the underlying data did not change any reported within-specification result (passing result) to an out-of-specification result (failing result). Subsequent testing of all impacted clinical development lots using the validated in vitro relative potency assay have also consistently demonstrated that each lot meets the specification for relative potency.

AveXis 极其严肃地对待所有临床和 GxP 数据的完整性。2019 年 3 月提出的指控涉及临床产品检验数据的一小部分，且如前所述，涉及的检验方法自 2018 年 6 月起已不再用于临床产品放行目的，也未在 BLA 中被确定作为商业最终产品放行检验或现用的稳定性试验。此外，调查期间发现的数据差异均未被确定对原有批次放行判定产生影响。值得注意的是，对基础数据的重新评估未将任何已报告的符合标准（合格）结果变为超标（不合格）结果。随后使用经验证的体外相对效力试验对所有受影响的临床开发批次进行的检验也一致表明，每个批次均符合相对效力标准。

Indeed, as described in detail, below, throughout the course of investigating the alleged data manipulation, there has been a consistent determination that the allegations had no impact on patient safety or product efficacy or quality.

事实上，如下文详述，在对所指控的数据操纵进行调查的全过程中，调查结果始终一致地认定：该等指控对患者安全或产品疗效或质量没有影响。

C. Receipt of the Data Manipulation Allegations

C. 收到数据操纵指控

As FDA is aware, on March 14, 2019, roughly 8 months after the discontinuation of the IVRPA, AveXis senior management first learned of alleged data manipulation issues involving certain mice used in the IVRPA. Specifically, an AveXis employee alleged that two AveXis senior executives altered or instructed others to alter certain raw data derived from the IVRPA. The

如 FDA 所知，2019 年 3 月 14 日，即 IVRPA 停用约 8 个月后，AveXis 高级管理层首次获悉涉及 IVRPA 中所用某些小鼠的数据操纵指控。具体而言，一名 AveXis 员工指控两名 AveXis 高级管理人员篡改或指示他人篡改源自 IVRPA 的某些原始数据。该

allegation primarily concerned the recorded date of death for some of the mice used in the IVRPA. Notably, there was no allegation that data manipulation had or could have any impact on the safety or effectiveness of the product.

指控主要涉及 IVRPA 中所用部分小鼠记录的死亡日期。值得注意的是，没有任何指控称数据操纵已经或可能对产品的安全性或有效性产生任何影响。

Consistent with FDA-recognized standard industry practice, AveXis opened and scoped the internal investigation to be conducted in a manner reasonable in the circumstances presented. For the first phase, AveXis engaged external counsel to lead an independent investigation. This was believed to be necessary because the two executives who were the subject of the allegations were still fixtures at AveXis with the potential to influence and impede the investigation. Given that the allegations involved data manipulation, the companies wanted to ensure that key evidence was preserved and made available for a thorough technical review. Toward that end, the two executives who were the subject of the allegations were not informed of the investigation during this initial phase. And because both had access to and would in the normal course be alerted to the opening of a formal quality investigation, AveXis chose not to open a formal nonconformance investigation through its quality system at that time.

按照 FDA 认可的业界标准做法，AveXis 启动并界定了内部调查的范围，以在当时所呈现的情况下合理的方式进行。第一阶段，AveXis 聘请外部法律顾问牵头开展独立调查。之所以认为有此必要，是因为作为指控对象的两名高管仍是 AveXis 的重要人物，有可能影响和阻碍调查。鉴于指控涉及数据操纵，公司希望确保关键证据得到保全并可供进行全面技术审查。为此，在该初始阶段，作为指控对象的两名高管未被告知调查事宜。而且，由于两人均可访问质量体系，且正常情况下会被告知正式质量调查的启动，AveXis 当时选择不通过其质量体系启动正式的不符合项调查。

D. The Initial Investigation Phase

D. 初始调查阶段

Immediately upon learning of what was then an allegation of data manipulation, AveXis launched an internal investigation on March 14, 2019, led by senior officials from AveXis HR, Quality, and Legal, to fully understand the allegations and determine their merit, and to assess the veracity of the claims and potential scope of the data manipulation. AveXis personnel immediately contacted the individual who made the allegations, but were informed that the individual was unavailable until March 26, 2019. AveXis personnel pursued other initial investigational steps, including the development of an investigation plan, gathering necessary materials, preparing the necessary Upjohn warnings, and additional investigational activities. The individual who reported the allegations was interviewed on March 26, 2019. After conducting the interview and completing a thorough review of the testing records described by the reporter, AveXis determined that the allegations merited further investigation and informed Novartis on March 28, 2019.

在获悉当时尚属指控性质的数据操纵信息后，AveXis 于 2019 年 3 月 14 日立即启动内部调查，由 AveXis 人力资源、质量和法律部门的高级官员牵头，以全面了解指控并评估其依据，同时评估主张的真实性及数据操纵的潜在范围。AveXis 人员立即联系了提出指控的个人，但被告知该人要到 2019 年 3 月 26 日才有空。AveXis 人员开展了其他初步调查步骤，包括制定调查计划、收集必要材料、准备必要的 Upjohn 警告以及开展其他调查活动。2019 年 3 月 26 日，调查人员对举报人进行了访谈。在完成访谈并对举报人所描述的检验记录进行全面审查后，AveXis 认定该指控值得进一步调查，并于 2019 年 3 月 28 日通知了诺华。

For this phase of the investigation, an external law firm was then engaged to conduct an internal investigation into the allegations, on April 3, 2019. Because the allegations involved two founders who were still senior executives and fixtures at AveXis, and because the allegations involved data manipulation, this initial internal investigation was led by external counsel to ensure that key evidence was preserved, efficiently gathered, and made available for a thorough technical review without interference from the two implicated senior AveXis executives.

2019 年 4 月 3 日，公司在该调查阶段聘请了一家外部律师事务所对指控开展内部调查。由于指控涉及两名仍是 AveXis 高级管理人员和重要人物的创始人，且指控涉及数据操纵，此次初始内部调查由外部法律顾问牵头，以确保关键证据得到保全、高效收集，并可供进行全面技术审查，且不受两名涉案的 AveXis 高级管理人员的干扰。

records concerning the life history of individual mice and comparison of those records to entries on hundreds of spreadsheets. To accomplish this, we estimate that more than 2,000 hours were spent collectively by the investigation team from the engagement of the external counsel until the start of the non-conformance investigation phase discussed below. When discrepancies were identified, technical experts were required to assess the discrepancies to determine whether they had any impact on the results of the underlying IVRPA studies, batch release decisions, and clinical data that may have been generated through use of those batches. In each case, these technical reviews found that the data manipulation issues had no impact on patient safety or product efficacy or quality.

此外，由于涉案高级管理人员不予配合并断然否认指控——这一状况持续至今——调查被显著拉长。因此需要投入大量资源来审查数以千计的手写和电子记录，这些记录涉及每只小鼠的生命历程，并将这些记录与数百张电子表格中的条目进行比对。为此，我们估计，从聘请外部法律顾问到下文所述不符合项调查阶段开始，调查团队累计投入了 2,000 多个小时。发现差异后，需要技术专家评估这些差异，以确定其是否对基础 IVRPA 研究的结果、批次放行决定以及因使用这些批次而可能产生的临床数据有任何影响。在每种情况下，这些技术审查均发现，数据操纵问题对患者安全或产品疗效或质量没有影响。

This phase of the investigation consisted primarily of four components and was intended to gather the facts and determine if the allegations could be corroborated or disproved. The four components included:

该调查阶段主要包括四个组成部分，旨在收集事实并确定指控能否得到证实或被推翻。四个组成部分包括：

Interviews of key AveXis employees;

• 对 AveXis 关键员工的访谈；

Analysis of the underlying data to determine if there were unexplained discrepancies in the data referenced in the allegations (between data recorded on the mouse “cage” card and the individual mouse data sheets used in the IVRPA);

• 对基础数据进行分析，以确定指控中所提及的数据是否存在无法解释的差异（小鼠“笼卡”上记录的数据与 IVRPA 中使用的各小鼠单独数据单之间的差异）；

Review of tens of thousands of documents and electronic records from relevant AveXis employees; and

• 审查相关 AveXis 员工的数万份文件和电子记录；以及

An impact assessment conducted by technical experts to determine the impact of any discrepancies identified on the results of the underlying IVRPA studies, batch release decisions, or clinical data that may have been generated through use of those batches, as well as the impact of any data discrepancies on patient safety, product efficacy, or quality.

• 由技术专家开展影响评估，以确定所发现的任何差异对基础 IVRPA 研究结果、批次放行决定或因使用这些批次而可能产生的临床数据的影响，以及任何数据差异对患者安全、产品疗效或质量的影响。

Thus, the initial phase of the internal investigation focused on confirming the allegations, and involved a number of time-intensive steps and significant resources, including:

因此，内部调查的初始阶段侧重于核实指控，涉及多项耗费时间的步骤和大量资源，包括：

Preparing an investigation plan;

• 制定调查计划；

Reviewing inspectional logs and observations from FDA inspections, non-conformance reports (NCRs), and regulatory documents from the BLA file in order to understand the allegations and their potential implications;

• 审查 FDA 现场检查的检查日志和检查发现项、不符合项报告（NCR）以及 BLA 档案中的监管文件，以了解指控及其潜在影响；

Reviewing background materials to fully understand the potency assays and how they were conducted;

• 审查背景材料，以全面了解效力试验及其开展方式；

Reviewing relevant policies and procedures, including with regard to documentation of data and the conduct of the potency assays, in order to understand potential discrepancies in the data;

• 审查相关政策和程序，包括与数据记录和效力试验实施相关的政策和程序，以了解数据中可能存在的差异；

Preparing for and conducting interviews with key individuals;

• 准备并开展对关键人员的访谈；

Identifying and obtaining the relevant data and documents for analysis; and

• 识别并获取用于分析的相关数据和文件；以及

Data analysis and preparation of spreadsheets comparing the sources of the potency assay data.

• 进行数据分析并编制电子表格，比对效力试验数据的各来源。

Again, at every point of the initial internal investigation, the assessment of the technical experts was that there was no impact on patient safety or product efficacy or quality. Moreover, during this time, AveXis was actively engaged in the investigation and in monitoring the results of the investigation. The initial investigation and interviews demonstrated that the two senior AveXis executives alleged to have been responsible could not offer a credible explanation for revisions to and inconsistencies in the data, and they were placed on administrative leave on May 3, 2019 to ensure that they had no access to data, systems, or staff. These two senior AveXis executives were later terminated for cause on August 13, 2019. 5 As a reminder, this phase of the investigation took 39 working days.

同样，在初始内部调查的每一个节点，技术专家的评估均为：对患者安全或产品疗效或质量没有影响。此外，在此期间，AveXis 积极参与调查并监测调查结果。初始调查和访谈表明，被指控负有责任的两名 AveXis 高级管理人员无法对数据修改和数据不一致之处作出可信解释，二人于 2019 年 5 月 3 日被安排行政停职，以确保其无法接触数据、系统或员工。这两名 AveXis 高级管理人员后来于 2019 年 8 月 13 日因故被解雇。5 提醒一下，该调查阶段用时 39 个工作日。

E. The Non-Conformance Investigation Phase

E. 不符合项调查阶段

Following the initial investigation’s determination that the allegations were credible and merited continued investigation, as a second phase, a non-conformance (NC) investigation was initiated on May 8, 2019 to further investigate the issues, including conducting a comprehensive rootcause analysis, conducting a more detailed risk assessment, and developing and implementing corrective and preventive actions to address the data integrity issues. A non-conformance report—NCR-1922—was opened in AveXis’s ACE document management system on May 15, 2019 to document the investigation activities. A team consisting of AveXis senior Quality leadership, AveXis San Diego Quality Assurance and Quality Control, and Novartis GxP Compliance conducted the NC investigation.

在初始调查认定指控可信且值得继续调查之后，作为第二阶段，公司于 2019 年 5 月 8 日启动了一项不符合项（NC）调查，以进一步调查相关问题，包括开展全面的根本原因分析、进行更详细的风险评估，以及制定和实施纠正和预防措施以解决数据完整性问题。2019 年 5 月 15 日，AveXis 的 ACE 文件管理系统中开启了一份不符合项报告——NCR-1922——以记录调查活动。NC 调查由 AveXis 高级质量领导层、AveXis 圣迭戈质量保证和质量控制部门以及诺华 GxP 合规部门组成的团队开展。

The NC investigation—which remains open—is focused on concerns relating to in vivo mouse studies 1-10, which implicated IVRPA data for four product lots: Lot NCHAAV95MN0613 stability data at the 3-month time point; Lot 600307 release data; Lot 600729 release data; and Lot 600539 release data. Three of these lots had been consumed or were expired, with all

NC 调查（目前仍在进行中）聚焦于与体内小鼠研究 1-10 相关的关切，该等研究牵涉四个产品批次的 IVRPA 数据：批次 NCHAAV95MN0613 3 个月时间点的稳定性数据；批次 600307 的放行数据；批次 600729 的放行数据；以及批次 600539 的放行数据。其中三个批次已被使用耗尽或已过期，其余

5 As noted in the public statements of his counsel, one of these executives continues to deny any wrongdoing.

5 正如其中一名高管的律师的公开声明所述，该高管继续否认任何不当行为。

material in the remaining lot placed on hold at the AveXis Libertyville, Illinois site as of May 5, 2019.

批次中的物料自 2019 年 5 月 5 日起在 AveXis 伊利诺伊州利伯蒂维尔厂区被置于待验（扣留）状态。

AveXis continued to follow standard industry practice, operating procedures, and precedent, all of which supported completion of the preliminary NC investigation before submission of a report to the FDA given that there was no evidence of impact on patient safety, product efficacy or quality.

AveXis 继续遵循业界标准做法、操作规程和先例。鉴于没有证据表明对患者安全、产品疗效或质量有影响，这些做法均支持在向 FDA 提交报告前先完成初步 NC 调查。

The NC investigation proceeded according to the following methodology:

NC 调查按照以下方法进行：

Review of all possible sources of data pertaining to the assay in question, such as GMP data sheets for the IVRPA, original records used in the management of animals (cage cards), spreadsheets created by employees to hold data and calculate results of the assays, and laboratory logbooks;

• 审查与所涉试验相关的所有可能的数据来源，例如 IVRPA 的 GMP 数据单、用于动物管理的原始记录（笼卡）、员工为保存数据和计算试验结果而创建的电子表格，以及实验室日志；

Identification of possible data discrepancies;

• 识别可能存在的数据差异；

Determination of possible alternative values for reported relative potency for lots involved in studies implicated;

• 确定受牵涉研究中所涉批次已报告相对效力的可能替代值；

Evaluation of clinical studies potentially impacted by data integrity allegations;

• 评估可能受数据完整性指控影响的临床研究；

Evaluation of regulatory impact;

• 评估监管影响；

Interviews with staff and management; and

• 对员工和管理层进行访谈；以及

Recalculation of the results and material impact assessments.

• 对结果进行重新计算并进行实质性影响评估。

Comparative reviews of data sources and interviews have confirmed that there were multiple instances of discrepancies of data used for in vivo studies 1-10. In order to either verify existing values, or to determine data values with an increased level of reliability for studies 1-10, a protocol was developed to verify the raw data and to establish procedures for evaluating such discrepancies. Employing this new protocol, raw data were revised when primary records supported revision, potency was recalculated for the IVRPA studies 1-10, and the resulting values from these studies would be annotated as having reduced validity, and that these results should be reported to the appropriate regulatory agencies, which was subsequently done in a timely manner.

对数据来源的比对审查和访谈证实，用于体内研究 1-10 的数据存在多处差异。为核实现有数值，或以更高可靠性确定研究 1-10 的数据值，制定了一份方案以核实原始数据并建立评估此类差异的程序。采用该新方案后，当原始记录支持修改时即对原始数据进行修改，对 IVRPA 研究 1-10 的效力进行了重新计算，所得数值将被标注为有效性降低，并且这些结果应报告给相应的监管机构——随后已及时照此办理。

NCR-1922’s impact assessment further found that despite the IVRPA data concerns, the original clinical conclusions were not in question given the overall technical assessment of all QC release

testing, including the in vitro potency a ssay, and the consistent performance of AVXS-101 in the clinical trials. Specifically, during the development of the product and prior to submission of the BLA, FDA previously r aised concern regarding the variability of the in vivo data from studies 1- 10 and requested clinical results from ongoing studies. FDA also requested in vitro relative potency data to support the clinical profile of Zolgensma®. Accordingly, while studies 1-10 were used in the development of the product, these data would not have been relied upon to reach any clinical determinations given this variability.

NCR-1922 的影响评估进一步认定，尽管存在 IVRPA 数据方面的关切，但鉴于对所有 QC 放行检验（包括体外效力试验）的总体技术评估以及 AVXS-101 在临床试验中的一致性表现，原有临床结论并不存疑。具体而言，在产品开发期间及提交 BLA 之前，FDA 曾对研究 1-10 的体内数据变异性提出关切，并要求提供进行中研究的临床结果。FDA 还要求提供体外相对效力数据，以支持 Zolgensma® 的临床特征。因此，尽管研究 1-10 在产品开发中得到使用，但鉴于这种变异性，这些数据本不会被依赖来作出任何临床判定。

Finally, because the NC investigation was focused on the immediate allegation and identified data integrity issues, AveXis engaged independent third-party cGMP consultants, includingandas described in Section II, below, to expand AveXis’s data integrity investigation.

最后，由于 NC 调查聚焦于眼前的指控及已识别的数据完整性问题，AveXis 聘请了独立的第三方 cGMP 顾问（包括和，详见下文第二部分），以扩大 AveXis 的数据完整性调查。

F. AveXis Notifies FDA

F. AveXis 通知 FDA

The timing of AveXis’s self-disclosure to FDA was based in part on the fact that the investigation into the data integrity manipulation issues was highly complex, and involved review of a significant amount of data, including manual comparisons of raw data on the individual mouse data sheets and cage cards, and identification of technical experts to assess the impact. In addition to the sheer volume of data to be reviewed, the investigation required distinguishing between discrepancies that were attributable to a lack of clear instructions in the relevant procedures and those that were the result of deliberate wrongdoing. For example, discrepancies in another investigation were ultimately a ttributed to a lack of clarity as to whether to include the day of birth in the survival days calculation. In addition, just as with the initial phase of the, throughout the NC investigation, the assessment of technical experts was that there was no impact on patient safety or product efficacy or quality. Accordingly, AveXis selfreported the matter to FDA once the interim NCR was issued. The interim investigation report— interim NCR-1922—was issued on June 27, 2019. The next day, June 28, 2019, AveXis selfreported to FDA the allegations and the interim results of its investigation via submission through the electronic gateway. The lead clinical reviewer was informed by phone just prior to electronic submission. The interim results of the investigation were also provided to the regulatory authorities in all jurisdictions where applications for marketing of Zolgensma® had been made, including two jurisdictions where the application is still pending.

AveXis 向 FDA 自我披露的时机，部分基于以下事实：对数据完整性操纵问题的调查高度复杂，涉及审查大量数据，包括人工比对各小鼠单独数据单和笼卡上的原始数据，以及确定评估影响的技术专家。除待审查的数据量庞大之外，调查还需要区分可归因于相关程序缺乏明确指令的差异与蓄意不当行为造成的差异。例如，另一项调查中的差异最终被归因于生存天数计算中是否应包括出生日期这一问题不够明确。此外，与初始阶段一样，在整个 NC 调查过程中，技术专家的评估均为对患者安全或产品疗效或质量没有影响。因此，AveXis 在中期 NCR 出具后即向 FDA 自我报告了此事。中期调查报告——中期 NCR-1922——于 2019 年 6 月 27 日出具。次日，即 2019 年 6 月 28 日，AveXis 通过电子网关提交的方式向 FDA 自我报告了指控及其调查的中期结果。在电子提交之前，AveXis 通过电话告知了首席临床审评员。调查的中期结果也已提供给所有已提交 Zolgensma® 上市申请的辖区（包括两个申请仍在审的辖区）的监管机构。

G. Additional b) (4)

G. 其他(b)(4)

As part of the investigation, (b) (4)

作为调查的一部分，(b)(4)

(b) (4)

(b)(4)

To further investigate investigation was ongoing. As previously communicated to FDA, based on information obtained pursuant to the investigation, AveXis concluded that it was likely that Although AveXis’s investigation was ongoingduring theJuly/Augustinspection, AveXisprovided adraftcopyofNCR-2018 to theFDAinvestigators,who requested and retained acopyofthedraft investigation reportand related documentation.AveXis will

为进一步调查，调查仍在进行中。正如先前向 FDA 通报的那样，根据调查获得的信息，AveXis 得出结论，的可能性较大。尽管在 7/8 月检查期间 AveXis 的调查仍在进行中，AveXis 还是向 FDA 检查员提供了一份 NCR-2018 的草稿副本；检查员索取并保留了该调查草稿报告及相关文件的副本。AveXis 将

H. FDA Inspects AveXis

H. FDA 检查 AveXis

Subsequent to AveXis’s self-reporting of the data integrity issues and the interim results of its investigation to FDA, FDA conducted an inspection of AveXis’s San Diego site from July 24 to August 2, 2019 based on the company’s June 28, 2019, submission. This inspection resulted in the issuance of a five-item Form FDA 483, which is addressed in Section III, below.

在 AveXis 向 FDA 自我报告数据完整性问题及其调查中期结果之后，FDA 依据公司 2019 年 6 月 28 日的提交材料，于 2019 年 7 月 24 日至 8 月 2 日对 AveXis 圣迭戈厂区进行了现场检查。此次检查导致签发了一份含五项检查发现项的 FDA 483 表，该 483 表在下文第三部分中予以回复。

I. FDA Makes Statement Regarding the Data Issues—Patient Safety and Product Efficacy not Implicated

I. FDA 就数据问题发表声明——患者安全与产品疗效未受影响

On August 6, 2019, the Director of FDA’s Center for Biologics Evaluation and Research (CBER) issued a public statement about the data accuracy issues relating to the product testing

2019 年 8 月 6 日，FDA 生物制剂评价与研究中心（CBER）主任就与产品检验相关的数据准确性问题发表公开声明

during the development of Zolgensma®, recognizing that its concerns at the time were “limited to only a small portion of the product testing data that was contained in the marketing application.”6 FDA stated that at this stage the data manipulation issues self-reported by AveXis do “not change the agency’s positive assessment of the information from the human clinical trials that were conducted as part of the development program. The totality of the evidence demonstrating the product’s effectiveness and its safety profile continues to provide compelling evidence supporting an overall favorable benefit-risk profile.” FDA expressed that it “remains confident that Zolgensma should remain on the market.”7

该声明承认，其当时的关切“仅限于上市申请中所载产品检验数据的一小部分”。6 FDA 表示，在此阶段，AveXis 自我报告的数据操纵问题“不会改变该机构对作为开发计划一部分开展的人体临床试验信息的积极评价。证明产品有效性及其安全性特征的证据总体继续提供令人信服的证据，支持总体获益-风险特征良好。” FDA 表示，其“仍然确信 Zolgensma 应继续留在市场上”。7

6 Statement on data accuracy issues with recently approved gene therapy (Aug. 6, 2019), https://www.fda.gov/news-events/press-announcements/statement-data-accuracy-issues-recentlyapproved-gene-therapy. 7 Id.

6 《关于近日获批基因治疗药物数据准确性问题的声明》（2019 年 8 月 6 日），https://www.fda.gov/news-events/press-announcements/statement-data-accuracy-issues-recently-approved-gene-therapy。 7 同上。

II. The Compliance Action Plan

二、合规行动计划

AveXis’s goal is to ensure that a robust culture of quality and sustainable GxP compliance exist at all of its sites. Accordingly, in light of the data integrity issues discussed in Section I, above, and the 483, AveXis, with significant input and oversight from Novartis, has developed—and is in the process of implementing—a company-wide Compliance Action Plan (the CAP).8 As detailed below, the core elements of the CAP are (A) the Quality Integration Plan and (B) the Data Integrity Remediation Plan. AveXis is confident the CAP, together with the actions discussed in AveXis’s specific responses to the 483 observations, will fully address any data integrity and broader GxP compliance concerns raised in the 483.

AveXis 的目标是确保其所有厂区均建立起强大的质量文化和可持续的 GxP 合规。因此，鉴于上文第一部分所述的数据完整性问题及 483，AveXis 在诺华的强有力意见输入和监督下，已制定并正在实施一项全公司范围的合规行动计划（CAP）。8 如下文详述，CAP 的核心要素为（A）质量整合计划与（B）数据完整性整改计划。AveXis 相信，CAP 连同 AveXis 对各 483 检查发现项的具体回复中所讨论的措施，将全面解决 483 中提出的任何数据完整性及更广泛的 GxP 合规关切。

A. The Quality Integration Plan

A. 质量整合计划

AveXis recognizes that the 483 highlights areas for improvement in the company’s quality systems and quality culture. Accordingly, the CAP seeks to make enhancements in these areas, and one key aspect of strengthening AveXis’s quality systems and quality culture is by further integrating the AveXis sites into Novartis’s global quality network. The plan for doing so is set forth below.

AveXis 认识到，483 凸显了公司质量体系和质量文化中需要改进的领域。因此，CAP 力求在这些领域作出改进，而加强 AveXis 质量体系和质量文化的一个关键方面，是将 AveXis 各厂区进一步整合到诺华的全球质量网络中。相关计划如下所述。

As FDA is aware and as stated above, AveXis was acquired by Novartis in May 2018. In early 2019, Novartis began the process of more closely aligning the AveXis quality organization with the Novartis global quality network. Until recently, Novartis’s alignment with AveXis focused primarily on establishing and defining the lines of communication between the AveXis and Novartis quality organizations from a functional perspective.

如 FDA 所知且如上所述，AveXis 于 2018 年 5 月被诺华收购。2019 年初，诺华开始着手使 AveXis 质量组织与诺华全球质量网络更加紧密地保持一致。直至不久前，诺华与 AveXis 的对齐主要侧重于从职能角度建立和界定 AveXis 与诺华质量组织之间的沟通渠道。

In light of the data integrity issues discussed in Section I, above, and the 483, Novartis senior leadership has made the decision to completely integrate AveXis into Novartis’s global quality network and will accelerate several key integration actions to ensure that this integration occurs quickly and effectively. Novartis understands the need to further instill a culture of quality in AveXis’s operations, and that creating and sustaining such a culture is a complex task requiring a structured plan, engagement of personnel at every level, and visible leadership support. In this regard, the Quality Integration Plan is attached at Exhibit 1.

鉴于上文第一部分所述的数据完整性问题及 483，诺华高级领导层已决定将 AveXis 完全整合进诺华全球质量网络，并将加快若干关键整合行动，以确保整合快速、有效地实现。诺华理解有必要在 AveXis 的运营中进一步灌输质量文化，也理解建立和维持这样一种文化是一项复杂任务，需要有结构化的计划、各层级人员的参与以及高层领导可见的支持。就此而言，质量整合计划见附件 1。

These actions include integrating the AveXis quality organization into the Novartis global quality organization from an operational perspective. As a result of this restructuring of the relationship between the AveXis and Novartis quality organizations, the AveXis quality organization will formally become a part of the Novartis quality organization. As such, the

这些行动包括从运营角度将 AveXis 质量组织整合进诺华全球质量组织。通过重组 AveXis 与诺华质量组织之间的关系，AveXis 质量组织将正式成为诺华质量组织的一部分。因此，

8 The enhancements detailed in the CAP, including the Quality Integration Plan, will also be implemented at AveXis’s two under-construction sites in Durham, NC and Longmont, CO as those sites come online.

8 CAP 中详述的各项改进（包括质量整合计划）也将在 AveXis 位于北卡罗来纳州达勒姆和科罗拉多州朗蒙特的两个在建厂区投入运营后予以实施。

AveXis Data Integrity Officer, for example, will be a part of the Novartis data integrity community. Similarly, Novartis’s global quality management systems (QMS) will be implemented at AveXis to ensure that the AveXis quality organization is using the same QMS.

例如，AveXis 数据完整性负责人将成为诺华数据完整性社区的一员。同样，诺华的全球质量管理体系（QMS）将在 AveXis 实施，以确保 AveXis 质量组织使用相同的 QMS。

In conjunction with this integration, Novartis willperformanorganizationalassessmentoftheAveXisqualityorganization with thegoalofcompletelyaligningthestructureoftheAveXisqualityorganization with thestructureofNovartis’s qualityorganization.Pleasenotethatthisorganizationalstructureassessmentis separatefromtheorganizationalcapabilitiesassessmentdiscussed in theresponseto Observation 1, which willbeperformed byand will assess the effectiveness and capabilities of the AveXis quality organization from a resources and staffing perspective.

结合这一整合，诺华将对 AveXis 质量组织进行组织评估，目标是使 AveXis 质量组织的结构与诺华质量组织的结构完全对齐。请注意，此次组织结构评估不同于对检查发现项 1 的回复中所讨论的组织能力评估；后者将由开展，从资源和人员配置角度评估 AveXis 质量组织的有效性和能力。

AveXis has also hired senior executive compliance personnel with previous Novartis experience to facilitate the further integration of AveXis into the Novartis organization. Additionally, the AveXis Head of QA Compliance will sit on the Novartis QA Compliance extended leadership team.

AveXis 还聘用了具有诺华工作经验的资深合规管理人员，以促进 AveXis 进一步融入诺华组织。此外，AveXis 质量保证合规负责人将加入诺华质量保证合规扩大领导团队。

At a procedural level, Novartis will conduct gap assessments of AveXis’s key quality policies and procedures against Novartis’s corresponding global quality policies and procedures to ensure alignment. Following this gap assessment, Novartis will oversee the revision and implementation of any AveXis policies or procedures, as needed. Novartis has already identified several procedures for revision, including POL-007, Data Integrity Policy, SOP-087, QC Laboratory Documentation, SOP-003, Good Documentation Practices, SOP-365, Notification to Management, and SOP-005, Non-Conformance and CAPA System. A number of Novartis procedures, constituting Novartis’s Core Quality & Compliance Systems, have been identified for expansion to AveXis. These include procedures relating to the process for management escalation, data and documentation, and pharmacovigilance.

在程序层面，诺华将对 AveXis 的关键质量方针和程序与诺华相应的全球质量方针和程序进行差距评估，以确保对齐。差距评估之后，诺华将视需要监督任何 AveXis 方针或程序的修订和实施。诺华已确定多份需要修订的程序，包括 POL-007《数据完整性方针》、SOP-087《QC 实验室文件记录》、SOP-003《良好记录规范》、SOP-365《向管理层报告》以及 SOP-005《不符合项与 CAPA 体系》。诺华已确定将其若干程序（构成诺华核心质量与合规体系）扩展至 AveXis。这些程序包括与管理层升级上报流程、数据和文件记录以及药物警戒相关的程序。

Novartis will also conduct baseline audits at the AveXis sites to assist with the determination of which integration activities should be prioritized based on the audit results and Novartis’s risk classification of the audit results. See Exhibit 2.

诺华还将在 AveXis 各厂区开展基线审计，以根据审计结果及诺华对审计结果的风险分级，协助确定哪些整合活动应优先开展。见附件 2。

In addition to these in-process organizational, procedural, and operational changes, Novartis is in the process of establishing and rolling out the Novartis “SpeakUp” program across AveXis. Novartis SpeakUp will provide AveXis employees a clearly defined pathway for reporting concerns regarding potential misconduct or fraud. Reports received through the Novartis SpeakUp portal are evaluated by Novartis’s SpeakUp Office, an independent office within Novartis. All AveXis employees will be trained on how to report suspected misconduct, fraud, and other concerns through the Novartis SpeakUp portal, and on the importance of immediately reporting suspected misconduct or fraud through the Novartis SpeakUp portal. Once fully

除这些正在进行中的组织、程序和运营变革外，诺华正在 AveXis 建立并推广诺华“SpeakUp”计划。诺华 SpeakUp 将为 AveXis 员工提供一条界定清晰的途径，用于报告有关潜在不当行为或欺诈的关切。通过诺华 SpeakUp 门户收到的报告由诺华内部的独立机构——诺华 SpeakUp 办公室——进行评估。所有 AveXis 员工都将接受培训，了解如何通过诺华 SpeakUp 门户报告涉嫌不当行为、欺诈及其他关切，以及立即通过诺华 SpeakUp 门户报告涉嫌不当行为或欺诈的重要性。一旦全面

deployed, Novartis SpeakUp will help improve transparency, provide an independent misconduct reporting pathway for AveXis employees, and ensure that Novartis has full visibility into any reports of misconduct or fraud at AveXis.

部署完成，诺华 SpeakUp 将有助于提高透明度，为 AveXis 员工提供独立的不当行为报告途径，并确保诺华对 AveXis 任何不当行为或欺诈报告拥有充分的可见性。

In addition, AveXis has approved Novartis quality incident SOP 7038922, Quality/GxP Escalation and Incident Management, to ensure that, going forward, potential quality issues, including any issues relating to or potentially relating to the integrity of quality data generated at AveXis’s sites, are timely escalated to senior quality leadership. Implementation of this procedure is underway.

此外，AveXis 已批准诺华质量事件 SOP 7038922《质量/GxP 升级上报与事件管理》，以确保今后潜在的质量问题（包括与 AveXis 各厂区生成的质量数据完整性相关的或可能相关的任何问题）得以及时上报至高级质量领导层。该程序正在实施中。

Novartis is confident that the integration actions detailed above will result in significant, sustainable improvement across AveXis’s quality systems. As noted in the Cover Letter, AveXis will provide periodic updates to FDA on the status of its ongoing activities and will also keep FDA apprised of any new actions related to integration that are developed and implemented.

诺华相信，上文详述的整合行动将为 AveXis 的质量体系带来显著、可持续的改进。如封面函所述，AveXis 将定期向 FDA 通报其正在开展的活动的进展，并将随时告知 FDA 任何新制定和实施的与整合相关的措施。

B. The Data Integrity Remediation Plan

B. 数据完整性整改计划

AveXis fully recognizes the importance of ensuring the accuracy, reliability, and traceability of quality data, including all data submitted to FDA as well as all data generated pursuant to commercial manufacturing activities. Accordingly, as part of the CAP, AveXis, with support from the Novartis global quality organization, has developed and is implementing a Data Integrity Remediation Plan to ensure that the data integrity issues discussed in Section I, above, and the issues identified in the 483 are fully investigated and addressed. The Data Integrity Remediation Plan will be implemented over the coming weeks and months with the goal of assuring FDA that AveXis has broadly addressed FDA’s data integrity concerns, and AveXis will update the agency as progress is made and on relevant findings. The Data Integrity Remediation Plan is part of overarching PLAN-313 Version 4.0, AveXis Data Integrity Plan, see Exhibit 3, which contains additional actions to improve data integrity standards throughout AveXis.

AveXis 充分认识到确保质量数据准确性、可靠性和可追溯性的重要性，其中包括提交给 FDA 的所有数据以及依据商业生产活动生成的所有数据。因此，作为 CAP 的一部分，AveXis 在诺华全球质量组织的支持下，已制定并正在实施一项数据完整性整改计划，以确保上文第一部分所述的数据完整性问题及 483 中识别的问题得到充分调查和解决。数据完整性整改计划将在未来数周和数月内实施，目标是让 FDA 确信 AveXis 已广泛解决 FDA 的数据完整性关切；AveXis 将随着进展取得和相关调查结果的产生向该机构进行更新。数据完整性整改计划是总纲性文件 PLAN-313 第 4.0 版《AveXis 数据完整性计划》的一部分（见附件 3），该计划载有在整个 AveXis 提高数据完整性标准的其他措施。

Based on AveXis’s investigations to date, the data integrity issues discussed in Section I, above, and the examples noted in the 483 appear to be limited to a few discrete incidents where (1) due to a lack of GxP experience, a lack of understanding of the importance of data integrity and good documentation practices, and a lack of robust controls and oversight, documentation anomalies went unnoticed, and (2) two members of AveXis’s executive leadership team—both of whom have been terminated—either manipulated or pressured laboratory personnel to manipulate data. Additional root causes identified to date include a lack of a cultural emphasis on data integrity at the site, a lack of adequate training and real-time data recording, and a lack of a formal escalation policy for GxP issues. Further, as detailed below, AveXis is confident that the data

根据 AveXis 迄今为止的调查，上文第一部分所述的数据完整性问题及 483 中指出的实例似乎仅限于少数孤立事件，其中（1）由于缺乏 GxP 经验、对数据完整性和良好记录规范的重要性认识不足，以及缺乏强有力的控制和监督，文件记录异常未被发现；（2）AveXis 高管领导团队的两名成员——两人均已被解雇——要么亲自篡改数据，要么施压实验室人员篡改数据。迄今为止识别出的其他根本原因包括：厂区缺乏对数据完整性的文化重视、缺乏充分的培训和实时数据记录，以及缺乏正式的 GxP 问题升级上报方针。此外，如下文详述，AveXis 相信，上述及 483 中指出的数据

integrity issues discussed above and noted in the 483 do not impact the safety, efficacy, or quality of Zolgensma®.

完整性问题不会影响 Zolgensma® 的安全性、有效性或质量。

AveXis understands the significance of the data integrity issues discussed in Section I, above, and the 483 observations and is taking numerous actions to address them and prevent recurrence. The company would also note that prior to the start of the July/August 2019 inspection, numerous controls had already been implemented across the San Diego site to ensure the accuracy, reliability, and traceability of quality records and data. These include:

AveXis 理解上文第一部分所述数据完整性问题及 483 检查发现项的重要性，并正在采取多项措施加以解决和防止复发。公司还要指出，在 2019 年 7/8 月检查开始之前，圣迭戈厂区已经实施了大量控制措施，以确保质量记录和数据的准确性、可靠性和可追溯性。这些措施包括：

SOP-279, Computerized System Qualification and Validation, which sets forth the qualification and validation requirements for computerized systems used for GxP activities. These requirements ensure that GxP computerized systems perform as expected in accordance with predetermined specifications, user-defined requirements, and applicable FDA regulations, including 21 CFR Part 11.

• SOP-279《计算机化系统确认与验证》，规定了用于 GxP 活动的计算机化系统的确认和验证要求。这些要求确保 GxP 计算机化系统按照预定规格、用户定义的需求以及适用的 FDA 法规（包括 21 CFR 第 11 部分）如期运行。

Plan 313, Data Integrity Plan and Assessment, pursuant to which AveXis performed a global data integrity assessment of computerized systems used for GxP operations, including laboratory computerized systems, for adherence to ALCOA data integrity principles and 21 CFR Part 11 compliance.

• 计划 313《数据完整性计划与评估》，AveXis 据此对用于 GxP 运营的计算机化系统（包括实验室计算机化系统）进行了全球数据完整性评估，以考察其对 ALCOA 数据完整性原则的遵守情况及 21 CFR 第 11 部分的合规情况。

SOP-003, Good Documentation Practices, which provides that:

• SOP-003《良好记录规范》，其中规定：

o Falsification of records is strictly prohibited. Pursuant to SOP-003, falsification includes back dating or entering a future date; signing someone else’s name; signing a document or record before the activity is performed; signing for, witnessing, or verifying a step without witnessing or verifying the activity; copying and/or pasting scanned signatures for use as approval signatures; entering data/information not directly obtained, that did not occur, or that was not observed; entering data when testing was not performed, completed, or that is not reflective of the actual result obtained; and destroying or voiding original data or information without documenting such action.

o 严禁伪造记录。根据 SOP-003，伪造行为包括：倒填日期或填写未来日期；代签他人姓名；在活动执行之前签署文件或记录；未实际见证或核实某项活动即代为签署、见证或确认该步骤；复制和/或粘贴扫描签名用作批准签名；录入并非直接获得、并未发生或并未观察到的数据/信息；在检验未进行、未完成或录入结果不能反映实际所得结果的情况下录入数据；以及在未记录该行为的情况下销毁或使原始数据或信息失效。

o All data/information are to be recorded by the person who has performed the activity/task unless the document clearly indicates that information is being recorded by someone other than the performer AND the performer’s signature is also present.

o 所有数据/信息均应由执行该活动/任务的人员记录，除非文件明确表明信息由执行者以外的人员记录，且同时有执行者的签名。

o All entries must be made at the time tasks are performed. Records must indicate the date and/or time tasks were performed/recorded as indicated by specification, procedure, or record format.

o 所有记录必须在执行任务时同步作出。记录必须注明按规格、程序或记录格式要求执行/记录任务的日期和/或时间。

o Raw data must be retained in its entirety and original form, e.g. printouts of all attempts at system suitability (whether passing or not) OR all calibration attempts, including failures.

o 原始数据必须以完整和原始形式保留，例如系统适用性所有尝试的打印输出（无论合格与否），或所有校准尝试（包括失败的尝试）。

SOP-238, Data Integrity Controls, which provides that all data generated at AveXis must be accurate, legible, contemporaneous, original, and attributable (ALCOA). SOP-238 also prohibits deleting, manipulating, or modifying GxP data.

• SOP-238《数据完整性控制》，规定 AveXis 生成的所有数据必须准确（accurate）、清晰可读（legible）、同步记录（contemporaneous）、原始（original）且可归因（attributable）（ALCOA）。SOP-238 还禁止删除、操纵或修改 GxP 数据。

In addition, the investigators performed an extensivereviewofAveXis’s rawdata, includinginvivofunctionalitydataforallcommerciallots ofZolgensma®,in vivofunctionalityandin vitro relativepotencydataforalllots ofZolgensma®forwhich LotReleaseProtocolshavebeensubmitted to FDA, rawdataforalllotsofAVXS-101 tested usingSOP-346 and SOP-347, method validation dataforSOP-346, In-vivoFunctionalityTestusing a SingleDoseAVXS-101 in SMN∆7 Mouse Model, and SOP-347, Determination ofIn-vitroRelativePotencyforAVXS-101 Drug Substanceand Drug Product, and therawdata, includingaudittrails,fortesting performed pursuant to

此外，检查员对 AveXis 的原始数据进行了广泛审查，包括 Zolgensma® 所有商业批次的体内功能数据、已向 FDA 提交批放行方案（Lot Release Protocols）的所有 Zolgensma® 批次的体内功能和体外相对效力数据、使用 SOP-346 和 SOP-347 检验的所有 AVXS-101 批次的原始数据、SOP-346《在 SMNΔ7 小鼠模型中使用单剂量 AVXS-101 的体内功能试验》和 SOP-347《AVXS-101 原液和制剂体外相对效力的测定》的方法验证数据，以及依据进行的检验的原始数据（包括审计追踪）。

AveXis also recognizes that the 483 identifies several gaps with respect to the company’s data integrity and documentation practices, including comprehensiveness and robustness of the controls noted above. AveXis’s Data Integrity Remediation Plan, set forth below, will address these gaps and any additional gaps identified pursuant to AveXis’s implementation of the CAP.

AveXis 还认识到，483 指出了公司在数据完整性和文件记录规范方面的若干差距，包括上述控制措施的全面性和有效性（robustness）。AveXis 的数据完整性整改计划（如下所述）将解决这些差距以及 AveXis 在实施 CAP 过程中识别出的任何其他差距。

The Data Integrity Remediation Plan includes the following elements:

数据完整性整改计划包括以下要素：

A comprehensive investigation into the extent of the inaccuracies in data records and reporting, including:

• 对数据记录和报告不准确的程度进行全面的调查，包括：

o A detailed investigation protocol and methodology, including a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment;

o 详细的调查方案和方法，包括评估将覆盖的所有实验室、生产操作和系统的汇总；

o Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies.

o 对现任和前任员工进行访谈，以确定数据不准确的性质、范围和根本原因。

o An assessment of the extent of data integrity deficiencies at the San Diego site; and

o 对圣迭戈厂区数据完整性缺陷程度进行评估；以及

o A comprehensive retrospective evaluation of the nature of the data integrity deficiencies.

o 对数据完整性缺陷的性质进行全面回顾性评估。

A risk assessment of the potential effects of the observed data integrity deficiencies on the quality of Zolgensma®, the data submitted to FDA in the Zolgensma® BLA (BLA 125694), and AveXis’s other investigational products.

• 对所观察到的数据完整性缺陷对 Zolgensma® 质量、Zolgensma® BLA（BLA 125694）中提交给 FDA 的数据以及 AveXis 其他在研产品潜在影响的风险评估。

A management strategy establishing AveXis’s global corrective action and preventive action plan, including:

• 制定 AveXis 全球纠正措施和预防措施计划的管理策略，包括：

o A detailed corrective action plan describing AveXis’s strategy for ensuring the reliability and completeness of quality data, including data submitted to FDA;

o 详细的纠正措施计划，说明 AveXis 确保质量数据（包括提交给 FDA 的数据）可靠性和完整性的策略；

o Interim measures to protect patients and to ensure the quality of Zolgensma®; and

o 保护患者和确保 Zolgensma® 质量的中期措施；以及

o Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, quality culture, and human resources (e.g., training, staffing improvements) designed to ensure data integrity.

o 描述旨在确保数据完整性的任何整改工作以及对程序、流程、方法、控制措施、系统、管理监督、质量文化和人力资源（例如培训、人员配置改进）的改进的长期措施。

As discussed in the sections below, a number of corrective and preventive actions (CAPAs) have already been implemented to address the 483 observations, and the company will be implementing numerous additional CAPAs over the coming weeks and months. The effectiveness of these and any additional CAPAs implemented pursuant to the CAP will be verified by Novartis’s global quality department and by third parties. AveXis will provide periodic updates to FDA on the status of the actions undertaken pursuant to the CAP.

如下文各节所述，为应对 483 检查发现项，若干纠正和预防措施（CAPA）已经实施，公司还将在未来数周和数月内实施大量其他 CAPA。这些 CAPA 及依据 CAP 实施的任何其他 CAPA 的有效性将由诺华全球质量部门和第三方进行验证。AveXis 将定期向 FDA 通报依据 CAP 所采取措施的进展情况。

Third-Party Investigation

第三方调查

While AveXis remains confident in the thoroughness of the investigation activities and findings discussed in Section I, above, the company engagedan independent third-party cGMP consultant, to perform an assessment of the data manipulation and documentation issues noted in NCR-1922, which has been expanded to cover the issues noted in the 483assessment oftheSanDiegosite’s dataintegritycontrols and oversightwas originallyscheduledto starton July29, 2019, butwas rescheduled dueto theFDAinspection.assessment is now scheduled to begin on September 3, 2019.

尽管 AveXis 对上文第一部分所述调查活动和调查结果的彻底性仍然充满信心，公司仍聘请了独立的第三方 cGMP 顾问，对 NCR-1922 中指出的数据操纵和文件记录问题进行评估；该评估的范围已扩大，以涵盖 483 中指出的问题。对圣迭戈厂区数据完整性控制和监督的评估原定于 2019 年 7 月 29 日开始，但因 FDA 现场检查而改期。的评估现已定于 2019 年 9 月 3 日开始。

In light of the 483, the scope ofassessment has been expanded to coverAveXis’sdataintegritycontrolsand oversightmorebroadly, includingdocumentation practicecontrols;controls relatingto theissuanceofcontrolled forms and documents;computerized systemscontrols;processes forreviewingdatapursuantto release, includingthescopeofQAreviewofelectronic and paper records; and AveXis’s internal audit function.

鉴于 483，评估的范围已扩大，以更广泛地涵盖 AveXis 的数据完整性控制和监督，包括：文件记录规范控制；与受控表单和文件发放相关的控制措施；计算机化系统控制；依据放行要求审查数据的流程，包括 QA 对电子和纸质记录审查的范围；以及 AveXis 的内部审计职能。

In addition to assessing AveXis’s data integrity controls and oversight,will investigatewhetherthescopeofthesite’s dataintegritydeficienciesis limited to thespecificinstancesnoted in the483 and previouslyreported to FDA.Pursuantto this investigation,will evaluate raw data, including da ta submitted to FDA in the Zolgensma® BLA, for evidence of discrepancies or manipulation. At AveXis’s request,data integrity investigation will cover manufacturing, laboratory, and clinical data.investigation will be conducted pursuant to the written protocol detailinginvestigation methodology and summarizingallofthelaboratories, manufacturingoperations,and systemsto becovered bytheinvestigation.As detailed intheinvestigation protocol, in lightofthe483observations,investigation will include a comparison of raw data and reported data to ensure that any inconsistencies have been identified.findings and recommended actions will be documented in a written report.

除评估 AveXis 的数据完整性控制和监督外，还将调查厂区数据完整性缺陷的范围是否仅限于 483 中指出的及此前向 FDA 报告的特定实例。根据该调查，将评估原始数据（包括 Zolgensma® BLA 中提交给 FDA 的数据），以查找差异或操纵的证据。应 AveXis 的请求，的数据完整性调查将涵盖生产、实验室和临床数据。的调查将按照书面方案进行，该方案详述了的调查方法，并汇总了调查将覆盖的所有实验室、生产操作和系统。如调查方案所详述，鉴于 483 检查发现项，的调查将包括对原始数据和已报告数据的比对，以确保所有不一致之处均已被识别。的调查结果和建议措施将记录在书面报告中。

Further, although the 483 is limited to the San Diego site, AveXis recognizes that the actions detailed in the CAP and in the response should be implemented across the company. Accordingly, will also be performing similar assessments across the AveXis sites, including with respect to the company’s commercial manufacturing, laboratory, and clinical data.

此外，尽管 483 仅针对圣迭戈厂区，AveXis 认识到 CAP 和本回复中详述的措施应在全公司范围内实施。因此，还将在 AveXis 各厂区开展类似的评估，包括针对公司的商业生产、实验室和临床数据。

Risk Assessment

风险评估

As noted above, AveXis provided the interim NCR-1922 investigation report to FDA on June 28, 2019. This document summarized AveXis’s assessment of the product quality risk as of June 27, 2019. Briefly, because the primary potency assays during clinical development were the in vitro relative potency assay and the in vivo functionality assay, and because these tests, not the in vivo relative potency assay, are identified in the Zolgensma® BLA as the commercial final product release tests for potency, AveXis determined that the product quality risk was low. This is consistent with FDA’s August 6, 2019, press release stating that the “totality of the evidence demonstrating the product’s effectiveness and its safety profile continues to provide compelling evidence supporting a n overall favorable benefit-risk profile.”9

如上所述，AveXis 于 2019 年 6 月 28 日向 FDA 提供了中期 NCR-1922 调查报告。该文件汇总了 AveXis 截至 2019 年 6 月 27 日对产品质量风险的评估。简言之，由于临床开发期间的主要效力试验是体外相对效力试验和体内功能试验，且 Zolgensma® BLA 中确定将这两种试验（而非体内相对效力试验）作为商业最终产品的效力放行检验，AveXis 判定产品质量风险较低。这与 FDA 2019 年 8 月 6 日的新闻稿一致，该新闻稿称“证明产品有效性及其安全性特征的证据总体继续提供令人信服的证据，支持总体获益-风险特征良好。”9

Based onreview, as detailed above, AveXis will conduct a further risk assessment to ensure that any new or additional findings byare fullyevaluated.Thisriskassessmentwillalsoassesswhetheranyadditionalportions oftheZolgensma®BLAshould beamended to ensurethatalldatabeforetheagencyareaccurate, complete, and reliable.AveXiswill then provide FDA with the findings of the risk assessment.

基于上文详述的的审查，AveXis 将开展进一步的风险评估，以确保的任何新的或额外的调查结果都得到充分评估。该风险评估还将评估是否应修改 Zolgensma® BLA 的任何其他部分，以确保提交给该机构的所有数据准确、完整、可靠。随后，AveXis 将把风险评估结果提供给 FDA。

9 Statement on data accuracy issues with recently approved gene therapy (Aug. 6, 2019), https://www.fda.gov/news-events/press-announcements/statement-data-accuracy-issues-recentlyapproved-gene-therapy.

9 《关于近日获批基因治疗药物数据准确性问题的声明》（2019 年 8 月 6 日），https://www.fda.gov/news-events/press-announcements/statement-data-accuracy-issues-recently-approved-gene-therapy。

Management Strategy

管理策略

AveXis senior management recognizes the importance of providing direction, leadership, and resources to ensure that the company has the tools it needs to put in place and sustain best practices with respect to data integrity and good documentation practice. Accordingly, AveXis, together with the Novartis global quality organization, is developing and will implement a management strategy t o strengthen quality c ulture at every l evel across AveXis and to ensure the accuracy, reliability, and completeness of the company’s quality records. This management strategy will include:

AveXis 高级管理层认识到提供方向、领导和资源的重要性，以确保公司拥有所需工具来建立和维持数据完整性和良好记录规范方面的最佳实践。因此，AveXis 正与诺华全球质量组织一道，制定并将实施一项管理策略，以在 AveXis 各级强化质量文化，并确保公司质量记录的准确性、可靠性和完整性。该管理策略将包括：

Procedural enhancements. AveXis will implement additional procedural controls to ensure that quality records and data generated at its site are accurate, reliable, and complete. These improvements include:

程序性强化措施。AveXis 将实施额外的程序性控制措施，以确保其工厂产生的质量记录和数据准确、可靠且完整。这些改进包括：

o Revising AveXis’s global data management policy to align with Novartis procedures SOP-7018147, Document and Records Management in Novartis Pharma, and SOP-7023659, Good Documentation Practice in Novartis Pharma, to ensure that data are appropriately managed across all of AveXis’s sites. These revisions will provide a framework for managing and retaining data pertaining to every operational unit, including manufacturing and testing data.

o 修订 AveXis 的全球数据管理政策，使其与诺华（Novartis）程序 SOP-7018147《诺华制药文件和记录管理》及 SOP-7023659《诺华制药良好记录规范》保持一致，以确保 AveXis 所有工厂的数据得到妥善管理。这些修订将为管理和保存各运营单位的相关数据（包括生产和检验数据）提供一个框架。

o Revising SOP-238, Data Integrity Controls, to further define the controls relating to maintaining the integrity of data and records generated and maintained by AveXis for GxP purposes.

o 修订 SOP-238《数据完整性控制》，进一步明确与维护 AveXis 为 GxP 目的生成和保存的数据及记录完整性相关的控制措施。

o Extending Novartis’s global escalation procedure 7038922, Quality/GxP Escalation and Incident Management, to AveXis to ensure that, going forward, potential quality issues, including any issues relating to or potentially relating to the integrity of quality data generated at AveXis’s sites, are timely escalated to senior quality leadership.

o 将诺华全球升级程序 7038922《质量/GxP 升级与事件管理》扩展到 AveXis，以确保今后潜在的质量问题（包括与 AveXis 工厂产生的质量数据完整性相关或可能相关的任何问题）能够及时上报至高级质量领导层。

o Revising AveXis’s procedures regarding the issuance of controlled forms and records to align with Novartis procedure SOP-7018147, Document and Records Management in Novartis Pharma, to ensure that robust controls relating to the issuance, tracking, and reconciliation of controlled records are established and maintained.

o 修订 AveXis 关于受控表格和记录发放的程序，使其与诺华程序 SOP-7018147《诺华制药文件和记录管理》保持一致，以确保建立并维持关于受控记录发放、追踪和核对的有效控制措施。

o Revising AveXis’s procedures relating to the installation and qualification of manufacturing and laboratory equipment to ensure that such procedures include robust requirements relating to the verification of predicate rule and 21 CFR Part

o 修订 AveXis 关于生产和实验室设备的安装与确认程序，以确保此类程序包含如下明确要求：对基础法规（predicate rule）及《美国联邦法规》第 21 篇第

11 controls and oversight for each piece of manufacturing and laboratory equipment.

11 部分（21 CFR Part 11）控制措施进行验证，并对每台生产和实验室设备实施监督。

o Revising AveXis’s internal audit procedures to include robust data integrity selfinspection requirements.

o 修订 AveXis 的内部审计程序，纳入明确的数据完整性自检要求。

Strengthening quality oversight. To prevent the recurrence of the deficiencies noted in the 483, AveXis will increase quality oversight over the company’s day-to-day operations from a data integrity perspective. In particular, in addition the actions set forth above in the Quality Integration Plan section, AveXis will:

加强质量监督。为防止 483 中所述缺陷再次发生，AveXis 将从数据完整性的角度加强对公司日常运营的质量监督。具体而言，除上文“质量整合计划”部分所述的措施外，AveXis 还将：

o Establish a Data Integrity Officer role. This person will be responsible for overseeing the implementation of the data integrity controls and oversight set forth in this response, and for ensuring the accuracy, completeness, and reliability of GxP data generated across AveXis’s sites.

o 设立数据完整性官（Data Integrity Officer）岗位。该岗位人员将负责监督本回复中所述数据完整性控制与监督措施的实施，并确保 AveXis 各工厂产生的 GxP 数据准确、完整、可靠。

o On an interim basis, engageas an independent third party to monitor quality data and records generated across AveXis. (b) (4) On an interim bas is, en gage < Red acted B4

o 在过渡期内，聘请作为独立第三方，监督 AveXis 各工厂产生的质量数据和记录。(b) (4) 在过渡期内，聘请

> as an independent third party to monitor quality data and records generated across AveXis.

> 作为独立第三方，监督 AveXis 各工厂产生的质量数据和记录。

o Conduct periodic data management and good documentation practice selfinspections to ensure that GxP data are accurate, reliable, and complete.

o 定期开展数据管理和良好记录规范自检，以确保 GxP 数据准确、可靠、完整。

Increasing senior management engagement and oversight. Corporate leadership and senior management have been and will continue to be closely involved in the ongoing integration and improvement activities at the site. Leadership and senior management have been active both in ensuring needed resources are available and in ensuring this work remains the highest priority. Resources, both human and financial, have and will continue to be applied to the fullest extent needed to achieve our quality and compliance objectives.

加强高级管理层的参与和监督。公司领导层和高级管理层一直并将继续密切参与工厂正在进行的整合和改进活动。领导层和高级管理层积极确保所需资源到位，并确保这项工作始终处于最高优先级。为实现我们的质量和合规目标，人力与财力资源已经并将继续按所需的最大程度投入。

AveXis will enhance its quality management review process by establishing a monthly Quality Review Board to ensure timely escalation of critical and major quality issues to senior management across both quality organizations. Attendance at these monthly Quality Review Board meetings will be mandatory for the QA, QC, Manufacturing, Engineering, and Validation functional area heads, and, until completion of the CAP, AveXis senior management, including the Chief Quality Officer and President, and the Novartis Head of Quality and Novartis Head of QA Compliance. The CAP will be a standing review item at this meeting until its completion.

AveXis 将改进其质量管理评审流程，设立每月一次的质量评审委员会（Quality Review Board），以确保关键和重大质量问题及时上报至两个质量组织的高级管理层。QA、QC、生产、工程和验证职能部门负责人必须参加每月一次的质量评审委员会会议；在 CAP 完成之前，AveXis 高级管理层（包括首席质量官和总裁）以及诺华质量负责人和诺华 QA 合规负责人也必须参加。在 CAP 完成之前，CAP 将成为该会议的常设评审议题。

Quality organization and culture improvements. AveXis is committed to improving the quality culture across the company to ensure that the 483 observations do not recur. AveXis recognizes that building and sustaining a culture of quality requires visible leadership support and engagement of personnel at all levels. To instill a robust culture of quality throughout the company, AveXis will:

质量组织与质量文化改进。AveXis 致力于改善全公司的质量文化，确保 483 中的检查发现项不再发生。AveXis 认识到，建立并维持质量文化需要领导层的明确支持和各级人员的参与。为在全公司树立牢固的质量文化，AveXis 将：

o Train employees across the company on the SpeakUp program, how to report suspected misconduct or fraud through the SpeakUp portal, and on the importance of timely reporting and suspected misconduct or fraud.

o 对全公司员工进行 SpeakUp 项目培训，包括如何通过 SpeakUp 门户举报疑似不当行为或欺诈，以及及时举报疑似不当行为或欺诈的重要性。

o Develop a quality culture and communication plan to more effectively engage company personnel, communicate management expectations with regard to good documentation practice and data management across the sites, and define accountability. Part of this effort will be increasing senior management’s knowledge of data integrity and their engagement and visibility on the importance of data integrity compliance, including site visits by AveXis senior management. Emphasis during the site visits and during the meetings will be on quality, data integrity, and good documentation practice, with particular focus on accountability at the shop floor and middle management levels within the company.

o 制定质量文化和沟通计划，以更有效地让公司人员参与进来，传达管理层对各工厂良好记录规范和数据管理的期望，并明确问责机制。这项工作的一部分将包括提高高级管理层对数据完整性的认识，以及他们对数据完整性合规重要性的参与度和可见度，包括 AveXis 高级管理层的现场走访。现场走访和会议期间将重点强调质量、数据完整性和良好记录规范，尤其关注公司车间和中级管理层层面的问责。

o Train managers and supervisors on data governance to ensure qualified personnel are aware of the criticality of the company’s data governance system, role of senior management, and system review. AveXis will establish separate training modules focusing on foundational data integrity, advanced data integrity, data integrity for auditors, and data integrity for executives.

o 对管理人员和主管进行数据治理培训，确保相关人员了解公司数据治理体系的关键性、高级管理层的角色以及系统评审。AveXis 将建立独立的培训模块，分别侧重于基础数据完整性、高级数据完整性、面向审计员的数据完整性和面向高管的数据完整性。

o Initiate organizational assessments in an effort to confirm the effectiveness and capabilities of the current quality organization in ensuring and monitoring quality effectiveness and control. The process will involve assessment of the resources, capabilities, and governance of AveXis’s quality unit. AveXis has already engaged to perform these assessments. (b) (4) Initiate organizational assessments in an effort to confirm the effectiveness and capabilities of the current quality organization in ensuring and monitoring quality effectiveness and control. The process will involve assessment of the resources, capabilities, and governance of AveXis’s quality unit. AveXis has already engaged to perform these assessments.

o 启动组织评估，以确认现有质量组织在确保和监督质量有效性与控制方面的有效性和能力。该过程将涉及对 AveXis 质量部门的资源、能力和治理情况进行评估。AveXis 已聘请开展这些评估。(b) (4) 启动组织评估，以确认现有质量组织在确保和监督质量有效性与控制方面的有效性和能力。该过程将涉及对 AveXis 质量部门的资源、能力和治理情况进行评估。AveXis 已聘请开展这些评估。

o Emphasize and enhance procedures whereby any employee found to be intentionally violating the company’s good documentation practice and/or data integrity policies will be subject to removal from their cGMP role and which may include termination.

o 强调并强化相关程序：任何被发现故意违反公司良好记录规范和/或数据完整性政策的员工，将被解除其 cGMP 岗位职责，并可能被解雇。

Enhanced training. AveXis will enhance training opportunities and requirements for staff at all levels at all sites across AveXis, with a focus on increasing employees’

加强培训。AveXis 将加强 AveXis 各工厂各级人员的培训机会和培训要求，重点是提高员工

understanding of the importance of good documentation practice and data management. For example, AveXis will:

对良好记录规范和数据管理重要性的认识。例如，AveXis 将：

o Train all employees across the company on the importance of good documentation practice and data management, including the criticality of reliable data and effective data governance.

o 对全公司所有员工进行良好记录规范和数据管理重要性的培训，包括可靠数据和有效数据治理的关键性。

o Provide additional training for personnel engaged in GxP activities on data management and quality culture. This additional training will be conducted to ensure that appropriate personnel have received comprehensive training on FDA’s requirements and how to prevent and detect threats to the integrity of data.

o 为从事 GxP 活动的人员提供数据管理和质量文化方面的额外培训。开展该额外培训是为了确保相关人员全面了解 FDA 的要求，以及如何预防和发现对数据完整性的威胁。

o Add a good documentation practice, data management, and quality culture component to all sites’ annual training programs.

o 在所有工厂的年度培训计划中加入良好记录规范、数据管理和质量文化的内容。

o Develop and provide advanced training for QA personnel on data integrity risk detection and mitigation. This training will include data integrity learning maps, educational modules focusing on data integrity case studies based on real-world situations, and tutorials on data integrity risk identification and reporting.

o 为 QA 人员开发并提供关于数据完整性风险识别与缓解的高级培训。该培训将包括数据完整性学习路线图、基于真实情形案例的数据完整性教育模块，以及数据完整性风险识别与报告的教程。

Engagement of third-parties. As noted above, AveXis has already engagedan independent third-partycGMPconsultant,to performathorough assessmentofAveXis’s dataintegritycontrols and oversight, and to investigatetheextentofthedataintegritydeficiencies noted in the483 and thedatamanipulation issues previouslyreported to FDA.Separately, AveXis has alsoengagedto perform aretrospectiveassessmentofcriticalandmajorNCRs,which includesout-of-specification testresults,to assesstheadequacy of AveXis’s investigations and determinewhetheranyinvestigations should bere-opened undersupervision and oversight. will also provide an independent review of GxP activities.

聘请第三方。如上所述，AveXis 已聘请——一家独立的第三方 cGMP 咨询机构——对 AveXis 的数据完整性控制和监督进行全面评估，并调查 483 中指出的数据完整性缺陷以及此前向 FDA 报告的数据操纵问题的严重程度。此外，AveXis 还聘请了对关键和重大 NCR（不符合项报告，包括超出检验标准（OOS）的检验结果）进行回顾性评估，以评价 AveXis 调查的充分性，并确定是否有任何调查应在的监督和监管下重新启动。还将对 GxP 活动提供独立审查。

III. AveXis’s Specific Responses to the 483 Observations

三、AveXis 对 483 检查缺陷项的具体回复

OBSERVATION 1

检查发现项 1

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

未能彻底审核任何无法解释的差异，无论该批次是否已上市销售。

A. Non-conformance Report NCR-1922 (which was open at the time of the current inspection) was opened on 15 May 2019 due to a report that was made to the CQO (Chief Quality Officer) alleging that data derived from the AVXS-101 In-Vivo Relative Potency Assay Studies 1-10 may have been mismanaged or even potentially manipulated. Aside from evaluations of Studies 1-10 and a planned evaluation of toxicological studies under NCR-2018 there is no documentation in this NCR that an audit of all other potentially impacted data, studies, and reports was conducted or is planned to determine if there was evidence of data mismanagement or manipulation or a justification for not conducting or planning such an audit. Additionally, there is no documentation in NCR-1922 as to why the NCR was not opened until 15 May 2019 when the initial allegation is documented as having been reported on 14 March 2019.

A. 不符合项报告 NCR-1922（在当前检查期间处于开启状态）于 2019 年 5 月 15 日开启，原因是首席质量官（CQO）收到一份报告，指控 AVXS-101 体内相对效力试验研究 1-10 所得数据可能被管理不当甚至被篡改。除对研究 1-10 的评估以及 NCR-2018 项下计划开展的对毒理学研究的评估外，该 NCR 中没有文件证明已开展或计划开展对所有其他可能受影响的数据、研究和报告的审计，以确定是否存在数据管理不当或数据操纵的证据，也没有说明不开展或不计划开展此类审计的理由。此外，NCR-1922 中没有任何文件说明，为何在初始指控被记录为于 2019 年 3 月 14 日报告的情况下，该 NCR 直到 2019 年 5 月 15 日才开启。

B. Non-conformance Report NCR-409 was opened on 31 Jan 2018 and has an "Event Description" of "On 31Jan2018, during a historical data review of the potency results for Drug Product Lot 600156 per SOP-285, Determination of In Vivo Relative Potency for AVXS-101 Drug Product, it was discovered that the associated assay form (FORM-212) was not completed at the time of CoA generation and approval for Lot 600156...." During the inspection, the associated FORM-212 was reviewed and it was observed that the date/time stamps on the 4 page form are discrepant in that 3 of the 4 pages have a "Generated" date /time of "05 Jan 2018 09:44AM" and 1 page (page 2) has a "Generated" date/time of " 04 Jan 2018 09:39AM". There is no documentation in NCR-409 that this discrepancy was noticed or investigated. Additionally, current SOP-381 Version 2.0 entitled "Control of QC Test Forms" does not specifically require verification of consistent date/time stamps on each page of a test form during reconciliation of the form.

B. 不符合项报告 NCR-409 于 2018 年 1 月 31 日开启，“事件描述”为：“2018 年 1 月 31 日，在依据 SOP-285《AVXS-101 制剂体内相对效力的测定》对制剂批次 600156 的效力结果进行历史数据审核时发现，在生成和批准批次 600156 的 COA（检验报告单）时，相关的检验表格（FORM-212）尚未填写完成……”在检查期间，对相关 FORM-212 进行了审核，发现该 4 页表格上的日期/时间戳不一致：4 页中有 3 页的“生成”日期/时间为“2018 年 1 月 5 日 09:44”，而 1 页（第 2 页）的“生成”日期/时间为“2018 年 1 月 4 日 09:39”。NCR-409 中没有文件证明这一差异已被注意或调查。此外，现行 SOP-381 第 2.0 版（题为《QC 检验表格控制》）并未明确规定在表格核对时须验证检验表格每一页的日期/时间戳一致。

C. Non-conformance Report NCR-965 was opened on 23 Aug 2018 and has and "Event Description" of "On 23Aug 2018, during the review of Δ7SMA mouse database, it was discovered that there were discrepancies in the data that was used to calculate relative potency for AVXS-101 Drug Product. Lot 816836 had single mouse survival days recorded that were different from the actual value...." As documented in the investigation most of the discrepancies noted were discrepant by a single day which was attributed to ambiguity in SOP-285 "Determination of ln-Vivo Relative Potency for AVXS-101 Drug Product" however in 4 cases discrepancies of greater than 1 day were noted (ranging from 2-19 days). There is no documentation in NCR-965 that these 4 cases were investigated further to determine a potential root cause.

C. 不符合项报告 NCR-965 于 2018 年 8 月 23 日开启，“事件描述”为：“2018 年 8 月 23 日，在审核 Δ7SMA 小鼠数据库时发现，用于计算 AVXS-101 制剂相对效力的数据存在差异。批次 816836 记录的单只小鼠存活天数与实际值不同……”如调查中所记载，所记录的多数差异仅相差一天，归因于 SOP-285《AVXS-101 制剂体内相对效力的测定》中的表述模糊不清；但有 4 例差异超过一天（介于 2 至 19 天之间）。NCR-965 中没有文件证明对这 4 例进行了进一步调查以确定潜在根本原因。

D. Non-conformance Report NCR-1116 was opened on 15 Oct 2018 and has "Event Description" of " Inconsistencies were identified during the review and approval of the data previously reported within REC-1606 v1.0 'Mouse Survival Data: Results for In-vivo Relative Potency for AVXS-101 Drug Product'...." As documented in the investigation " ... During investigational review of the Quality Employee's process, it was determined that some of the early raw data results were initially communicated verbally from the ... to the AveXis Quality Employee...." There is no documentation in NCR-1116 explaining why the Quality Employee accepted verbal communication of raw data without corresponding written documentation.

D. 不符合项报告 NCR-1116 于 2018 年 10 月 15 日开启，“事件描述”为：“在审核和批准 REC-1606 v1.0《小鼠存活数据：AVXS-101 制剂体内相对效力结果》中此前报告的数据时发现了不一致之处……”如调查中所记载：“……在对质量员工的工作流程进行调查性审核时确定，部分早期原始数据结果最初是由……通过口头方式传达给 AveXis 质量员工的……”NCR-1116 中没有文件解释为何质量员工在没有相应书面文件的情况下接受了以口头方式传达的原始数据。

General Response to Observation 1

对检查发现项 1 的总体回复

AveXis recognizes the importance of ensuring that quality records are accurate, consistent and reliable, as well as the need to thoroughly investigate any unexplained discrepancies, including data discrepancies. As described in detail in Section II, above, Novartis is accelerating the integration of AveXis into the Novartis quality system through the Quality Integration Plan (QIP). The QIP includes not only a thorough review of AveXis’s practices and procedures to ensure alignment with Novartis’s quality standards, but also a commitment to enhance the culture of quality and compliance at AveXis through visible, senior management support, comprehensive quality training, and employee accountability.

AveXis 认识到确保质量记录准确、一致和可靠的重要性，也认识到有必要彻底调查任何无法解释的差异，包括数据差异。如上方第 II 节详细所述，诺华正通过质量整合计划（QIP）加快将 AveXis 整合到诺华质量体系中。QIP 不仅包括对 AveXis 的做法和程序进行全面审查以确保与诺华质量标准保持一致，还承诺通过高级管理层明确的支持、全面的质量培训和员工问责制，来增强 AveXis 的质量与合规文化。

In particular, the QIP will focus on enhancing site controls for data integrity and good documentation practice, as well as performing thorough quality investigations when unexpected discrepancies occur. AveXis understands that such investigations must extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy; and a written record of the investigation must be made, including the investigation conclusions and follow-up.

具体而言，QIP 将重点加强工厂的数据完整性和良好记录规范控制，并在出现意外差异时开展彻底的质量调查。AveXis 理解，此类调查必须延伸至同一制剂的其他批次以及可能与特定失败或差异相关的其他制剂；并且必须形成书面调查记录，包括调查结论和后续措施。

Further, through the Data Integrity Remediation Plan, as described in detail in Section II, above, AveXis has engagedto perform an independent, third-partydataintegrityinvestigation and assessmentatAveXis. Theassessment willincludeacomprehensivereviewofdataand records managementpractices atAveXis, as wellas reviewofAveXis’s historicaldataintegrityinvestigations. Based ontheresults oftheassessment, AveXis willdevelopand implement additional CAPAs related to data integrity controls and investigations.

此外，通过上方第 II 节详细描述的数据完整性整改计划，AveXis 已聘请在 AveXis 开展独立、第三方数据完整性调查和评估。该评估将包括对 AveXis 数据和记录管理实践的全面审查，以及对 AveXis 既往数据完整性调查的审查。根据评估结果，AveXis 将制定并实施与数据完整性控制和调查相关的额外纠正和预防措施（CAPA）。

AveXis currently has in place processes to thoroughly investigate non-conformances and ensure CAPAs are implemented. Specifically, SOP-005, Non-Conformance and CAPA System, outlines the process for reporting non-conformances. This procedure ensures proper evaluation of product and process impact. This procedure also determines the need for further investigation into root cause and CAPA initiation, as outlined in SOP-005, and ensures that nonconforming

AveXis 目前已有相关流程来彻底调查不符合项并确保 CAPA 得到实施。具体而言，SOP-005《不符合项与 CAPA 体系》概述了报告不符合项的流程。该程序确保对产品和工艺影响进行恰当评估。该程序还按照 SOP-005 的规定，确定是否有必要进一步调查根本原因并启动 CAPA，并确保不符合

product is appropriately managed and dispositioned. Any incidents relating to the safety, quality, purity or potency of distributed product must be considered for escalation and review by a crossfunctional team of management responsible for managing such incidents, in accordance with SOP-365, Notification to Management.

产品得到适当的管理和处置。根据 SOP-365《向管理层通报》，任何与已上市产品的安全性、质量、纯度或效力相关的事件，都必须考虑上报并由负责管理此类事件的跨职能管理团队进行评审。

The non-conformance investigation process begins by launching a non-conformance or NC in ACE, AveXis’s quality tracking system. An initial risk assessment is performed and a determination made whether, in accordance with applicable procedures, a root cause investigation is required. Upon completion of the investigation, if any, appropriate CAPAs are identified for implementation. Product impact assessments and disposition decisions are also contained within the non-conformance. The above-described investigational activities are tracked as tasks within ACE to ensure a thoroughly documented non-conformance investigation has been conducted. In addition, to ensure appropriate quality oversight, progress of quality investigations and CAPAs are monitored at AveXis’s monthly Quality Review Board meetings.

不符合项调查流程始于在 AveXis 的质量跟踪系统 ACE 中启动不符合项（NC）。首先进行初始风险评估，并根据适用程序确定是否需要进行根本原因调查。调查完成后（如有），确定应实施的适当 CAPA。产品影响评估和处置决定也包含在不符合项中。上述调查活动在 ACE 中作为任务进行跟踪，以确保已开展记录完整的不符合项调查。此外，为确保适当的质量监督，质量调查和 CAPA 的进展将在 AveXis 每月一次的质量评审委员会会议上进行监控。

AveXis recognizes the opportunity to further strengthen its data management and investigation programs and is committed to providing the necessary human and capital resources to spur continuous improvement at all AveXis sites. For example, through the QIP and Data Integrity Remediation Plan, AveXis will:

AveXis 认识到有机会进一步加强其数据管理和调查项目，并致力于提供必要的人力和资金资源，以推动 AveXis 所有工厂的持续改进。例如，通过 QIP 和数据完整性整改计划，AveXis 将：

Adopt the practices and requirements from the Novartis Global Operating Procedure, SOP 7039029, GOP: Deviation Handling;

o 采用诺华全球操作规程 SOP 7039029《GOP：偏差处理》中的做法和要求；

Enhance the established non-conformance management process and the escalation process by aligning AveXis’s process with relevant Novartis corporate procedures to ensure that, going forward, potential quality issues, including any issues relating to or potentially relating to the integrity of quality data generated at AveXis’s sites, are timely escalated to senior quality leadership;

o 通过使 AveXis 的流程与诺华相关公司程序保持一致，加强现有的不符合项管理流程和升级流程，以确保今后潜在的质量问题（包括与 AveXis 工厂产生的质量数据完整性相关或可能相关的任何问题）能够及时上报至高级质量领导层；

Implement a certification process for investigators and QA approvers to ensure that all personnel handling investigation activities undergo focused training on root-cause analysis methodology and the use of investigation tools, including specific training on investigating and remediating data integrity and GDP anomalies, and demonstrate the ability to successfully perform their investigation and oversight responsibilities;

o 为调查人员和 QA 批准人实施认证流程，确保所有处理调查活动的人员接受关于根本原因分析方法和调查工具使用的专项培训，包括针对数据完整性和良好记录规范（GDP）异常情况的调查与整改的专门培训，并证明其有能力成功履行调查和监督职责；

As an interim control, AveXis has engagedto provide independent oversight to the investigations and quality system, including r eview and approval of investigations;

o 作为过渡性控制措施，AveXis 已聘请对调查和质量体系提供独立监督，包括对调查的审核和批准；

Increase data integrity awareness through senior leadership engagement and companywide communication efforts;

o 通过高级领导层的参与和全公司范围的沟通活动，提高数据完整性意识；

Re-train all employees engaged in GxP activities on POL-007, Data Integrity Policy, and SOP-003, Good Documentation Practices.;

o 对所有从事 GxP 活动的员工进行 POL-007《数据完整性政策》和 SOP-003《良好记录规范》的再培训；

Establish and train AveXis personnel on the Novartis “SpeakUp” program with an emphasis on the importance of reporting concerns regarding potential misconduct or fraud;

o 建立诺华“SpeakUp”项目并对 AveXis 人员进行培训，重点强调报告潜在不当行为或欺诈相关疑虑的重要性；

Create a new Data Integrity Officer position reporting directly to AveXis’s Head of QA and responsible for overseeing the implementation of the data integrity controls and oversight set forth in this response, and for ensuring the accuracy, completeness, and reliability of GxP data generated across AveXis’s sites; and

o 新设数据完整性官（Data Integrity Officer）岗位，直接向 AveXis 的 QA 负责人汇报，负责监督本回复中所述数据完整性控制与监督措施的实施，并确保 AveXis 各工厂产生的 GxP 数据准确、完整、可靠；以及

Establish a mentorship program between AveXis quality personnel and Novartis data integrity and investigations subject matter experts (SMEs) to enhance skill building and instill best practices.

o 在 AveXis 质量人员与诺华数据完整性和调查主题专家（SME）之间建立导师计划，以加强技能培养并灌输最佳实践。

AveXis is confident that the above-described controls and enhancements will ensure sustainable compliance with FDA’s and the company’s own expectations for AveXis’s data management and investigation programs. AveXis notes that to assure the effectiveness of the company’s data integrity program, focused data integrity modules will be included in routine internal and corporate self-inspections at AveXis sites.

AveXis 相信，上述控制措施和强化措施将确保持续符合 FDA 及公司自身对 AveXis 数据管理和调查项目的要求。AveXis 指出，为确保公司数据完整性项目的有效性，AveXis 各工厂的常规内部自检和公司级自检都将包含专门的数据完整性模块。

With respect to AveXis’s San Diego site, the company wishes to note that until May 2018, the site functioned solely as a research and development facility, with limited quality oversight. Since May 2018, the San Diego site has implemented quality controls consistent with the AveXis quality management system, including for data management and investigations. Furthermore, as described above, key AveXis quality controls will be integrated and aligned with the corresponding Novartis global quality policies and procedures, as part of the overall integration of AveXis with the Novartis quality network.

关于 AveXis 的圣地亚哥工厂，公司希望说明：在 2018 年 5 月之前，该工厂仅作为研发设施运作，质量监督有限。自 2018 年 5 月以来，圣地亚哥工厂已实施与 AveXis 质量管理体系一致的质量控制措施，包括数据管理和调查方面的控制措施。此外，如上所述，作为 AveXis 与诺华质量网络整体整合的一部分，AveXis 的关键质量控制措施将与相应的诺华全球质量政策和程序进行整合并保持一致。

Observation 1 Corrective and Preventive Actions

检查发现项 1 的纠正和预防措施

In addition to the actions noted above in Section II, including the actions undertaken pursuant to the QIP and the Data Integrity Remediation Plan, AveXis will undertake the following actions to ensure that the issues specifically noted in Observation 1 are fully addressed.

除上方第 II 节所述的措施（包括根据 QIP 和数据完整性整改计划采取的措施）外，AveXis 还将采取以下措施，以确保检查发现项 1 中指出的问题得到充分解决。

1.1 The ongoing integration of AveXis into the Novartis quality system, including AveXis’s adoption of the practices and requirements from the Novartis Global Operating Procedure, SOP 7039029, GOP: Deviation Handling, will be accelerated.

1.1 将加快 AveXis 持续并入诺华质量体系的进程，包括 AveXis 采用诺华全球操作规程 SOP 7039029《GOP：偏差处理》中的做法和要求。

Target Completion Date (TCD): Ongoing

目标完成日期（TCD）：持续进行中

1.2 AveXis will adopt the practices and requirements from the Novartis Global Operating Procedure, SOP 7039029, GOP: Deviation Handling.

1.2 AveXis 将采用诺华全球操作规程 SOP 7039029《GOP：偏差处理》中的做法和要求。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

1.3 AveXis will enhance the established non-conformance management process and the escalation process by aligning AveXis’s process with relevant Novartis corporate procedures, including SOP 7038922, to ensure that, going forward, potential quality issues, including any issues relating to or potentially relating to the integrity of quality data generated at AveXis’s sites, are timely escalated to senior quality leadership.

1.3 AveXis 将通过使 AveXis 的流程与诺华相关公司程序（包括 SOP 7038922）保持一致，加强现有的不符合项管理流程和升级流程，以确保今后潜在的质量问题（包括与 AveXis 工厂产生的质量数据完整性相关或可能相关的任何问题）能够及时上报至高级质量领导层。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

1.4 AveXis will implement a certification process for investigators and QA approvers to ensure that all personnel handling investigation activities undergo focused training on root-cause analysis methodology and the use of investigation tools, including specific training on investigating and remediating data integrity and GDP anomalies, and demonstrate the ability to successfully perform their investigation and oversight responsibilities.

1.4 AveXis 将为调查人员和 QA 批准人实施认证流程，确保所有处理调查活动的人员接受关于根本原因分析方法和调查工具使用的专项培训，包括针对数据完整性和 GDP 异常情况的调查与整改的专门培训，并证明其有能力成功履行调查和监督职责。

TCD: January 2020

目标完成日期（TCD）：2020 年 1 月

1.5 As an interim control, AveXis will engageto provide independen t oversight to the company’s NC investigations, including review and approval of investigations. (b) (4)

1.5 作为过渡性控制措施，AveXis 将聘请对公司的 NC 调查提供独立监督，包括对调查的审核和批准。(b) (4)

TCD: Complete;protocol for reviewing NC investigations is under development (b) (4)

目标完成日期（TCD）：已完成；审查 NC 调查的方案正在制定中 (b) (4)

1.6 AveXis engaged to perform an independe nt, t hird-party data integrity investigation and assessment at AveXis pursuant to a written protocol. (b) (4)

1.6 AveXis 已聘请按照书面方案在 AveXis 开展独立、第三方数据完整性调查和评估。(b) (4)

TCD: Complete;data integrity investigation protocol is under development (b) (4)

目标完成日期（TCD）：已完成；数据完整性调查方案正在制定中 (b) (4)

1.7 Increase data integrity awareness through senior leadership engagement and site-wide communication efforts.

1.7 通过高级领导层的参与和全工厂范围的沟通活动，提高数据完整性意识。

TCD: Ongoing

目标完成日期（TCD）：持续进行中

1.8 AveXis will re-train all employees engaged in GxP activities on POL-007, Data Integrity Policy, and SOP-003, Good Documentation Practices.

1.8 AveXis 将对所有从事 GxP 活动的员工进行 POL-007《数据完整性政策》和 SOP-003《良好记录规范》的再培训。

TCD: October 2019; additional training will be provided pursuant to the CAP

目标完成日期（TCD）：2019 年 10 月；将根据 CAP 提供额外培训

1.9 Establish and train AveXis personnel on the Novartis “SpeakUp” program with an emphasis on the importance of reporting concerns regarding potential misconduct or fraud

1.9 建立诺华“SpeakUp”项目并对 AveXis 人员进行培训，重点强调报告潜在不当行为或欺诈相关疑虑的重要性。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

1.10 Create a new Data Integrity Officer position reporting directly to AveXis’s Head of QA and responsible for overseeing the implementation of the data integrity controls and oversight set forth in this response, and for ensuring the accuracy, completeness, and reliability of GxP data generated across AveXis’s sites.

1.10 新设数据完整性官（Data Integrity Officer）岗位，直接向 AveXis 的 QA 负责人汇报，负责监督本回复中所述数据完整性控制与监督措施的实施，并确保 AveXis 各工厂产生的 GxP 数据准确、完整、可靠。

TCD: December 2019

目标完成日期（TCD）：2019 年 12 月

1.11 Establish a mentorship program between AveXis quality personnel and Novartis data integrity and investigations subject matter experts (SMEs) to enhance skill building and instill best practices.

1.11 在 AveXis 质量人员与诺华数据完整性和调查主题专家（SME）之间建立导师计划，以加强技能培养并灌输最佳实践。

TCD: Ongoing

目标完成日期（TCD）：持续进行中

OBSERVATION 1(A)

检查发现项 1(A)

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

未能彻底审核任何无法解释的差异，无论该批次是否已上市销售。

Specific Response to Observation 1(A)

对检查发现项 1(A) 的具体回复

Please note that the investigation into the data manipulation allegations noted in Observation 1(A) was conducted with focus, diligence, and significant resources.10 As explained above, upon learning of what was then an allegation of data manipulation, AveXis immediately launched an internal investigation on March 14, 2019, led by senior officials from AveXis HR, Quality, and Legal, which included the development of an investigation plan, gathering of materials, preparing the necessary Upjohn warnings, and additional investigative steps. AveXis personnel immediately contacted the individual who made the allegations, but were informed that the individual was unavailable until March 26, 2019. AveXis personnel pursued other initial investigational steps and the individual who reported the allegations was interviewed on March 26, 2019. After conducting the interview and completing a thorough review of the testing records described by the reporter, AveXis determined that the allegations merited further investigation and informed Novartis on March 28, 2019.

请注意，对检查发现项 1(A) 中所述数据操纵指控的调查是在高度聚焦、勤勉尽责并投入大量资源的情况下进行的。10 如上所述，在获悉当时尚属指控的数据操纵情况后，AveXis 于 2019 年 3 月 14 日立即启动了内部调查，该调查由 AveXis 人力资源、质量和法律部门的高级官员牵头，包括制定调查计划、收集材料、准备必要的 Upjohn 警告以及采取其他调查步骤。AveXis 人员立即联系了提出指控的人员，但被告知该人员要到 2019 年 3 月 26 日才有空。AveXis 人员继续开展其他初步调查步骤，并于 2019 年 3 月 26 日对举报人进行了访谈。在完成访谈并对举报人所描述的检验记录进行全面审查后，AveXis 认定该指控值得进一步调查，并于 2019 年 3 月 28 日告知诺华。

10 As described in more detail in Section I, above, the investigation noted in Observation 1(A) involved a mouse potency assay—known as the in vivo relative potency assay (IVRPA)—for release and stability testing of clinical product. The IVRPA used SMNΔ7 mice to determine the relative potency of lots of AVXS-101 for clinical product release and stability testing. It is important to note that IVRPA has not been used for clinical product release purposes since June 2018, nearly a year before Zolgensma® was approved, and was never used for the release of commercial product. Rather, a different in vitro cellbased assay and new in vivo functionality assay were validated and included in the Zolgensma® BLA as the tests to be used to assess potency for commercial release and stability.

10 如上方第 I 节更详细所述，检查发现项 1(A) 中提到的调查涉及一种用于临床产品放行和稳定性试验的小鼠效力试验——即体内相对效力试验（IVRPA）。IVRPA 使用 SMNΔ7 小鼠测定 AVXS-101 各批次的相对效力，用于临床产品放行和稳定性试验。需要指出的是，自 2018 年 6 月起（即 Zolgensma® 获批前近一年），IVRPA 已不再用于临床产品放行，且从未用于商业产品的放行。相反，一种不同的体外细胞学试验和新的体内功能性试验已完成验证，并被纳入 Zolgensma® 的 BLA，作为评估商业放行和稳定性的效力检验方法。

For this phase of the investigation, an external law firm was engaged to conduct an internal review of the allegations, on April 3, 2019. Because the allegations involved two founders who were still senior executives and fixtures at AveXis, and because the allegations involved data manipulation, this initial internal investigation was led by external counsel to ensure that key evidence was preserved, efficiently gathered, and made available for a thorough technical review without interference from the two implicated senior AveXis executives.

在调查的这一阶段，AveXis 于 2019 年 4 月 3 日聘请了一家外部律师事务所对指控进行内部审查。由于指控涉及两位仍是 AveXis 高级管理人员和核心人物的创始人，且指控涉及数据操纵，本次初步内部调查由外部法律顾问牵头，以确保关键证据得到保全、高效收集，并在不受这两位涉案 AveXis 高级管理人员干扰的情况下供进行彻底的技术审查。

Moreover, the investigation was significantly drawn out due to the implicated senior executives’ lack of cooperation and categorical denial of the allegations, which continues to this day. Significant resources were therefore required to review thousands of hand-written and electronic records concerning the life history of individual mice and comparison of those records to entries on hundreds of spreadsheets. To accomplish this, we estimate that more than 2,000 hours were spent collectively by the investigation team from the engagement of external counsel until the start of the non-conformance phase of the investigation. When discrepancies were identified, technical experts were required to assess the discrepancies to determine whether they had any impact on the results of the underlying IVRPA studies, batch release decisions, and clinical data that may have been generated through use of those batches. In each case, these technical reviews found that the data manipulation issues had no impact on patient safety or product efficacy or quality.

此外，由于涉案高级管理人员不予配合并断然否认指控（这种状况持续至今），调查被大大拖延。因此需要投入大量资源，审查数千份关于单只小鼠生命史的纸质和电子记录，并将这些记录与数百张电子表格中的条目进行比对。为此，我们估计从聘请外部法律顾问到调查进入不符合项阶段之前，调查团队累计投入了 2,000 多个小时。在发现差异时，需要由技术专家评估这些差异，以确定它们是否对相关 IVRPA 研究的结果、批次放行决定以及可能因使用这些批次而产生的临床数据有任何影响。在每种情况下，这些技术审查均发现，数据操纵问题对患者安全或产品的有效性和质量没有影响。

During this time, AveXis was actively engaged in the investigation and in monitoring the results of the investigation. The initial investigation and interviews demonstrated that the two senior AveXis executives alleged to have been responsible could not offer a credible explanation for revisions to and inconsistencies in the data, and they were placed on administrative leave on May 3, 2019 to ensure that they had no access to data, systems, or staff. These two senior AveXis executives were later terminated for cause on August 13, 2019.11 As a reminder, this phase of the investigation took 39 working days.

在此期间，AveXis 积极参与调查并监测调查结果。初步调查和访谈表明，被指控负有责任的两名 AveXis 高级管理人员无法对数据的修改和不一致之处提供可信的解释，二人于 2019 年 5 月 3 日被安排行政休假，以确保他们无法接触数据、系统或员工。这两名 AveXis 高级管理人员后来于 2019 年 8 月 13 日因故被解雇。11 需要提醒的是，调查的这一阶段历时 39 个工作日。

Following the initial investigation’s determination that the allegations were credible and merited continued investigation, as a second phase, a NC investigation was opened on May 8, 2019 to further investigate the issues, including conducting a comprehensive root-cause analysis, conducting a more detailed risk assessment, and developing and implementing corrective and preventive actions to address the data integrity issues. A non-conformance report—NCR1922—was opened in AveXis’s ACE document management system on May 15, 2019 to document the investigation activities. A team consisting of AveXis senior Quality leadership, AveXis San Diego Quality Assurance and Quality Control, and Novartis GxP Compliance conducted the NC investigation.

在初步调查认定指控可信且值得继续调查之后，作为第二阶段，AveXis 于 2019 年 5 月 8 日开启了一项 NC 调查，以进一步调查相关问题，包括开展全面的根本原因分析、进行更详细的风险评估，以及制定并实施纠正和预防措施以解决数据完整性问题。2019 年 5 月 15 日，AveXis 在 ACE 文件管理系统中开启了一份不符合项报告——NCR1922——以记录调查活动。由 AveXis 高级质量领导层、AveXis 圣地亚哥质量保证（QA）和质量控制（QC）部门以及诺华 GxP 合规部门组成的一个团队开展了本次 NC 调查。

11 As noted in the public statements of his counsel, one of these executives continues to deny any wrongdoing.

11 正如其中一名高管的律师在公开声明中所指出的，其中一名高管仍否认有任何不当行为。

该 NC 调查（目前仍处于开启状态）聚焦于与体内小鼠研究 1-10 相关的疑虑，涉及四个产品批次的 IVRPA 数据：批次 NCHAAV95MN0613 的 3 个月时间点稳定性数据；批次 600307 的放行数据；批次 600729 的放行数据；以及批次 600539 的放行数据。其中三个批次已被用完或已过期，剩余批次的所有物料自 2019 年 5 月 5 日起被置于 AveXis 伊利诺伊州利伯蒂维尔（Libertyville）工厂予以扣留。

The NC investigation proceeded according to the following methodology:

NC 调查按照以下方法进行：

Review of all possible sources of data pertaining to the assays in question, such as GMP data sheets for the IVRPA, original records used in the management of animals (cage cards), spreadsheets created by employees to hold data and calculate results of the assays, and laboratory logbooks;

o 审查与相关试验有关的所有可能的数据来源，如 IVRPA 的 GMP 数据表、用于动物管理的原始记录（笼卡）、员工为保存数据和计算试验结果而创建的电子表格，以及实验室记录本；

Identification of possible data discrepancies;

o 识别可能的数据差异；

Determination of possible alternative values for reported relative potency for lots involved in studies implicated;

o 确定涉案研究相关批次已报告的相对效力可能存在替代值的情况；

Evaluation of clinical studies potentially impacted by data integrity allegations;

o 评估可能受数据完整性指控影响的临床研究；

Evaluation of regulatory impact;

o 评估监管影响；

Interviews with staff and management; and

o 对员工和管理层进行访谈；以及

Recalculation of the results and material impact assessments.

o 重新计算结果并开展实质性影响评估。

对数据来源的比对审查和访谈已证实，体内研究 1-10 所使用的数据存在多处差异。为了核实现有数值，或为研究 1-10 确定可靠度更高的数据值，AveXis 制定了一份方案来核实原始数据并建立评估此类差异的程序。采用这一新方案后，当原始记录支持修订时对原始数据进行了修订，对 IVRPA 研究 1-10 的效力进行了重新计算，这些研究得出的数值将被标注为有效性降低，且这些结果应报告给相应的监管机构，随后已及时完成报告。

NCR-1922’s impact assessment further found that despite the IVRPA data concerns, the original clinical conclusions were not in question given the overall technical assessment of all QC release testing, including the in vitro potency assay, and the consistent performance of AVXS-101 in the

NCR-1922 的影响评估进一步认定，尽管 IVRPA 数据存在疑虑，但鉴于对所有 QC 放行检验（包括体外效力试验）的总体技术评估，以及 AVXS-101 在

. clinical trials. Specifically, during the development of the product and prior to submission of the BLA, FDA previously r aised concern regarding the variability of the in vivo data from studies 1- 10 and requested clinical results from ongoing studies. FDA also requested in vitro relative potency data to support the clinical profile of Zolgensma®. Accordingly, while studies 1-10 were used in the development of the product, these data would not have been relied upon to reach any clinical determinations given this variability.

临床试验中表现的一致性，原始临床结论不受质疑。具体而言，在产品开发期间及 BLA 提交之前，FDA 曾对研究 1-10 体内数据的变异性提出关切，并要求提供正在进行的研究的临床结果。FDA 还要求提供体外相对效力数据，以支持 Zolgensma® 的临床特征。因此，尽管研究 1-10 曾被用于产品开发，但鉴于这种变异性，这些数据不会被依赖来作出任何临床判定。

AveXis recognizes thatathorough dataintegrityinvestigation should extend to allotherpotentiallyimpacted data, studies, and reports to determineiftherewas evidenceofdatamismanagementormanipulation.Thus, theinterimNCR-1922 includedaCAPAto engageathird-partyto performan auditofAveXis dataintegritycomplianceand recommend additionalCAPAs. Accordingly, as thenextphaseoftheinvestigation, AveXis engagedan independent third-partycGMPconsultant, to performathoroughassessmentofAveXis’s dataintegritycontrolsandoversight,andto investigatetheextentofthedataintegritydeficiencies noted in the483 and thedatamanipulation issues previouslyreported to FDA.Further, AveXis has alsoengagedto perform aretrospectiveassessmentofcriticaland majorNCRs,which includes out-of-specification testresults,to assesstheadequacyofthesite’s investigationsand determinewhetheranyinvestigations should bere-opened undersupervision and oversightwill also provide an independent review of GxP activities.

AveXis 认识到，彻底的数据完整性调查应延伸至所有其他可能受影响的数据、研究和报告，以确定是否存在数据管理不当或数据操纵的证据。因此，临时性 NCR-1922 中包含一项 CAPA，即聘请第三方对 AveXis 的数据完整性合规情况进行审计，并建议采取额外的 CAPA。据此，作为调查的下一阶段，AveXis 聘请了独立第三方 cGMP 咨询机构，对 AveXis 的数据完整性控制和监督进行全面评估，并调查 483 中指出的数据完整性缺陷以及此前向 FDA 报告的数据操纵问题的严重程度。此外，AveXis 还聘请了对关键和重大 NCR（包括超出检验标准（OOS）的检验结果）进行回顾性评估，以评价工厂调查的充分性，并确定是否有任何调查应在的监督和监管下重新启动。还将对 GxP 活动提供独立审查。

Further showing that the company understands a thoroughinvestigation should extend to all other potentially impacted data, studies, and reports, AveXis notes that through this investigation,

为进一步表明公司理解彻底的调查应延伸至所有其他可能受影响的数据、研究和报告，AveXis 指出，通过本次调查，

AveXis opened an additional NC investigation onto investigate this(documented in NCR-2018). Based on information obtained pursuant to the investigation, AveXis concluded that . Although AveXis’s investigation was ongoing during the July/August inspection, AveXis provided a draftcopyofNCR-2018 to theFDAinvestigators,who requestedand retainedacopyofthedraftinvestigation report and related documentation.AveXis will

AveXis 于就此事开启了另一项 NC 调查（记录于 NCR-2018）。根据调查所获信息，AveXis 得出结论：。尽管在 7/8 月检查期间 AveXis 的调查仍在进行中，AveXis 仍向 FDA 检查员提供了一份 NCR-2018 的草稿副本，检查员索取并保留了该调查草稿报告及相关文件的副本。AveXis 将

investigation, AveXis concluded that (b) (4)

调查，AveXis 得出结论：(b) (4)

. Although AveXis’s investigation was ongoing during the July/August inspection, AveXis provided a draft copy of NCR-2018 to the FDA investigators, who requested and retained a copy of the draft investigation report and related documentation. AveXis will (b) (4)

。尽管在 7/8 月检查期间 AveXis 的调查仍在进行中，AveXis 仍向 FDA 检查员提供了一份 NCR-2018 的草稿副本，检查员索取并保留了该调查草稿报告及相关文件的副本。AveXis 将 (b) (4)

AveXis takes seriously the responsibility to ensure the accuracy and reliability of the company’s data and are actively working to strengthen practices and procedures for data management activities as well as identifying, investigating and remediating any non -conformances with company requirements.

AveXis 认真对待确保公司数据准确性和可靠性的责任，并正积极致力于加强数据管理活动的做法和程序，以及识别、调查和整改任何不符合公司要求的情况。

In this regard, AveXis has initiated CAPA-777, which was reviewed by FDA investigators during the July 2019 Inspection. The CAPA includes performing an expanded data integrity investigation pursuant to a written protocol, see Exhibit 4, to fully assess the GxP activities impacted by both of the senior executives associated with data manipulation and to perform a risk-based assessment of those activities to determine whether any further investigation or review is required.

在这方面，AveXis 已启动 CAPA-777，FDA 检查员在 2019 年 7 月检查期间对该 CAPA 进行了审查。该 CAPA 包括按照书面方案（见附件 4）开展扩大范围的数据完整性调查，以全面评估受与数据操纵相关的两名高级管理人员影响的 GxP 活动，并对这些活动进行基于风险的评估，以确定是否需要开展任何进一步的调查或审查。

Observation 1(A) Corrective and Preventive Actions

检查发现项 1(A) 的纠正和预防措施

除上方第 II 节所述的措施（包括根据 QIP 和数据完整性整改计划采取的措施）外，AveXis 还将采取以下措施，以确保检查发现项 1(A) 中指出的问题得到充分解决。

1.12 AveXis has initiated CAPA-777 to perform an expanded data integrity investigation pursuant to a written protocol to fully assess the GxP activities impacted by both of the senior AveXis executives associated with data manipulation and to perform a risk-based assessment of those activities to determine whether any further investigation or review is required.

1.12 AveXis 已启动 CAPA-777，按照书面方案开展扩大范围的数据完整性调查，以全面评估受与数据操纵相关的两名 AveXis 高级管理人员影响的 GxP 活动，并对这些活动进行基于风险的评估，以确定是否需要开展任何进一步的调查或审查。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

OBERVATION 1(B)

检查发现项 1(B)

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

未能彻底审核任何无法解释的差异，无论该批次是否已上市销售。

Specific Response to Observation 1(B)

对检查发现项 1(B) 的具体回复

AveXis recognizes the importance of control of quality documents. AveXis notes that prior to FDA’s inspection, in July 2018, the company implemented SOP-381, Control of QC Test Forms, which includes enhanced controls for quality documents, including establishing a process for reconciliation of quality forms. As part of the QIP, AveXis, with the assistance of Novartis quality personnel, will perform a comprehensive review of document control practices, procedures, and systems. As appropriate, CAPAs will be generated to enhance AveXis Quality Assurance’s control of quality documents.

AveXis 认识到质量文件控制的重要性。AveXis 指出，在 FDA 检查之前，公司于 2018 年 7 月实施了 SOP-381《QC 检验表格控制》，其中包括对质量文件的强化控制，例如建立了质量表格的核对流程。作为 QIP 的一部分，AveXis 将在诺华质量人员的协助下，对文件控制做法、程序和体系进行全面审查。AveXis 将酌情制定 CAPA，以加强 AveXis 质量保证（QA）部门对质量文件的控制。

With respect to NCR-409, AveXis will amend the investigation report with an analysis of the apparent form issuance discrepancy, including root cause determinations and impact assessment. At a minimum, AveXis will revise SOP-381, Control of QC Test Forms, to require verification of consistent time/date stamps during reconciliation of the form. In addition, AveXis will perform a review of all forms and procedures used to record and report GxP data in order to ensure consistent practices for issuance, time/date stamps, reconciliation, and data management verification.

关于 NCR-409，AveXis 将修订调查报告，加入对明显表格发放差异的分析，包括根本原因判定和影响评估。AveXis 至少将修订 SOP-381《QC 检验表格控制》，要求在表格核对时验证时间/日期戳的一致性。此外，AveXis 将对用于记录和报告 GxP 数据的所有表格和程序进行审查，以确保在发放、时间/日期戳、核对和数据管理验证方面做法一致。

With respect to the investigation, as described above, AveXis is implementing substantial enhancements to assure robust quality investigations including an investigation certification program. As an interim control, AveXis has engagedto independently review A veXis NCRs pri or to clo s ure. Fu rther, AveXis will e ngageto perform a protocol-based retrospective review of closed major and critical NCRs, and a statistically significant sample of closed minor NCRs to assure that adequate investigations were performed and scientifically justified conclusions reached. In the event that this review identifies material deficiencies in conclusion or impact, the specific investigation will be amended and subject to review by

关于调查方面，如上所述，AveXis 正在实施重大改进，以确保质量调查的稳健性，其中包括调查认证计划。作为过渡性控制措施，AveXis 已聘请在 AveXis 不符合项报告（NCR）关闭前对其进行独立审查。此外，AveXis 将聘请按照方案对已关闭的重大和关键 NCR 以及具有统计学显著样本量的已关闭次要 NCR 进行回顾性审查，以确保开展了充分的调查并得出有科学依据的结论。如果该审查发现结论或影响方面存在实质性缺陷，相关调查将予以修订，并由进行审查

retrospective review of closed major and critical NCRs, and a statistically significant sample of closed minor NCRs to assure that adequate investigations were performed and scientifically justified conclusions reached. In the event that this review identifies material deficiencies in conclusion or impact, the specific investigation will be amended and subject to review by

对已关闭的重大和关键 NCR 以及具有统计学显著样本量的已关闭次要 NCR 进行回顾性审查，以确保开展了充分的调查并得出有科学依据的结论。如果该审查发现结论或影响方面存在实质性缺陷，相关调查将予以修订，并由

Observation 1(B) Corrective and Preventive Actions (b) (4)

检查发现项 1(B) 的纠正和预防措施 (b) (4)

除上方第 II 节所述的措施（包括根据 QIP 和数据完整性整改计划采取的措施）外，AveXis 还将采取以下措施，以确保检查发现项 1(B) 中指出的问题得到充分解决。

1.13 With respect to NCR-409, AveXis will amend the investigation report with an analysis of the apparent form issuance discrepancy, including root cause determinations and impact assessment.

1.13 关于 NCR-409，AveXis 将修订调查报告，加入对明显表格发放差异的分析，包括根本原因判定和影响评估。

TCD: October 2019

目标完成日期（TCD）：2019 年 10 月

1.14 AveXis will revise SOP-381, Control of QC Test Forms, and SOP-076, Issuance and General Use of Logbooks, to require verification of consistent time/date stamps during reconciliation of the form.

1.14 AveXis 将修订 SOP-381《QC 检验表格控制》和 SOP-076《记录本的发放与一般使用》，要求在表格核对时验证时间/日期戳的一致性。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

1.15 AveXis will perform a review of all forms and procedures used to record and report GxP data in order to ensure consistent practices for time/date stamps, reconciliation and for data management verification and authorization.

1.15 AveXis 将对用于记录和报告 GxP 数据的所有表格和程序进行审查，以确保在时间/日期戳、核对以及数据管理验证和授权方面做法一致。

TCD: December 2019

目标完成日期（TCD）：2019 年 12 月

1.16 AveXis engagedto perform a protocol-based retrospectivereviewofclosed majorand criticalNCRs, and astatisticallysignificantsampleofclosed minorNCRs toassurethatadequateinvestigations wereperformed and scientifically justified conclusions reached.

1.16 AveXis 已聘请按照方案对已关闭的重大和关键 NCR 以及具有统计学显著样本量的已关闭次要 NCR 进行回顾性审查，以确保开展了充分的调查并得出有科学依据的结论。

TCD: Complete; retrospective review protocol is under development

目标完成日期（TCD）：已完成；回顾性审查方案正在制定中

OBERVATION 1(C)

检查发现项 1(C)

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

未能彻底审核任何无法解释的差异，无论该批次是否已上市销售。

C. Non-conformance Report NCR-965 was opened on 23 Aug 2018 and has and "Event Description" of "On 23Aug 2018, during the review of 7SMA mouse database, it was discovered that there were discrepancies in the data that was used to calculate relative potency for AVXS101 Drug Product. Lot 816836 had single mouse survival days recorded that were different from the actual value...." As documented in the investigation most of the discrepancies noted were discrepant by a single day which was attributed to ambiguity in SOP-285 "Determination of lnVivo Relative Potency for AVXS-101 Drug Product" however in 4 cases discrepancies of greater than 1 day were noted (ranging from 2-19 days). There is no documentation in NCR-965 that these 4 cases were investigated further to determine a potential root cause.

Specific Response to Observation 1(C)

对检查发现项 1(C) 的具体回复

AveXis recognizes that unexplained discrepancies must be appropriately investigated, including root cause determination. AveXis notes that since the initiation of investigation noted in NCR965, the company has made significant quality enhancements to the San Diego site’s performance of in vivo relative potency assay, including the establishment of quality oversight during the testing of the in vivo functionality assay.

AveXis 认识到，必须对无法解释的差异进行适当调查，包括确定根本原因。AveXis 指出，自 NCR-965 中所述调查启动以来，公司已对圣地亚哥工厂的体内相对效力试验实施进行了重大质量改进，包括在体内功能性试验的检验过程中建立质量监督。

The investigation documented in NCR-965 wasinitiated on August23, 2018, followingareviewof the Δ7SMA mouse database that found discrepancies in the data that was used to calculate relativepotencyforAVXS-101 DrugProductlot816836, releasedin September2017 basedon relativepotencyresults obtained underSOP-285, theIVRPA. Specifically,recordedsinglemousesurvivaldays weredetermined to varyfrom actualsurvivaldays.Theinvestigationdetermined thatdueto thesurvivalcalculation discrepancy, thereported relativepotencyvalueoffor lot 816836 should have been reported as%. The relevant specification for potency was%, therefore the investigation concluded that there was no impact on product quality or subject safety.

NCR-965 中记载的调查于 2018 年 8 月 23 日启动，此前对 Δ7SMA 小鼠数据库的审查发现，用于计算 AVXS-101 制剂批次 816836 相对效力的数据存在差异。批次 816836 于 2017 年 9 月根据 SOP-285（IVRPA）项下获得的相对效力结果放行。具体而言，经确定，记录的单只小鼠存活天数与实际存活天数不符。调查确定，由于存活天数计算的差异，批次 816836 已报告的相对效力值本应报告为%。相应的效力标准为%，因此调查结论认为对产品质量或受试者安全没有影响。

AveXis performed a comprehensive data review as part of the investigation into survival date discrepancies associated with SOP-285. The investigation found thatout oftest animals were associated with asurvival-days discrepancy attributed to lack ofclearinstructionsin therelevantprocedures forcountingthedayofbirth ofatestanimalin thesurvivaldayscalculation, as wellas failureoflaboratorypersonnelto employconsistentcountingmethods. An additionalcalculations were found in which the survival days calculation discrepancies was. Specifically, the review found discrepancies ofdays. Theinvestigation found no impacton any oftheassociated batches,except with respecttoabove-described impacton therelative-potencycalculation forlot816836.Amousefromtherelevant group thatreceived Lot816836 was associated with theday discrepancy, which contributed to the change in reported relative potency to% from%. Atthetimeoftheinvestigation, SOP-285 was no longerused forreleaseorstabilitytesting.Nonetheless, theprocedurewas updated to provideaclearprocessforcalculating survivaldaysin theeventthatitis used again, for example as part of testing during an investigation.

作为对与 SOP-285 相关的存活天数差异调查的一部分，AveXis 进行了全面的数据审查。调查发现，只受试动物中有只与天的存活天数差异相关，其原因是在存活天数计算中，相关程序缺乏关于如何计算受试动物出生日的明确说明，以及实验室人员未能采用一致的计数方法。另有项计算被发现存在天的存活天数计算差异。具体而言，审查发现的差异为天。调查认为，除上述对批次 816836 相对效力计算的影响外，对任何相关批次均无影响。接受批次 816836 的相关组中有一只小鼠与天的差异相关，该差异导致报告的相对效力从% 变为%。在调查之时，SOP-285 已不再用于放行或稳定性试验。尽管如此，该程序仍进行了更新，以便在再次使用（例如作为调查期间检验的一部分）时提供明确的存活天数计算流程。

days. The investigation found no impact on any o f the associated batches, except with respect to above-described impact on the relative-potency calculation for lot 816836. A mouse from the relevant group that received Lot 816836 was associated with the (b) (4) day discrepancy, which contributed to the change in reported relative potency to (b) (4)% from (b) (4)%. At the time of the investigation, SOP-285 was no longer used for release or stability testing. Nonetheless, the procedure was updated to provide a clear process for calculating survival days in the event that it is used again, for example as part of testing during an investigation.

天。调查认为，除上述对批次 816836 相对效力计算的影响外，对任何相关批次均无影响。接受批次 816836 的相关组中有一只小鼠与 (b) (4) 天的差异相关，该差异导致报告的相对效力从 (b) (4)% 变为 (b) (4)%。在调查之时，SOP-285 已不再用于放行或稳定性试验。尽管如此，该程序仍进行了更新，以便在再次使用（例如作为调查期间检验的一部分）时提供明确的存活天数计算流程。

With respect to root cause determination, AveXis notes that NCR-1922 addressees the same data set as NCR-965 and the interim NCR-1922 identified data manipulation as the likely cause of the four referenced cases of data discrepancy that were greater than 1 day. AveXis will amend NCR-965 with a summary of those conclusions and related impact assessment.

关于根本原因判定，AveXis 指出，NCR-1922 涉及与 NCR-965 相同的数据集，临时性 NCR-1922 将数据操纵认定为所提及的四例超过 1 天的数据差异事件的可能原因。AveXis 将在 NCR-965 中补充这些结论的摘要及相关影响评估，以对其进行修订。

In addition, to assure that there is no ambiguity in the current in vivo test method, AveXis will review, and as necessary revise, SOP-346, In-vivo Functionality Test using a Single Dose AVXS101 in SMNΔ7 Mouse Model, to provide specific instruction on how to calculate survival days.

此外，为确保现行体内检验方法不存在歧义，AveXis 将审查并在必要时修订 SOP-346《在 SMNΔ7 小鼠模型中使用单剂量 AVXS-101 进行体内功能性试验》，以提供关于如何计算存活天数的具体说明。

Observation 1(C) Corrective and Preventive Actions

检查发现项 1(C) 的纠正和预防措施

除上方第 II 节所述的措施（包括根据 QIP 和数据完整性整改计划采取的措施）外，AveXis 还将采取以下措施，以确保检查发现项 1(C) 中指出的问题得到充分解决。

1.17 AveXis will amend NCR-965 with a summary of the conclusions from NCR-1922, which addresses the same dataset and related impact assessment.

1.17 AveXis 将在 NCR-965 中补充 NCR-1922 结论的摘要（NCR-1922 涉及相同的数据集）及相关影响评估，以对其进行修订。

TCD: October 2019

目标完成日期（TCD）：2019 年 10 月

1.18 To assure that there is no ambiguity in the current in vivo test method, AveXis will review, and as necessary revise, SOP-346, In-vivo Functionality Test using a Single Dose AVXS-101 in SMNΔ7 Mouse Model, to provide specific instruction on how to calculate survival days.

1.18 为确保现行体内检验方法不存在歧义，AveXis 将审查并在必要时修订 SOP-346《在 SMNΔ7 小鼠模型中使用单剂量 AVXS-101 进行体内功能性试验》，以提供关于如何计算存活天数的具体说明。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

OBERVATION 1(D)

检查发现项 1(D)

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

未能彻底审核任何无法解释的差异，无论该批次是否已上市销售。

D. Non-conformance Report NCR-1116 was opened on 15 Oct 2018 and has "Event Description" of "Inconsistencies were identified during the review and approval of the data previously reported within REC-1606 v1.0 'Mouse Survival Data: Results for In-vivo Relative Potency for AVXS-101 Drug Product'...." As documented in the investigation " ... During investigational review of the Quality Employee's process, it was determined that some of the early raw data results were initially communicated verbally from the... to the AveXis Quality Employee...." There is no documentation in NCR-1116 explaining why the Quality Employee accepted verbal communication of raw data without corresponding written documentation.

Specific Response to Observation 1(D)

对检查发现项 1(D) 的具体回复

AveXis understands that quality data should be appropriately recorded and maintained. As identified in NCR-1116, AveXis data management procedures in place at the time of the relevant events did not provide specific details on verbal communication of data. Current AveXis procedures controlling data management include controls to prevent the acceptance of verbal communication of raw data without written documentation. Specifically, SOP-003, Good Documentation Practices, incorporated ALCOA principles in version 2.0 effective October 6, 2017, and was further updated August 2019 to incorporate the definition of raw data recorded on paper or electronically.

AveXis 理解，质量数据应得到适当的记录和维护。如 NCR-1116 所指出的，AveXis 在相关事件发生时实施的数据管理程序并未就数据口头沟通提供具体细节。AveXis 现行控制数据管理的程序包括防止在没有书面文件的情况下接受口头传达的原始数据的控制措施。具体而言，SOP-003《良好记录规范》在 2017 年 10 月 6 日起生效的第 2.0 版中纳入了 ALCOA 原则，并于 2019 年 8 月进一步更新，纳入了以纸质或电子方式记录的原始数据的定义。

In addition, Policy POL-007, Data Integrity Policy, was established in April 2017 and also incorporates ALCOA principles, including the definition of an original record as “Data as the file or format in which it was originally generated, preserving the integrity (accuracy, completeness, content and meaning) of the record, e.g., original paper record of manual observation, or electronic raw data file from a computerized system.” To ensure that relevant employees fully understand the importance of these controls, AveXis will re-train all personnel who handle GxP data on these established data management procedures.

此外，POL-007《数据完整性政策》于 2017 年 4 月制定，同样纳入了 ALCOA 原则，包括将原始记录定义为“数据以最初生成时的文件或格式存在，保持记录的完整性（准确性、完整性、内容及含义），例如手工观察的原始纸质记录，或计算机化系统产生的电子原始数据文件”。为确保相关员工充分理解这些控制措施的重要性，AveXis 将依据这些既定的数据管理程序，对所有处理 GxP 数据的人员进行再培训。

More broadly, as outlined abovein Section II, AveXis is implementingaDataIntegrityRemediation Plan.Onepillar ofthis plan is improvingqualitycultureand improvingdataintegrityawarenessacrossthecompany. AspartoftheDataIntegrityRemediation Plan, will investigate the scope of data integrity anomalies at AveXis. This will include improper documentation of quality data. will also evaluate AveXis’s data integrity controls and oversight.

更广泛而言，如上文第二节所述，AveXis 正在实施数据完整性整改计划。该计划的支柱之一是在全公司范围内提升质量文化并增强数据完整性意识。作为数据完整性整改计划的一部分，将调查 AveXis 数据完整性异常情况的范围，包括质量数据记录不规范的情况。还将评估 AveXis 的数据完整性控制措施及监督机制。

Observation 1(D) Corrective and Preventive Actions

观察项 1(D) 纠正和预防措施

除上文第二节所述措施（包括根据质量改进计划（QIP）和数据完整性整改计划采取的措施）外，AveXis 将采取以下措施，以确保观察项 1(D) 中明确指出的问题得到全面解决。

1.19 AveXis revised SOP-003, Good Documentation Practices, to incorporate the definition of raw data recorded on paper or electronically.

1.19 AveXis 修订了 SOP-003《良好记录规范》，纳入了以纸质或电子方式记录的原始数据的定义。

TCD: Complete

目标完成日期（TCD）：已完成

Further, as noted above in the response to Observation 1:

此外，如上文对观察项 1 的回复所述：

1.8 AveXis will re-train all personnel engaged in GxP activities on POL-007, Data Integrity Policy, and SOP-003, Good Documentation Practices.

1.8 AveXis 将依据 POL-007《数据完整性政策》和 SOP-003《良好记录规范》，对所有从事 GxP 活动的人员进行再培训。

TCD: October 2019; additional training will be provided pursuant to the CAP

目标完成日期（TCD）：2019 年 10 月；将根据合规行动计划（CAP）提供补充培训

OBSERVATION 2

检查发现项 2

Laboratory records do not include complete data derived from all tests, examinations and assay necessary to assure compliance with established specifications and standards.

实验室记录未包含为确保符合既定规格和标准所需的全部检验、检查和试验所得出的完整数据。

A. Analytical Balance ID #which is used to weigh micehandled underSOP-268 Version 2.0 entitled “Observation and Handling ofStudyMicefor AVXS-101 PotencyAssay”does nothaveaudittrailcapability. Thesemiceareused for SOP-346Version 3.0 entitled “In-vivo FunctionalityTestusing a SingleDoseAVXS-101 in SMN7 Mouse Model”.

A. 用于对按照 SOP-268 第 2.0 版《AVXS-101 效力试验研究小鼠的观察与处理》处理的小鼠进行称重的分析天平（设备编号：）不具备审计追踪功能。这些小鼠用于 SOP-346 第 3.0 版《单剂量 AVXS-101 在 SMNΔ7 小鼠模型中的体内功能性试验》。

B. Printoutsfortheweighing ofmicearenotmadeand included in thelogbookwheretheweights arecurrentlymanuallyrecorded.AnalyticalbalanceID#:which is used to weigh the miceis capableofproducing printouts ofweighings; howeverprintoutsofmouseweights arenotmadeand included with thedata thatis manuallyrecordedin thelogbook,thatas an examplecan beseen in LogbookIDNumber 000139 “AVXS-101 In-vivo Functionality”on FORM-339“Weightand Survival Data for AVXS-101 FunctionalityTest”.Thesemiceareused forSOP-346 Version 3.0 entitled “In-vivo Functionality Test using a Single Dose AVXS-101 in SMNΔ7 Mouse Model”.

B. 小鼠称重的打印输出未生成，也未纳入目前以手工方式记录体重的日志本中。用于小鼠称重的分析天平（设备编号：）具备生成称重打印输出的能力；然而，小鼠体重的打印输出并未生成并随手工记录的数据一并纳入日志本，例如可在日志本编号 000139《AVXS-101 体内功能性》中的 FORM-339《AVXS-101 功能性试验体重与生存数据》看到。这些小鼠用于 SOP-346 第 3.0 版《单剂量 AVXS-101 在 SMNΔ7 小鼠模型中的体内功能性试验》。

C. The equipment number of the analytical balance which is used to weigh mice handled under SOP-268 Version 2.0 entitled “Observation and Handling of Study Mice for AVXS101 Potency Assay” is not recorded in the logbook which, as an example can be seen in Logbook ID Number 000139 “AVXS-101 In-vivo Functionality”. These mice are used for SOP-346 Version 3.0 entitled “In-vivo Functionality Test using a Single Dose AVXS-101 in SMNΔ7 Mouse Model”.

C. 用于对按照 SOP-268 第 2.0 版《AVXS-101 效力试验研究小鼠的观察与处理》处理的小鼠进行称重的分析天平的设备编号未记录在日志本中，例如可在日志本编号 000139《AVXS-101 体内功能性》中看到。这些小鼠用于 SOP-346 第 3.0 版《单剂量 AVXS-101 在 SMNΔ7 小鼠模型中的体内功能性试验》。

General Response to Observation 2

对检查发现项 2 的总体回复

AveXis fully recognizes the importance of ensuring that laboratory records include complete data derived from all tests, examinations, and assays necessary to assure compliance with establish specifications and standards. Assuring the accuracy, completeness, and reliability of GxP data is a fundamental principle of data integrity and good documentation practice, and one that AveXis takes extremely seriously.

AveXis 充分认识到确保实验室记录包含为确保符合既定规格和标准所需的全部检验、检查和试验所得出的完整数据的重要性。确保 GxP 数据的准确性、完整性和可靠性是数据完整性和良好记录规范的基本原则，也是 AveXis 极为重视的原则。

Indeed, as discussed with the FDA investigators during the July 2019 inspection and as outlined above in Section II, at the time of the inspection, AveXis had several controls in place to ensure the completeness, accuracy, and reliability of laboratory records. For example, computerized systems generating electronic data, including electronic laboratory data, are subject to the qualification and validation requirements set forth in SOP-279, Computerized System Qualification and Validation. See Exhibit 5. These requirements include the establishment of user requirements specifications, vendor audits and assessments, risk assessments, configuration

事实上，正如 2019 年 7 月现场检查期间与 FDA 检查人员讨论的以及上文第二节所述，检查之时，AveXis 已建立多项控制措施以确保实验室记录的完整性、准确性和可靠性。例如，生成电子数据（包括电子实验室数据）的计算机化系统须符合 SOP-279《计算机化系统确认与验证》中规定的确认与验证要求（见附件 5）。这些要求包括建立用户需求说明、开展供应商审计与评估、进行风险评估、制定配置

specifications, design qualifications, installation qualification, operational qualification, performance qualification, a traceability matrix, a validation plan summary report, operational manuals, training, and the establishment of administration procedures. These requirements ensure that GxP computerized systems perform as expected in accordance with predetermined specifications, user-defined requirements, and applicable FDA regulations, including 21 CFR Part 11. As such, these requirements also ensure that electronic records generated at AveXis, including laboratory records, are accurate, complete, and reliable.

规格、设计确认、安装确认、运行确认、性能确认、可追溯性矩阵、验证计划摘要报告、操作手册、培训以及管理规程的建立。这些要求确保 GxP 计算机化系统按照预定规格、用户定义的要求以及适用的 FDA 法规（包括 21 CFR 第 11 部分）按预期运行。因此，这些要求也确保 AveXis 生成的电子记录（包括实验室记录）准确、完整、可靠。

More broadly, pursuant to Plan 313 Version 4.0, AveXis Data Integrity Plan, see Exhibit 3, AveXis is performing data integrity assessments of computerized systems used for GxP operations across the company, including laboratory computerized systems, for adherence to ALCOA data integrity principles and 21 CFR Part 11 compliance. Please note that these assessments commenced in January 2019. AveXis’s assessment of computertized systems is focused on identifying gaps in the following areas:

更广泛而言，根据计划 313 第 4.0 版《AveXis 数据完整性计划》（见附件 3），AveXis 正在对公司范围内用于 GxP 运营的计算机化系统（包括实验室计算机化系统）开展数据完整性评估，以确认其遵守 ALCOA 数据完整性原则并符合 21 CFR 第 11 部分的要求。请注意，这些评估于 2019 年 1 月启动。AveXis 对计算机化系统的评估侧重于识别以下领域的差距：

Physical Security and Logical Security

物理安全和逻辑安全

User Access and Segregation of Roles

用户访问与职责分离

Electronic Records and Electronic Signatures

电子记录与电子签名

Periodic Reviews of Audit Trails and Access Rights

审计追踪与访问权限的定期审查

Validation life cycle documentation

验证生命周期文件

Data Life Cycle and Data Management

数据生命周期与数据管理

Data Modifications, Review, and Approval

数据修改、审核与批准

Procedures and Agreements

程序与协议

Gaps identified pursuant to these computerized system assessments—which are ongoing—are documented in controlled forms, and these gaps are being remediated pursuant to written remediation plans.

根据这些正在进行中的计算机化系统评估所识别出的差距，均以受控表格予以记录，并正依据书面的整改计划对这些差距进行整改。

With respect to non-electronic (i.e., paper) GxP records, SOP-003, Good Documentation Practices, attached at Exhibit 6, provides that:

对于非电子（即纸质）GxP 记录，SOP-003《良好记录规范》（见附件 6）规定：

Falsification of records is strictly prohibited. Pursuant to SOP-003, falsification includes back dating or entering a future date; signing someone else’s name; signing a document or record before the activity is performed; signing for, witnessing, or verifying a step without witnessing or verifying the activity; copying and/or pasting

严禁伪造记录。根据 SOP-003，伪造行为包括：倒填日期或填写未来日期；代他人签名；在活动实施之前签署文件或记录；未经亲眼见证或核实活动即对某一步骤进行签署、见证或确认；复制和/或粘贴

scanned signatures for use as approval signatures; entering data/information not directly obtained, that did not occur, or that was not observed; entering data when testing was not performed, completed, or that is not reflective of the actual result obtained; and destroying or voiding original data or information without documenting such action.

扫描签名用作批准签名；录入并非直接获得、未实际发生或未经观察的数据/信息；在检验未进行、未完成或所录数据不能反映实际所得结果的情况下录入数据；以及在未记录该行为的情况下销毁或作废原始数据或信息。

o All data/information are to be recorded by the person who has performed the activity/task unless the document clearly indicates that information is being record by someone other than the performer AND the performer’s signature is also present.

o 所有数据/信息均应由执行该活动/任务的人员记录，除非文件明确注明信息由执行者以外的人员记录，且执行者的签名同时在场。

o All entries must be made at the time tasks are performed. Records must indicate the date and/or time tasks were performed/recorded as indicated by specification, procedure, or record format.

o 所有记录必须在执行任务之时完成。记录必须按规格、程序或记录格式的要求注明任务执行/记录的日期和/或时间。

o Raw data must be retained in its entirety and original form, e.g. printouts of all attempts at system suitability (whether passing or not) OR all calibration attempts, including failures.

o 原始数据必须以完整且原始的形式保存，例如系统适用性所有尝试的打印输出（无论通过与否），或所有校准尝试（包括失败的校准）的打印输出。

SOP-238, Data Integrity Controls, attached at Exhibit 7, further provides that all data generated at AveXis must be accurate, legible, contemporaneous, original, and attributable (ALCOA). SOP-238 also prohibits deleting, manipulating, or modifying GxP data.

SOP-238《数据完整性控制措施》（见附件 7）进一步规定，AveXis 生成的所有数据必须准确（Accurate）、清晰（Legible）、同步（Contemporaneous）、原始（Original）、可归属（Attributable）（即 ALCOA 原则）。SOP-238 还禁止删除、操纵或修改 GxP 数据。

Against this backdrop, please note that during the inspection, the FDA investigators spent more than one full inspection day evaluating AveXis’s installation qualification, operational qualification, and performance qualification (collectively, the qualification package) for the computerized imaging equipment used to perform the in vitro relative potency assay, which, as detailed above, was developed by AveXis to address widely recognized issues of variability with the in vivo relative potency assay. The investigators also assessed AveXis’s oversight and controls relative to the computerized imaging equipment, including audit trail capability, access controls, and user privileges. The investigators’ review of AveXis’s qualification package for the computerized imaging equipment used to perform the in vitro relative potency assay and AveXis’s oversight and controls relative to this instrument did not result in any inspectional observations. The investigators also reviewed raw in vitro relative potency assay data generated using the computerized imaging equipment. Their review did not result in any inspectional observations.

在此背景下，请注意，在现场检查期间，FDA 检查人员花费超过一个完整检查日，评估 AveXis 用于执行体外相对效力试验的计算机化成像设备的安装确认、运行确认和性能确认（统称为确认资料包）。如上文详述，该体外方法由 AveXis 开发，旨在解决体内相对效力试验公认的变异性问题。检查人员还评估了 AveXis 对该计算机化成像设备的监督和控制措施，包括审计追踪能力、访问控制和用户权限。检查人员对 AveXis 用于执行体外相对效力试验的计算机化成像设备确认资料包以及 AveXis 对该仪器的监督和控制措施的审查，未产生任何检查缺陷。检查人员还审查了使用该计算机化成像设备生成的体外相对效力试验原始数据，其审查同样未产生任何检查缺陷。

This being said, with respect to the specific laboratory records noted in Observation 2—i.e., mice weighing records—AveXis recognizes that 483 identifies areas where documentation practices relating to mice weighing could be strengthened. The company also recognizes that the recently identified data manipulation relating to mice weighing records and SOP-285—which AveXis reported to FDA on June 28, 2019—is a serious issue. Indeed, as FDA is aware, upon learning of this alleged data manipulation, AveXis performed an internal investigation to assess the

话虽如此，对于观察项 2 中指出的具体实验室记录——即小鼠称重记录——AveXis 承认 483 中指出的与小鼠称重相关的记录规范方面可以进一步加强。公司还承认，最近发现的与小鼠称重记录和 SOP-285 相关的数据操纵（AveXis 已于 2019 年 6 月 28 日向 FDA 报告）是一个严重问题。事实上，如 FDA 所知，在得知该涉嫌数据操纵后，AveXis 立即开展了内部调查，以评估

Observation 2 Corrective and Preventive Actions veracity of the claims and to determine the potential scope of the data inaccuracies. AveXis engaged an independent third party to interview key personnel regarding the data manipulation, including laboratory and vivarium personnel, and to perform a comprehensive review of all available records relating to SOP-285.

【观察项 2 纠正和预防措施】上述说法的真实性，并确定数据不准确情况的潜在范围。AveXis 聘请了独立第三方，就数据操纵事件对关键人员进行访谈（包括实验室和动物房人员），并对与 SOP-285 相关的所有可用记录进行全面审查。

While AveXis believes, based on this initial investigation, that there are no systemic or widespread data integrity or document management deficiencies at the company, AveXis has engagedto perform adataintegrityassessmentofthecompany’smanufacturing,laboratory, and clinicaldata.In lightofthe483, thescopeofassessment has been expanded to coverthecompany’sdataintegritycontrols and oversightmorebroadly,including documentation practicecontrols;controlsrelatingto theissuanceofcontrolled forms anddocuments;thesite’s computerized systemscontrols;processes forreviewingdatapursuantto release, includingthescopeofQAreviewofelectronic and paperrecords;and AveXis’s internal audit function.

尽管根据初步调查，AveXis 认为公司不存在系统性或普遍性的数据完整性或文件管理缺陷，但 AveXis 已聘请对公司生产、实验室和临床数据开展数据完整性评估。鉴于 483 的内容，的评估范围已扩大，更广泛地覆盖公司的数据完整性控制措施和监督机制，包括：记录规范控制；受控表格和文件发放相关的控制；本场所计算机化系统控制；根据放行要求进行数据审核的流程，包括 QA 对电子和纸质记录审核的范围；以及 AveXis 的内部审计职能。

In addition to assessing AveXis’s data integrity controls and oversight,will investigatewhetherthescopeofthedataintegritydeficiencies is limited to thespecificinstances previouslyreported to FDAand whetherthescopeofthedocumentation deficiencies is limitedto thespecificinstances noted in the483.Pursuantto this investigation,will evaluate raw data, including laboratory data submitted to FDA in the Zolgensma® BLA, for evidence of discrepancies or manipulation.

除评估 AveXis 的数据完整性控制措施和监督机制外，还将调查数据完整性缺陷的范围是否仅限于先前向 FDA 报告的特定事件，以及文件缺陷的范围是否仅限于 483 中指出的特定事件。根据此项调查，将评估原始数据（包括 Zolgensma® BLA 中提交给 FDA 的实验室数据），查找差异或操纵的证据。

AveXis also recognizes that Observation 2 identifies areas where the company’s controls and oversight to ensure the completeness, accuracy, and reliability of GxP records, including laboratory records, could be further strengthened, particularly respect to records that, historically, have not been classified as electronic records. In this regard, as detailed above in the section setting forth the CAP, AveXis is implementing a Data Integrity Remediation Plan to ensure that the 483 observations are comprehensively addressed and to prevent recurrence of such issues in the future. CAPAs relating to the specific instances noted in Observation 2 are detailed below.

AveXis 还承认，观察项 2 指出了公司为确保 GxP 记录（包括实验室记录）的完整性、准确性和可靠性而设置的控制和监督措施可进一步加强的领域，特别是对于历史上未被归类为电子记录的那些记录。在这方面，如上文阐述合规行动计划（CAP）的部分所详述，AveXis 正在实施数据完整性整改计划，以确保 483 检查缺陷得到全面解决，并防止此类问题在未来再次发生。与观察项 2 中指出的具体事件相关的纠正和预防措施（CAPA）详见下文。

除上文第二节所述措施（包括根据质量改进计划（QIP）和数据完整性整改计划采取的措施）外，AveXis 将采取以下措施，以确保观察项 2 中明确指出的问题得到全面解决。

2.1 AveXis engagedto perform an independent, third-party data integrity investigation and assessment at AveXis pursuant to a written protocol.

2.1 AveXis 已聘请按照书面方案在 AveXis 开展独立、第三方的数据完整性调查与评估。

TCD: Complete; data integrity investigation protocol is under development

目标完成日期（TCD）：已完成；数据完整性调查方案正在制定中

OBSERVATION 2(A)

观察项 2(A)

Laboratory records do not include complete data derived from all tests, examinations and assay necessary to assure compliance with established specifications and standards.

实验室记录未包含为确保符合既定规格和标准所需的全部检验、检查和试验所得出的完整数据。

A. Analytical Balance ID #:which is used to weigh micehandled underSOP-268 Version 2.0 entitled “Observation and Handling ofStudyMicefor AVXS-101 PotencyAssay”does nothaveaudittrailcapability. Thesemiceareused for SOP-346Version 3.0 entitled “In-vivo FunctionalityTestusing a SingleDoseAVXS-101 in SMN7 Mouse Model”.

Specific Response to Observation 2(A)

对检查发现项 2(A) 的具体回复

As outlined above, AveXis has established several procedural controls to ensurethatelectronicrecords,includinglaboratoryrecords,areaccurate, complete, and reliable.Becausetheanalyticalbalancenoted in Observation 2(A)(EquipmentIDNo. does not generateelectronicrecords and, further, becausethis particularanalyticalbalancewas located intheR&Dareaand used historicallyforR&Dpurposes,itwas notsubjectto theserobust procedural controls.

如上所述，AveXis 已建立多项程序性控制措施，以确保包括实验室记录在内的电子记录准确、完整、可靠。由于观察项 2(A) 中指出的分析天平（设备编号：）不生成电子记录，且该分析天平位于研发区域，历史上一直用于研发目的，因此不受这些健全程序性控制措施的约束。

In light of the investigators’ observation regarding the audit trail capability of Analytical Balance ID No. AveXis will initiateachangecontrolto updateorreplacethis analyticalbalancewith aweighingsolution with audittrailcapability.AveXis is currentlyevaluatingtwo options—onewheretheexistinganalyticalbalanceis connected to aserverusing MettlerToledo’s LabX®laboratorydatamanagementsoftwareand anotherwhereAveXis willreplace EquipmentID No.with an audit-trail enabled weighing solution.

鉴于检查人员对分析天平（设备编号：）审计追踪功能的观察意见，AveXis 将启动一项变更控制，更新或更换该分析天平，采用具备审计追踪能力的称量解决方案。AveXis 目前正在评估两个方案：一是将现有分析天平通过 Mettler Toledo 的 LabX® 实验室数据管理软件连接到服务器；二是用具备审计追踪功能的称量解决方案更换设备编号的天平。

As an interim control, AveXis will ensure that the print function for Analytical Balance ID No.is enabled and that weightslips areautomaticallygenerated everytimethebalanceis used, eitherforweightcheck, calibration, orofficial testingpurposes.Toensurefulltraceabilityoftheweighingresults,theseprintouts willincludeabalanceidentifierin theheaderoftheprintout, auniquesequencenumber, and adateand timestamp. Theseprintouts willbeincluded in theofficialtestingrecords,and willbeinitialed bytheoperatorattheendofeach session.

作为临时控制措施，AveXis 将确保分析天平（设备编号：）的打印功能处于启用状态，并且无论天平用于称量核查、校准还是正式检验目的，每次使用都会自动生成称重凭条。为确保称重结果的完全可追溯性，这些打印输出将在页眉中包含天平标识符、唯一序列号以及日期和时间戳。这些打印输出将纳入正式检验记录，并由操作员在每个操作时段结束时签署姓名首字母。

AveXis will also revise SOP-066, Operation of QC Balances, to state that every use of the analytical balance must be recorded in the analytical balance logbook. In addition, pending the introduction of the enhanced weighing solution noted above, AveXis will introduce second person verification for all mouse weighing activities performed pursuant to SOP-268 to ensure that the data recorded in the testing records are complete, accurate, and reliable. The individual responsible for performing second person verification will document their review in the

AveXis 还将修订 SOP-066《质量控制天平的操作》，规定分析天平的每次使用都必须在分析天平日志本中予以记录。此外，在上述增强型称量解决方案投入使用之前，AveXis 将对依据 SOP-268 进行的所有小鼠称重活动引入双人复核，以确保检验记录中记录的数据完整、准确、可靠。负责执行双人复核的人员将在

analytical balance logbook and testing records, including their name and the date and time they witnessed and verified the weighing activities.

分析天平日志本和检验记录中记录其复核情况，包括其姓名以及亲眼见证并核实称重活动的日期和时间。

AveXis will also revise SOP-268, Observation and Handling of Study Mice for AVXS-101 Potency Assay, and related FORM-339, to state that printouts related to weighing performed in the vivarium must be reviewed and verified against the analytical balance logbooks to ensure that the data between the balance printout and the logbooks, including date of analysis, time of analysis, analyst name, and equipment number, are consistent.

AveXis 还将修订 SOP-268《AVXS-101 效力试验研究小鼠的观察与处理》及相关表格 FORM-339，规定必须将动物房内进行的称重相关打印输出与分析天平日志本进行核对和验证，以确保天平打印输出与日志本之间的数据一致，包括分析日期、分析时间、分析人员姓名和设备编号。

More broadly, AveXis will conduct a company-wide data integrity and documentation practice gap assessment for equipment used to perform quality control testing. This gap assessment will evaluate analytical balances used for GxP operations, including any analytical balances used for mice weighing activities, to determine whether such balances comply with FDA’s and AveXis’s data integrity expectations. Any equipment that does not meet FDA’s data integrity expectations will be upgraded, and any equipment that cannot be upgraded will be replaced. In each case, AveXis will implement second person verification, as outlined above, as an interim control to ensure data accuracy, reliability, and completeness.

更广泛而言，AveXis 将对用于执行质量控制检测的设备开展全公司范围的数据完整性和记录规范差距评估。该差距评估将评估用于 GxP 运营的分析天平，包括任何用于小鼠称重活动的分析天平，以确定这些天平是否符合 FDA 和 AveXis 的数据完整性期望。任何不符合 FDA 数据完整性期望的设备都将进行升级，无法升级的设备将予以更换。在每种情况下，AveXis 都将如上文所述实施双人复核，作为确保数据准确性、可靠性和完整性的临时控制措施。

Additionally, while the company believes that the data inaccuracies relating to mice weighing are limited to the specific instances reported to FDA on June 28, 2019, AveXis has engagedto perform adataintegrity a ssessment.As detailed above, this assessmentwillcoverAveXis’s dataintegritycontrols and oversightaswellasdatasubmitted to FDAin theZolgensma® BLA.

此外，尽管公司认为与小鼠称重相关的数据不准确情况仅限于 2019 年 6 月 28 日向 FDA 报告的特定事件，AveXis 仍已聘请开展数据完整性评估。如上文详述，该评估将涵盖 AveXis 的数据完整性控制措施与监督机制，以及 Zolgensma® BLA 中提交给 FDA 的数据。

Observation 2(A) Corrective and Preventive Actions

观察项 2(A) 纠正和预防措施

除上文第二节所述措施（包括根据质量改进计划（QIP）和数据完整性整改计划采取的措施）外，AveXis 将采取以下措施，以确保观察项 2(A) 中明确指出的问题得到全面解决。

2.2 AveXis will update or replace Analytical Balance ID No.with a weighing solution with audit trail capability.

2.2 AveXis 将更新分析天平（设备编号：）或将其更换为具备审计追踪能力的称量解决方案。

TCD: December 2019

目标完成日期（TCD）：2019 年 12 月

2.3 As an interim control, AveXis will ensure that the print function for Analytical Balance ID No.is enabled and that weight slips are automatically generated every time the balance is used, either for weight check, calibration, or official testing purposes.

2.3 作为临时控制措施，AveXis 将确保分析天平（设备编号：）的打印功能启用，并且无论天平用于称量核查、校准还是正式检验目的，每次使用都会自动生成称重凭条。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

2.4 AveXis will revise SOP-066, Operation of QC Balances, to state that every use of the analytical balance must be recorded in the analytical balance logbook.

2.4 AveXis 将修订 SOP-066《质量控制天平的操作》，规定分析天平的每次使用都必须在分析天平日志本中予以记录。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

2.5 AveXis will introduce second person verification for all mouse weighing activities performed pursuant to SOP-268 to ensure that the data recorded in the testing records are complete, accurate, and reliable.

2.5 AveXis 将对依据 SOP-268 进行的所有小鼠称重活动引入双人复核，以确保检验记录中记录的数据完整、准确、可靠。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

2.6 AveXis will revise SOP-268, Observation and Handling of Study Mice for AVXS-101 Potency Assay, and related FORM-339, to state that printouts related to weighings performed in the vivarium must be reviewed and verified against the analytical balance logbooks to ensure that the data between the balance printout and the logbooks, including date of analysis, time of analysis, analyst name, and equipment number, are consistent.

2.6 AveXis 将修订 SOP-268《AVXS-101 效力试验研究小鼠的观察与处理》及相关表格 FORM-339，规定必须将动物房内进行的称重相关打印输出与分析天平日志本进行核对和验证，以确保天平打印输出与日志本之间的数据一致，包括分析日期、分析时间、分析人员姓名和设备编号。

TCD: November 2019

目标完成日期（TCD）：2019 年 11 月

2.7 AveXis will conduct a company-wide data integrity and documentation practice gap assessment for equipment used to perform quality control testing.

2.7 AveXis 将对用于执行质量控制检测的设备开展全公司范围的数据完整性和记录规范差距评估。

TCD: December 2019

目标完成日期（TCD）：2019 年 12 月

OBSERVATION 2(B)

观察项 2(B)

Laboratory records do not include complete data derived from all tests, examinations and assay necessary to assure compliance with established specifications and standards.

实验室记录未包含为确保符合既定规格和标准所需的全部检验、检查和试验所得出的完整数据。

B. Printouts fortheweighing ofmicearenotmadeand included in thelogbookwheretheweights arecurrentlymanuallyrecorded.AnalyticalbalanceID#:which is used to weigh the miceis capableofproducing printouts ofweighings; howeverprintoutsofmouseweights arenotmadeand included with thedata thatis manuallyrecordedin thelogbook,thatas an examplecan beseen in LogbookIDNumber 000139 “AVXS-101 In-vivo Functionality”on FORM-339“Weightand Survival Data for AVXS-101 FunctionalityTest”.Thesemiceareused forSOP-346 Version 3.0 entitled “In-vivo Functionality Test using a Single Dose AVXS-101 in SMNΔ7 Mouse Model”.

Specific Response to Observation 2(B)

对检查发现项 2(B) 的具体回复

AveXis understands the importance of ensuring that original raw data, such as analytical balance printouts, are included in laboratory records and available for review throughout the applicable record retention period. With respect to the mice weighing records noted in Observation 2(B), AveXis recognizes that the original raw data relating to the mice weighing for SOP-346, In-vivo Functionality Test using a Single Dose AVXS-101 in SMNΔ7 Mouse Model—i.e., the balance sheet printouts—should have been included in the testing records subject to quality review.

AveXis 理解确保原始数据（如分析天平打印输出）纳入实验室记录并在适用记录保留期内可供审核的重要性。对于观察项 2(B) 中指出的小鼠称重记录，AveXis 承认，与 SOP-346（单剂量 AVXS-101 在 SMNΔ7 小鼠模型中的体内功能性试验）小鼠称重相关的原始数据——即天平打印输出——本应纳入接受质量审核的检验记录中。

In light of the investigators’ observation, AveXis will revise SOP-268, Observation and Handling of Study Mice for AVXS-101 Potency Assay, and related FORM-339 to state that that analysts must generate balance printouts for every use of the analytical balance, including weight checks, calibrations, and mice weighing, and that the balance printouts must include a unique sequence number and a date and time stamp. The analysts will be required to write their initials and individual mouse ID on the printout to assure full traceability.

鉴于检查人员的观察意见，AveXis 将修订 SOP-268《AVXS-101 效力试验研究小鼠的观察与处理》及相关表格 FORM-339，规定分析人员必须在每次使用分析天平（包括称量核查、校准和小鼠称重）时生成天平打印输出，且天平打印输出必须包含唯一序列号以及日期和时间戳。分析人员必须在打印输出上签署姓名首字母并注明单只小鼠编号（小鼠 ID），以确保完全可追溯性。

Revised SOP-268 will also require second person verification for all mouse weighing activities performed pursuant to SOP-268 to ensure that the data recorded in the testing records are complete, accurate, and reliable. The individual responsible for performing second person verification will document their review in the analytical balance logbook and testing records, including their name and the date and time they witnessed and verified the weighing activities.

修订后的 SOP-268 还将要求对依据 SOP-268 进行的所有小鼠称重活动实施双人复核，以确保检验记录中记录的数据完整、准确、可靠。负责执行双人复核的人员将在分析天平日志本和检验记录中记录其复核情况，包括其姓名以及亲眼见证并核实称重活动的日期和时间。

AveXis believes that these additional controls will ensure the accuracy, reliability, and completeness of mice weighing data.

AveXis 相信，这些额外的控制措施将确保小鼠称重数据的准确性、可靠性和完整性。

Additionally, as detailed above, while thecompanybelieves thatthedatainaccuracies relatingtomiceweighingarelimited to thespecificinstances reportedto FDAon June28, 2019,AveXishas engagedto perform a data integrity assessment. This assessment will cover

此外，如上文详述，尽管公司认为与小鼠称重相关的数据不准确情况仅限于 2019 年 6 月 28 日向 FDA 报告的特定事件，AveXis 仍已聘请开展数据完整性评估。该评估将涵盖

AveXis’s data integrity controls and oversight at the San Diego site, as well as manufacturing, laboratory, and clinical data submitted to FDA in the Zolgensma® BLA. (b) (4) will also be performing assessments across the AveXis sites, including with respect to the company’s commercial manufacturing, laboratory, and clinical data.

AveXis 圣地亚哥场所的数据完整性控制措施与监督机制，以及 Zolgensma® BLA 中提交给 FDA 的生产、实验室和临床数据。(b) (4) 还将在 AveXis 各场所开展评估，包括与公司商业生产、实验室和临床数据相关的评估。

Observation 2(B) Corrective and Preventive Actions

观察项 2(B) 纠正和预防措施

除上文第二节所述措施（包括根据质量改进计划（QIP）和数据完整性整改计划采取的措施）外，AveXis 将采取以下措施，以确保观察项 2(B) 中明确指出的问题得到全面解决。

As noted above in the response to Observation 2:

如上文对观察项 2 的回复所述：

2.3 AveXis will ensure that the print function for Analytical Balance ID No. is enabled and that weight slips are automatically generated every time the balance is used, either for weight check, calibration, or official testing purposes.

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

2.4 AveXis will revise SOP-066, Operation of QC Balances, to state that every use of the analytical balance must be recorded in the analytical balance logbook.

2.4 AveXis 将修订 SOP-066《质量控制天平的操作》，规定分析天平的每次使用都必须在分析天平日志本中予以记录。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

2.5 AveXis 将对依据 SOP-268 进行的所有小鼠称重活动引入双人复核，以确保检验记录中记录的数据完整、准确、可靠。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

TCD: November 2019

目标完成日期（TCD）：2019 年 11 月

OBSERVATION 2(C)

观察项 2(C)

Laboratory records do not include complete data derived from all tests, examinations and assay necessary to assure compliance with established specifications and standards.

实验室记录未包含为确保符合既定规格和标准所需的全部检验、检查和试验所得出的完整数据。

Specific Response to Observation 2(C)

对检查发现项 2(C) 的具体回复

AveXis understands the importance developing and implementing sufficient controls and oversight to ensure the traceability of GxP data. This includes ensuring that GxP records appropriately identify each piece of equipment used to perform the activities documented in such records. In light of the investigators’ observation relating to documentation of the analytical balance identification number in the corresponding testing logbooks, AveXis recognizes that including this information in the testing logbooks would enhance traceability. Accordingly, AveXis will revise FORM-339 to require the documentation of the balance ID in testing logbooks.

AveXis 理解制定和实施充分控制措施与监督机制以确保 GxP 数据可追溯性的重要性，其中包括确保 GxP 记录能恰当标明用于执行记录中所载活动的每一台设备。鉴于检查人员对相应检验日志本中分析天平标识号记录情况的观察意见，AveXis 认识到在检验日志本中记录该信息将增强可追溯性。因此，AveXis 将修订 FORM-339，要求在检验日志本中记录天平 ID。

More broadly, AveXis will conduct a review of logbooks and accompanying procedures to ensure that all logbooks used to document GxP activities require documentation of the equipment used to perform the GxP activities documented in such logbooks.

更广泛而言，AveXis 将对日志本及配套程序开展审查，以确保所有用于记录 GxP 活动的日志本都要求记录执行这些日志本中所载 GxP 活动所用的设备。

Observation 2(C) Corrective and Preventive Actions

观察项 2(C) 纠正和预防措施

除上文第二节所述措施（包括根据质量改进计划（QIP）和数据完整性整改计划采取的措施）外，AveXis 将采取以下措施，以确保观察项 2(C) 中明确指出的问题得到全面解决。

2.8 AveXis will revise FORM-339 to require the documentation of the balance ID in testing logbooks.

2.8 AveXis 将修订 FORM-339，要求在检验日志本中记录天平 ID。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

2.9 AveXis will conduct a review of logbooks and accompanying procedures to ensure that all logbooks used to document GxP activities require documentation of the equipment used to perform the GxP activities documented in such logbooks.

2.9 AveXis 将对日志本及配套程序开展审查，以确保所有用于记录 GxP 活动的日志本都要求记录执行这些日志本中所载 GxP 活动所用的设备。

TCD: December 2019

目标完成日期（TCD）：2019 年 12 月

OBSERVATION 3

检查发现项 3

The responsibilities and procedures applicable to the quality control unit are not fully followed.

适用于质量控制部门的职责和程序未得到全面遵守。

Specifically, vivarium employees who haveresponsibilities for GMP functions such as animaldosing, tailsnips forgenotyping, weighing, death determination, and contemporaneousdocumentation reportdirectlyto an R&Dmanager.This is notin accordancewith the"QualityManual"version 3. Thereare employees thatperform thesefunctions for commercialproducttesting (SOP-346 - In-vivo FunctionalityTestusing a SingleDoseAVXS-101 in SMN7 MouseModel)who directlyreportand aresupervised bya "Senior Scientist"intheResearchand Development team. This Senior Scientisthasself- described no directpriorexperience in GMP controlled lab work.

具体而言，动物房中负责 GMP 职能（如动物给药、用于基因分型的尾尖剪取、称重、死亡判定以及同步记录）的员工直接向研发经理汇报。这不符合第 3 版《质量手册》的规定。有名员工为商业产品检验执行这些职能（SOP-346《单剂量 AVXS-101 在 SMNΔ7 小鼠模型中的体内功能性试验》），他们直接向研发团队中的“高级科学家”汇报并受其监督。据该高级科学家自称，其此前没有直接从事 GMP 受控实验室工作的经验。

Response to Observation 3

对检查发现项 3 的回复

AveXis recognizes the importance of a strong, independent quality unit at the San Diego site. The company further understands that the quality unit’s responsibilities and procedures must be in writing and must be followed. Accordingly, the company has in place a Global Quality Policy, Corporate Quality Manual, and the site-specific, San Diego Supporting Documentation (Quality Manual), which collectively establish the San Diego site quality unit’s responsibilities.

AveXis 认识到在圣地亚哥场所建立强大、独立的质量部门的重要性。公司还明白，质量部门的职责和程序必须形成书面文件并得到遵守。因此，公司已制定《全球质量政策》、《公司质量手册》以及针对该场所的《圣地亚哥支持性文件（质量手册）》，共同确立了圣地亚哥场所质量部门的职责。

AveXis has invested significant resources to strengthen its quality systems and to ensure sustainable compliance. AveXis notes that the San Diego site research and development personnel currently performing in vivo assays under GxP received training on AveXis’s good documentation practice procedure and data integrity policy in March 2018. As described in the response to Observation 1, above, until May 2018, the San Diego site functioned solely as a research and development facility, with limited quality oversight. The research and development personnel received additional classroom-based training on good documentation practice in November-December 2018. In addition, in January 2019, AveXis created a training curriculum for in vivo testing, including for the relevant research and development personnel. This curriculum will be reviewed by Novartis SMEs and updated, as required.

AveXis 已投入大量资源以强化其质量体系并确保持续合规。AveXis 指出，圣地亚哥场所目前在 GxP 条件下执行体内试验的研发人员已于 2018 年 3 月接受过 AveXis 良好记录规范程序和数据完整性政策的培训。如上文对观察项 1 的回复所述，直到 2018 年 5 月，圣地亚哥场所仅作为研发设施运营，质量监督有限。这些研发人员于 2018 年 11 月至 12 月额外接受了关于良好记录规范的课堂培训。此外，2019 年 1 月，AveXis 为体内试验（包括相关研发人员）制定了培训课程大纲。该课程大纲将由诺华主题专家（SME）审查，并根据需要进行更新。

Nonetheless, to further strengthen site practices, AveXis commits to transferring or hiring employees within the Quality organization dedicated to and solely responsible for performing in vivo testing. As an interim measure until such personnel are in place, an analyst within the Quality organization will provide second person review and contemporaneous verification of GxP in vivo testing operations performed by research and development personnel at the San Diego facility. AveXis notes that since October 2018 all data generated for the in vivo functionality assay has been reviewed by the Quality organization in accordance with SOP-087, QC Laboratory Documentation. This includes all commercially released batches.

尽管如此，为进一步强化场所实践，AveXis 承诺在质量组织内调配或招聘专职且全权负责执行体内试验的员工。在此类人员到位之前，作为临时措施，质量组织内的一名分析人员将对圣地亚哥场所研发人员执行的 GxP 体内检验操作提供双人复核和同步核实。AveXis 指出，自 2018 年 10 月以来，根据 SOP-087《质量控制实验室文件记录》，体内功能性试验生成的所有数据均已由质量组织审核，包括所有商业放行批次。

In addition, AveXis notes that as described above, organizationalassessments ofAveXis’squalityunitwillbeperformed to align with Novartis’s qualitystructure. Theassessment willincludeareviewofpersonnelassignments,reportingstructures,training, and experience.Aseparateorganizationalassessmentwillbeperformed byto assess the effectiveness and capabilities of the AveXis quality organization from a resources and staffing perspective.

此外，AveXis 指出，如前文所述，将对 AveXis 质量部门开展组织评估，以与诺华的质量架构保持一致。评估将包括对人员配置、汇报结构、培训和经验的审查。将另行开展一项组织评估，从资源和人员配备角度评估 AveXis 质量组织的有效性和能力。

In addition, AveXis will perform a comprehensive review of responsibility for all activities related to the operation of the vivarium and to the management of the SMNΔ7 mice. AveXis notes that a third-party, , manages the vivarium.personnel perform daily animal health checks (food, water, bedding, etc.), which currently includes documentation and notification when an animal is found missing or deceased.is managed by AveXis’sSupplierQualityprogramand was audited priorto beingqualified as asupplier.Regardlessofaffiliation orreportingstructure, allvivariumpersonnelengaged in GxPactivities haveappropriatetrainingand experienceto fulfilltheirresponsibilities and, asdescribed above, AveXis will implement additional quality oversight enhancements.

此外，AveXis 将对与动物房运营和 SMNΔ7 小鼠管理相关的所有活动的职责进行全面审查。AveXis 指出，第三方负责管理动物房。人员每天进行动物健康检查（食物、水、垫料等），目前包括在发现动物失踪或死亡时进行记录和通知。由 AveXis 的供应商质量计划管理，并在被确认为合格供应商之前已接受过审计。无论隶属关系或汇报结构如何，所有从事 GxP 活动的动物房人员都具备履行其职责的适当培训和经验；并且如前文所述，AveXis 将实施额外的质量监督强化措施。

Further, with respect toAveXis recognizes the opportunityto enhanceits supplieroversight.AveXis willperformareviewofresponsibility f orallactivitiesrelated to theoperation of the vivarium and to the management of the SMNΔ7 mice. Based on the review, enhancementswillbeimplemented, including, as appropriate, transferofGxPresponsibilitiesfromto AveXis personnel. In addition, Novartis SMEs will review the AveXis Supplier Quality program to ensure appropriate oversight of all qualified suppliers.

此外，关于，AveXis 认识到有机会加强其供应商监督。AveXis 将对与动物房运营和 SMNΔ7 小鼠管理相关的所有活动的职责进行审查。根据审查结果，将实施强化措施，包括在适当时将 GxP 职责从转移给 AveXis 人员。此外，诺华 SME 将审查 AveXis 的供应商质量计划，以确保对所有合格供应商实施适当的监督。

Observation 3 Corrective and Preventive Actions

观察项 3 纠正和预防措施

除上文第二节所述措施（包括根据质量改进计划（QIP）和数据完整性整改计划采取的措施）外，AveXis 将采取以下措施，以确保观察项 3 中明确指出的问题得到全面解决。

3.1 AveXis will assess the current training curriculum for personnel performing in vivo assay testing.

3.1 AveXis 将评估执行体内试验检测人员的现行培训课程大纲。

TCD: November 2019

目标完成日期（TCD）：2019 年 11 月

3.2 AveXis will transfer or hire employees within the Quality organization dedicated to and solely responsible for performing in vivo testing.

3.2 AveXis 将在质量组织内调配或招聘专职且全权负责执行体内试验的员工。

TCD: Ongoing; position posted and candidate identification in-progress

目标完成日期（TCD）：进行中；职位已发布，候选人筛选正在进行

(b) (4) 3.3 As an interim measure until such personnel are in place, an analyst within the AveXis Quality organization will provide second person review and contemporaneous verification of GxP in vivo QC testing operations performed by research and development personnel at the San Diego facility.

(b) (4) 3.3 在此类人员到位之前，作为临时措施，AveXis 质量组织内的一名分析人员将对圣地亚哥场所研发人员执行的 GxP 体内质量控制检验操作提供双人复核和同步核实。

TCD: September 2019

目标完成日期（TCD）：2019 年 9 月

3.4 AveXis willperformareviewofresponsibilityforallactivities related to theoperation ofthe vivarium and to the management of the SMNΔ7 mice. Based on the review, enhancementswillbeimplemented, including, as appropriate, transferofGxPresponsibilities fromto AveXis personnel.

3.4 AveXis 将对与动物房运营和 SMNΔ7 小鼠管理相关的所有活动的职责进行审查。根据审查结果，将实施强化措施，包括在适当时将 GxP 职责从转移给 AveXis 人员。

TCD: October 2019

目标完成日期（TCD）：2019 年 10 月

3.5 As part of the QIP, organizational assessments of AveXis’s quality unit will be performed to align with Novartis’s quality structure, including personnel assignments, reporting structures, training, and experience.

3.5 作为 QIP 的一部分，将对 AveXis 质量部门开展组织评估，以与诺华的质量架构保持一致，包括人员配置、汇报结构、培训和经验。

TCD: Ongoing

目标完成日期（TCD）：进行中

3.6 AveXis engagedto assess the effectiveness and capabilities of the AveXis quality organization from a resources and staffing perspective.

3.6 AveXis 已聘请从资源和人员配备角度评估 AveXis 质量组织的有效性和能力。

TCD: Complete;protocol for assessing the effectiveness and capabiliti es of AveXis’s quality organization is under development

目标完成日期（TCD）：已完成；关于评估 AveXis 质量组织有效性和能力的方案正在制定中

3.7 As part of the QIP, Novartis SMEs will review the AveXis Supplier Quality program to ensure appropriate oversight of all qualified suppliers.

3.7 作为 QIP 的一部分，诺华 SME 将审查 AveXis 的供应商质量计划，以确保对所有合格供应商实施适当的监督。

TCD: Ongoing

目标完成日期（TCD）：进行中

OBSERVATION 4

检查发现项 4

Laboratory records do not include complete records of any testing and standardization of laboratory reference standards.

实验室记录未包含实验室参考标准品任何检验和标准化的完整记录。

Specifically, reference standard lots have not been tested and shown to meet initial release criteria in applicable versions of SOP-285 (Determination of ln Vivo Relative Potency for AVXS101 Drug Product) such as minimum slope of increasing doses, minimum mouse cohort sizes, and minimum survivability medians at the test dose.

具体而言，参考标准品批次未按照 SOP-285《AVXS-101 制剂体内相对效力的测定》适用版本的初始放行标准进行检验并证明其符合要求，例如递增剂量的最小斜率、最小小鼠队列规模以及试验剂量下的最小存活中位数。

This is applicable to reference standard Lots #AAV9SMN0613 (NCH) and #600443 (RS-002) tested in March 2017 and February 2018 respectively which serve as reference standards for potency and in-vivo functionality methods performed for the AVXS-101 product over the past three years. These lots have potency values reported in BLA 125694.

这适用于参考标准品批次 #AAV9SMN0613（NCH）和 #600443（RS-002），它们分别于 2017 年 3 月和 2018 年 2 月接受检验，在过去三年中作为 AVXS-101 产品效力方法和体内功能性方法的参考标准品。这些批次的效力值已在 BLA 125694 中报告。

Response to Observation 4

对检查发现项 4 的回复

As described in detail above, in vivo relative potency testing was initially performed under SOP285, Determination of ln Vivo Relative Potency for AVXS-101 Drug Product. In June 2018, at FDA’s request, SOP-285, was replaced by the SOP-347, Determination of In-vitro Relative Potency for AVXS-101 Drug Substance and Drug Product and SOP-346, In-vivo Functionality Test using a Single Dose AVXS-101 in SMNΔ7 Mouse Model. SOP-347 and SOP-346 are the approved methods included in BLA 125694 and the commercial AVXS-101 Drug Product release specification.

如上文详述，体内相对效力检验最初依据 SOP-285《AVXS-101 制剂体内相对效力的测定》执行。2018 年 6 月，应 FDA 的要求，SOP-285 被 SOP-347《AVXS-101 原液和制剂体外相对效力的测定》和 SOP-346《单剂量 AVXS-101 在 SMNΔ7 小鼠模型中的体内功能性试验》取代。SOP-347 和 SOP-346 是 BLA 125694 及 AVXS-101 制剂商业放行标准中纳入的批准方法。

With respect to the reference standard lots referenced in 483 Observation 4, Lot AAV9SMN0613 was established as the initial reference standard for SOP-285 testing following assay development and subsequently used for all SOP-285 testing. Lot AAV9SMN0613 has not been used as a reference standard for SOP-347. Lot 600443 was released under SOP-285 and selected as a reference standard for SOP-347 method validation studies. During the method validation studies, AVXS-101 drug product lot-to-lot consistency was evaluated for lots tested per SOP-347 using Lot 600443 as a reference standard. The suitability of Lot 600443 for use as a reference standard for SOP-347 testing is supported by the observed consistency in potency from lot to lot.

对于 483 观察项 4 中引用的参考标准品批次，批次 AAV9SMN0613 在方法开发完成后被确定为 SOP-285 检验的初始参考标准品，随后用于所有 SOP-285 检验。批次 AAV9SMN0613 未曾用作 SOP-347 的参考标准品。批次 600443 根据 SOP-285 放行，并被选为 SOP-347 方法验证研究的参考标准品。在方法验证研究期间，以批次 600443 作为参考标准品，对依据 SOP-347 检验的各批次 AVXS-101 制剂进行了批次间一致性评估。观察到的各批次间效力一致性支持批次 600443 作为 SOP-347 检验参考标准品的适用性。

AveXis notes that since the qualification of lots AAV9SMN0613 and 600443 as reference standards, the company has revised SOP-330 Reference Standard Qualification Procedure, including adding a process for assignment of potency for a new reference standard through comparison to the current reference standard. AveXis notes that the revised qualification procedure was reviewed by FDA investigators during the July 2019 inspection and resulted in no observations.

AveXis 指出，自批次 AAV9SMN0613 和 600443 被确认为参考标准品以来，公司已修订 SOP-330《参考标准品确认程序》，包括增加了通过与现行参考标准品进行比较来为新参考标准品赋值效力的流程。AveXis 指出，修订后的确认程序已在 2019 年 7 月现场检查期间经 FDA 检查人员审查，未产生任何检查缺陷。

During FDA’s July 2019 inspection, it was found that in initial testing, lots AAV9SMN0613 and 600443 did not meet all relevant acceptance criteria in the applicable version of SOP-285.

在 FDA 2019 年 7 月的现场检查中，发现批次 AAV9SMN0613 和 600443 在初始检验中未完全满足 SOP-285 适用版本中的所有相关接受标准。

Lot AAV9SMN0613testingwasperformed duringtheinitial assaydevelopmentforSOP-285. Dueto aroundingerror, AveXis erroneously c oncluded thatthetestingmettheassay a cceptancecriteria offor theslopeofthedoseresponse curve.As identified duringtheJuly2019 inspection, absent theroundingerror,theassaytestshould havebeen considered invalidand retestingperformed.AveXis notes thattheroundingerrorwasunrelated to productspecification acceptancecriteria. AveXis notesthatsiteprocedures forroundingarecurrentlydescribed in SOP-003, Good Documentation Practices. Butin lightoftheinvestigators’ observation, AveXis willdevelop and implement aseparate SOPspecificallyforsignificant figures and rounding.

批次 AAV9SMN0613 的检验是在 SOP-285 的初始方法开发期间进行的。由于修约错误，AveXis 错误地得出结论，认为检验结果满足剂量反应曲线斜率的方法接受标准。正如 2019 年 7 月现场检查期间所发现的，若没有该修约错误，该次方法检验本应被视为无效并重新检验。AveXis 指出，该修约错误与产品规格接受标准无关。AveXis 指出，场所目前的修约程序在 SOP-003《良好记录规范》中有描述。但鉴于检查人员的观察意见，AveXis 将制定并实施一份专门针对有效数字和修约的独立 SOP。

AveXis further notes that in vitro testing of Lot AAV9SMN0613 was performed under SOP-347 as part of the bridging studyfor the BLA 125694 Late-Cycle Review Response. Testing using the validated in vitro method was within acceptance criteria, resulting in a within-specification relative potency value of%.

AveXis 进一步指出，作为 BLA 125694 周期末审评答复的桥接研究的一部分，批次 AAV9SMN0613 已依据 SOP-347 进行了体外检验。使用经验证的体外方法进行的检验结果在接受标准范围内，得出的相对效力值为%，符合规格要求。

As noted, Lot AAV9SMN0613 wasused as areferencestandardforlots released underSOP-285.Alllotstested underSOP-285 with lotAAV9SMN0613as thereferencestandard havesubsequentlybeen tested underSOP-347 duringstabilitytesting, side-by-sidecomparability or as a result of CAPAs related to NCR-1922. The results for all such lots were within the AVXS-101 release specification of% relative potency. As described above, the in vitro method is considered more reliable than the SOP-285 method, and was developed and validated at the request of FDA.

如前所述，批次 AAV9SMN0613 曾作为依据 SOP-285 放行的批次的参考标准品。所有以批次 AAV9SMN0613 为参考标准品、依据 SOP-285 检验的批次，随后均已依据 SOP-347 进行了检验，包括在稳定性试验、平行可比性研究中，或作为 NCR-1922 相关纠正和预防措施（CAPA）的结果。所有这些批次的结果均在 AVXS-101 相对效力% 的放行标准范围内。如上所述，体外方法被认为比 SOP-285 方法更可靠，并且是应 FDA 的要求开发和验证的。

For release testing of Lot 600443, performed under SOP-285, the assay acceptance criteria for the reference standard dose response curve and the mouse cohort size ofmice were not met followingtheremovalofdatadetermined to beunreliableas partoftheinvestigation documented in NCR-1922.AveXis notes thattheinvestigation confirmed thattherewas noimpacton drugproduct lots released usinglot600443 as areferencestandard.Further, in vitro testing of lot600443 during t hemethod validation forSOP-347 resulted in awithin-specificationrelative potency value of%.

对于依据 SOP-285 对批次 600443 进行的放行检验，在 NCR-1922 记录的调查过程中移除了被判定为不可靠的数据后，参考标准品剂量反应曲线和只小鼠队列规模的方法接受标准未能满足。AveXis 指出，调查确认使用批次 600443 作为参考标准品放行的制剂批次未受到影响。此外，在 SOP-347 方法验证期间对批次 600443 进行的体外检验得出的相对效力值为%，符合规格要求。

In addition to the in vitro testing already performed, to further assure the suitability of the impacted reference standard lots, AveXis will retest lots AAV9SMN0613 and 600443, under the in vivo functionality method, SOP-346, the approved in vivo method in BLA 125694. In addition, AveXis will revise BLA 125694 to remove the IVRPA results reported for lots

除已进行的体外检验外，为进一步确保受影响参考标准品批次的适用性，AveXis 将依据体内功能性方法 SOP-346（BLA 125694 中批准的体内方法）对批次 AAV9SMN0613 和 600443 进行复测。此外，AveXis 将修订 BLA 125694，删除为以下批次报告的体内相对效力试验（IVRPA）结果

AAV9SMN0613 and 600443 and instead report the data generated for each lot under SOP-347 and SOP-346.

AAV9SMN0613 和 600443 的 IVRPA 结果，并改为报告各批次依据 SOP-347 和 SOP-346 生成的数据。

Observation 4 Corrective and Preventive Action

观察项 4 纠正和预防措施

除上文第二节所述措施（包括根据质量改进计划（QIP）和数据完整性整改计划采取的措施）外，AveXis 将采取以下措施，以确保观察项 4 中明确指出的问题得到全面解决。

4.1 AveXis will develop and implement a separate SOP specifically for significant figures and rounding.

4.1 AveXis 将制定并实施一份专门针对有效数字和修约的独立 SOP。

TCD: November 2019

目标完成日期（TCD）：2019 年 11 月

4.2 AveXis will retest Lot AAV9SMN0613 and Lot 600443, per the in vivo functionality method (SOP-346), the approved method in BLA 125694.

4.2 AveXis 将依据体内功能性方法（SOP-346，即 BLA 125694 中批准的方法）对批次 AAV9SMN0613 和批次 600443 进行复测。

TCD: December 2019

目标完成日期（TCD）：2019 年 12 月

4.3 AveXis will revise BLA 125694 to include the in vivo functionality test data generated for Lot AAV9SMN0613 and Lot 600443.

4.3 AveXis 将修订 BLA 125694，纳入为批次 AAV9SMN0613 和批次 600443 生成的体内功能性试验数据。

TCD: March 2020

目标完成日期（TCD）：2020 年 3 月

OBSERVATION 5

检查发现项 5

Established test procedures are not followed.

既定的检验程序未被遵守。

Specifically, as per SOP-346 Version 3.0 "In- vivo Functionality Testusing aSingleDoseAVXS-101 in SMN7 MouseModel"themousedateofdeath is in partdefined as the" ... datetheanimal firstlost% of its body weight...". As per SOP-268 Version 2.0 "Observation and Handling of Study Mice for AVXS-101 Potency Assay" study animals are weighed "(separated by at leastuntil end of study... " AveXis has interpreted the date the animal first lost% ofits bodyweightas thedatethis lossis firstdocumented. Sincemicearenotweighed dailythereisno documentation showing theexactdatethemouselost % of its body weight.

具体而言，按照 SOP-346 第 3.0 版《单剂量 AVXS-101 在 SMNΔ7 小鼠模型中的体内功能性试验》，小鼠的死亡日期部分定义为“……动物首次体重下降% 的日期……”。按照 SOP-268 第 2.0 版《AVXS-101 效力试验研究小鼠的观察与处理》，研究动物称重“（间隔至少，直至研究结束）……”。AveXis 将动物首次体重下降% 的日期解释为首次记录到该体重下降的日期。由于小鼠并非每天称重，因此没有文件记录能够显示小鼠体重下降% 的确切日期。

Response to Observation 5

对检查发现项 5 的回复

AveXis understands theimportanceoffollowingestablished testprocedures,andthattesting activities should bedocumented atthetimeofperformance.Withrespectto thetestprocedures noted in Observation 5, SOP-346 Version 3.0, In-vivo FunctionalityTestusing a SingleDoseAVXS-101 in SMNΔ7 Mouse Model, and SOP-268 Version 2.0, Observation and Handling ofStudyMiceforAVXS-101 PotencyAssay, theobservation correctlynotesthesetestproceduresstate thatstudymiceshould beweighed, separated by at least and that, for study mice dosed with AVXS-101, the date on which an animal first loses% ormoreofits body w eightis oneofthemethods usedbyAveXis to determinemousedateofdeath.Theothermethod, theactualdeath ofastudymouse,was assessedpursuant to health checks performed by laboratory personnel.

AveXis 理解遵循既定检验程序的重要性，也理解检验活动应在执行之时予以记录。对于观察项 5 中指出的检验程序，即 SOP-346 第 3.0 版《单剂量 AVXS-101 在 SMNΔ7 小鼠模型中的体内功能性试验》和 SOP-268 第 2.0 版《AVXS-101 效力试验研究小鼠的观察与处理》，检查缺陷正确地指出，这些检验程序规定研究小鼠应按的频率称重（间隔至少），并且对于接受 AVXS-101 给药的研究小鼠，动物首次体重下降% 或以上的日期是 AveXis 用于确定小鼠死亡日期的方法之一。另一种方法是研究小鼠的实际死亡，由实验室人员按照健康检查进行评估。

With regard to the frequency of mouse weighing, as discussed with the FDA investigators during the inspection, AveXis selectedseparated by at leastto, among other reasons, minimize disruptions to the study mice, as the stress associated with handling could affect survival. As noted in the 483, this frequencyseparated by at leastis the frequency that analysts actually performed study mice weighing—i.e., analysts followed these established test procedures.

关于小鼠称重频率，正如现场检查期间与 FDA 检查人员讨论的那样，AveXis 选择（间隔至少）的频率，原因之一是尽量减少对研究小鼠的干扰，因为与操作相关的应激可能影响生存。正如 483 中指出的，这一频率（间隔至少）正是分析人员实际执行研究小鼠称重的频率——也就是说，分析人员遵循了这些既定的检验程序。

AveXis also understands FDA’s concern that due to the passage of time between weighings—at leastthere is a possibility a study mouse could exceed the% weight loss threshold without detection for. Accordingly,followingtheinspection, AveXis initiated aretrospectivereviewofallcommerciallots ofAVXS-101 (Zolgensma®)tested usingSOP346,with afocus on studymicethatweredeclared dead dueto losing% ormoreoftheirbodyweight. As FDAis aware, thereleasespecification forthein vivofunctionalitytest(SOP346)isamediansurvivalofdays or greater. Accordingly, AveXis investigated whether any median test article study mice that had been declared dead based on% weight loss had been so declared on or after dayensuring that study m ice who lost % or more of their body weight on dayswould be flagged forfurtherinvestigation and impactassessment.AveXis’sretrospectivereview, summarized in thememorandumattached atExhibit8, confirmed thatno study m iceatmedian survivalweredeclared deadbased on% weight loss except Lot 601537, for which% weight loss was detected on day Since the weight loss did not exceed% as recorded on day the median survival for Lot 601537 was at minimumdays, within the release specification.

AveXis 也理解 FDA 的担忧，即由于两次称重之间存在时间间隔（至少），研究小鼠有可能体重下降超过% 的阈值而在内未被发现。因此，在现场检查之后，AveXis 对使用 SOP-346 检验的所有 AVXS-101（Zolgensma®）商业批次启动了回顾性审查，重点针对因体重下降% 或以上而被判定死亡的研究小鼠。如 FDA 所知，体内功能性试验（SOP-346）的放行标准是中位生存期达到天或以上。因此，AveXis 调查了是否有任何基于% 体重下降而被判定死亡的中位生存期受试品研究小鼠，其判定日期在第天或之后，以确保在第天体重下降% 或以上的研究小鼠能够被标记出来，供进一步调查和影响评估。AveXis 的回顾性审查（详见附件 8 所附备忘录）确认，除批次 601537 外，没有任何中位生存期研究小鼠基于% 体重下降被判定死亡；批次 601537 在第天检测到% 的体重下降。由于按第天的记录，体重下降未超过%，批次 601537 的中位生存期至少为天，在放行标准范围内。

on days (b) (4) would be flagged for further investigation and impact assessment. AveXis’s

在第 (b) (4) 天将被标记出来，供进一步调查和影响评估。AveXis 的

retrospective review, summarized in the memorandum attached at Exhibit 8, confirmed that no study m ice at median survival were declared dead based on (b) (4)% weight loss except Lot 601537, for which (b) (4)% weight loss was detected on day (b) (4) Since the weight loss did not exceed (b) (4)% as recorded on day (b) (4) the median survival for Lot 601537 was at minimum (b) (4)days, within the release specification.

回顾性审查（详见附件 8 所附备忘录）确认，除批次 601537 外，没有任何中位生存期研究小鼠基于 (b) (4)% 体重下降被判定死亡；批次 601537 在第 (b) (4) 天检测到 (b) (4)% 的体重下降。由于按第 (b) (4) 天的记录，体重下降未超过 (b) (4)%，批次 601537 的中位生存期至少为 (b) (4) 天，在放行标准范围内。

Please notethatanyadditionalhandlingofmicecould bequitestressful(especiallyforthedam)and could affectsurvival.Accordingly,and in lightoftheFDAinvestigators’observation, AveXiswillreviewand revise, asnecessary, SOP346, In-vivo FunctionalityTestusing a SingleDose AVXS-101 in SMNΔ7 Mouse Model, SOP 268, Observation and Handling ofStudy Micefor AVXS-101 PotencyAssay, and relatedForm339 to evaluatewhetherstudymiceshould beweighedthroughout the study period.

请注意，对小鼠的任何额外操作都可能造成相当大的应激（尤其是对母鼠），并可能影响生存。因此，鉴于 FDA 检查人员的观察意见，AveXis 将视需要审查并修订 SOP-346《单剂量 AVXS-101 在 SMNΔ7 小鼠模型中的体内功能性试验》、SOP-268《AVXS-101 效力试验研究小鼠的观察与处理》及相关表格 FORM-339，以评估在整个研究期间是否应按的频率对研究小鼠进行称重。

Observation 5 Corrective and Preventive Action

观察项 5 纠正和预防措施

除上文第二节所述措施（包括根据质量改进计划（QIP）和数据完整性整改计划采取的措施）外，AveXis 将采取以下措施，以确保观察项 5 中明确指出的问题得到全面解决。

5.1 AveXis initiated aretrospectivereviewofallcommerciallots ofAVXS-101 (Zolgensma®)tested usingSOP346 with afocus on studymicethatweredeclared dead due to losing% or more of their body weight.

5.1 AveXis 已对使用 SOP-346 检验的所有 AVXS-101（Zolgensma®）商业批次启动了回顾性审查，重点针对因体重下降% 或以上而被判定死亡的研究小鼠。

TCD: Complete

目标完成日期（TCD）：已完成

5.2 AveXis willreviewand reviseas necessarySOP346, In-vivo FunctionalityTestusing aSingle Dose AVXS-101 in SMNΔ7 Mouse Model, SOP268, Observation and Handling ofStudyMiceforAVXS-101 PotencyAssay, and related Form339 to evaluatewhetherstudymice should be weighedthroughout the study period.

5.2 AveXis 将视需要审查并修订 SOP-346《单剂量 AVXS-101 在 SMNΔ7 小鼠模型中的体内功能性试验》、SOP-268《AVXS-101 效力试验研究小鼠的观察与处理》及相关表格 FORM-339，以评估在整个研究期间是否应按的频率对研究小鼠进行称重。

TCD: November 2019

目标完成日期（TCD）：2019 年 11 月