Regulatory Express_May. 2024

1. EMA Revised Draft Guideline on Quality, Nonclinical and Clinical Requirements for Investigational Advanced Therapy Medicinal Products (ATMP) in Clinical Trials

EMA修订的临床试验中试验性先进治疗药品（ATMP）的质量、非临床和临床要求指南草案

Summary:

The EMA has released a 'Draft guideline on quality, nonclinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials - Second version'.   

总结：

EMA发布了“临床试验中试验性先进治疗药品的质量、非临床和临床要求指南草案-第2版”。

The guideline:

· Provides guidance on the structure and data requirements for a clinical trial application for investigational ATMPs.

· Are multidisciplinary and addresses development, manufacturing, and quality control as well as non-clinical and clinical development of ATMPs.

· Provides requirements for exploratory trials (including First in Human studies) and confirmatory trials are described and a perspective towards Marketing Authorization Application (MAA) is provided.

· Has a non-clinical section that addresses the use of non-clinical models, and the minimum non-clinical data necessary to support first-in-human studies.

· Contains a clinical section that covers the documentation necessary to support exploratory clinical trials and long-term efficacy and follow-up.

· Replaces the previous draft version dated 31-Jan-2019. All comments received on the first draft version have been reviewed and incorporated, where possible, in the guideline.

· This second draft has been revised, including:

o a section on abbreviations has been added and the terminology revisited,

o the References section has been enriched and classified by type of documents (i.e. quality, clinical, non-clinical, multidisciplinary, GMOs).

o the adoption of a different structure in section S.2.2 on process controls, and revisions in the testing of replication-competent viruses (RCVs).

o there is greater alignment with the US Food and Drug Administration (FDA) on certain concepts and terminologies related to ATMPs.

o reworked the structure of the quality portion of the guideline to address commenters' concerns.

指南：

· 提供了研究用ATMP临床试验申请的结构和数据要求指南。

· 是多学科的，涉及ATMP的开发、生产和质量控制以及非临床和临床开发。

· 描述了探索性试验（包括首次人体试验）和确证性试验的要求，并提供了对上市许可申请(MAA)的态度。

· 非临床章节讨论了非临床模型的使用，以及支持首次人体试验所需的最少非临床数据。

· 包含支持探索性临床试验和长期疗效和随访所需文件的临床章节。

· 替代2019年1月31日的先前草案版本。已对收到的关于第一版草案的所有意见进行了审查，并在可能的情况下纳入本指南。

· 第二稿已经修订，包括：

o 增加了缩略语章节，并重新审查了术语，

o 已按照文件类型（即质量、临床、非临床、多学科、转基因生物（Genetically modified organism，GMO）对参考文献章节进行了丰富和分类。

o 在关于过程控制的第S.2.2节中采用了不同的结构，并修订了复制能力病毒(RCV)的检测。

o 与ATMP相关的某些概念和术语与美国食品药品监督管理局(FDA)有更大的一致性。

o 修改了指导原则质量部分的结构，以解决评论者的担忧。

Key Takeaways:

· The multidisciplinary guideline addresses gene therapy medicinal products, somatic cell therapy medicinal products, tissue-engineered products, and combined ATMPs. 

· Scientific knowledge on ATMPs is rapidly expanding, and to ensure that reliable data are generated on these complex products, well-conducted clinical trials are essential to determine their benefit-risk profile.

关键信息：

· 此多学科指南涉及基因治疗药品、体细胞治疗药品、组织工程产品和联合ATMP。

· 关于ATMP的科学知识正在迅速扩展，为了确保这些复杂产品产生可靠的数据，进行良好的临床试验对于确定其获益-风险特征至关重要。

2. CTCG Recommendation Paper on Principles of Good Laboratory Practices (GLP) for Clinical Trial Applications under the EU Clinical Trials Regulation (Regulation (EU) No 536/2014)

CTCG关于欧盟临床试验法规（法规(EU)第536/2014号）下临床试验申请的药物非临床研究质量管理规范(GLP)原则的建议文件

Summary:

Clinical Trial Coordinator Group (CTCG) jointly issued a new recommendation paper on principles of Good Laboratory Practices (GLP) for clinical trial applications under the EU Clinical Trials Regulation (Regulation (EU) No 536/2014), together with relevant EMA and EC working groups and parties. 

总结：

临床试验协调组(CTCG)与相关EMA和EC工作组及各方共同发布了一份关于欧盟临床试验法规（法规(EU)第536/2014号）下临床试验申请的药物非临床研究质量管理规范(GLP)原则的新建议文件。

Key Takeaways:

The scope of this recommendation paper is to:

· share the common approach agreed, on the requirements regarding OECD GLP compliance of pivotal non-clinical data submitted to support a clinical trial application (CTA);

· provide transparency on regulatory acceptability for sponsors and test facilities, and other interested parties.

关键信息：

本建议文件的范围是：

· 分享达成共识的通用方法，即关于为支持临床试验申请(CTA)而提交的关键非临床数据的OECD GLP合规性要求；

· 为申办方和试验机构以及其他相关方提供监管可接受性的透明度。

3. US FDA Draft Guidance: Key Information and Facilitating Understanding in Informed Consent Guidance for Sponsors, Investigators, and Institutional Review Boards

US FDA指南草案：申办方、研究者和机构审查委员会在知情同意指南中的关键信息和促进理解

Summary:

The US FDA has released a draft guidance titled: Key Information and Facilitating Understanding in Informed Consent Guidance for Sponsors, Investigators, and Institutional Review Boards. This draft guidance provides research sponsors, investigators, and institutional review boards with recommendations on how to implement two proposed requirements in the FDA proposed rule, "Protection of Human Subjects and Institutional Review Boards" and the corresponding current requirements under the revised Common Rule, including that:

Informed consent begins with key information about the research presented in a clear and concise manner.

Informed consent as a whole be presented in a way that facilitates understanding of the reasons why someone might or might not want to participate in the research.

总结：

美国FDA发布了一份指南草案，题为：申办方、研究者和机构审查委员会在知情同意指南中的关键信息和促进理解。本指南草案为研究申办方、研究者和机构审查委员会提供了如何实施FDA拟议规则“人类受试者保护和机构审查委员会”中的两项拟议要求以及修订后的通用规则下的相应现行要求的建议，包括：

知情同意从以清晰和简明的方式提供的关于研究的关键信息开始。

知情同意书作为一个整体呈现的方式，有助于理解某人可能或可能不希望参与研究的原因。

4. HMA-EMA Catalogues of Real-World Data Sources and Studies

HMA-EMA真实世界数据来源和研究目录

Summary:

EU regulators have launched two public electronic catalogs of real-world data (RWD):

RWD Studies: focuses on observational research

RWD Sources: describes real world data sources

总结：

欧盟监管机构发布了两个真实世界数据(RWD)的公共电子目录：

RWD研究：侧重于观察性研究

RWD来源：描述真实世界数据来源

Key Takeaways:

· The HMA-EMA Catalogues are repositories of metadata collected from real-world data (RWD) sources and RWD studies

· They are intended to help regulators, pharmaceutical companies and researchers to identify and use such data when investigating the use, safety and effectiveness of medicines

关键信息：

· HMA-EMA目录是从真实世界数据（RWD）的信息来源和RWD研究中收集的元数据的存储库

· 它们旨在帮助监管机构、制药公司和研究人员在研究药物的使用、安全性和有效性时识别和使用这些数据

5. US FDA Final Guidance: Charging for Investigational Drugs Under an IND: Questions and Answers

US FDA最终指南：IND研究药物收费：问与答

Summary:

The US FDA issued a final guidance titled Charging for Investigational Drugs Under an IND Questions and Answers Guidance for Industry February 2024.  The guidance responds to frequently asked questions about FDA's processes, policies and regulation regarding charging patients for investigational new drugs under certain circumstances in clinical trials or expanded access for treatment use.

总结：

2024年2月，美国FDA发布了标题为“IND项下研究药物的收费：问已答行业指南”的最终指南。该指南回应了一些常见问题，涉及FDA在临床试验的某些情况下对试验性新药收费的流程、政策和监管，或扩大治疗用途的可及性。

Key Takeaways:

· It replaces the 2016 final guidance, "Charging for Investigational Drugs Under an IND: Questions and Answers."  

· Only minor changes from the 2022 draft to the final guidance, includes defining expanded access

· Patients under expanded access can be charged and sponsor may request a review by OND CDER/CBER on how to preserve blind

· Patients charged must be informed via informed consent form

关键信息：

· 该文件替代了2016年最终指南“IND项下研究药物的收费：问与答”。

· 从2022草案到最终指南仅有微小变更，包括定义扩大使用

· 可以对扩大权限的患者收费，申办方可要求新药办公室（OND）、药物审评和研究中心（CDER）/生物制品审评和研究中心（CBER）审查如何保持盲态

· 收费患者必须通过知情同意书告知

6. US FDA Releases Draft Guidance on Use of Data Monitoring

美国FDA发布了数据监查使用指南草案

Summary:

The US FDA has released a draft guidance titled: Use of Data Monitoring Committees (DMC) in Clinical Trials.  A clinical trial DMC is established by a sponsor and is composed of a group of individuals with relevant expertise that reviews accumulating data on a regular basis from one or more clinical trials and recommends to the sponsor whether to continue, modify, or stop a trial or trials.  FDA notes the increased use of DMCs since the 2006 version for diseases not involving serious morbidity or mortality.

总结：

US FDA发布了标题为“临床试验中数据监查委员会(DMC)的使用”的指南草案。临床试验DMC由申办方建立，由具有相关专业知识的一组人员组成，定期审查一项或多项临床试验的累积数据，并向申办方建议是否继续、修改或停止一项或多项试验。FDA注意到，自2006年版本以来，DMC在不涉及严重发病率或死亡率的疾病中的使用增加。

Key Takeaways:

· This guidance is intended to assist sponsors of clinical trials in determining when a data monitoring committee (DMC) (also known as a data and safety monitoring board (DSMB), a data and safety monitoring committee (DSMC), or an independent data monitoring committee (IDMC)) would be useful for trial monitoring and what procedures and practices should be considered to guide their operation.

· Overall, the guidance addresses when a DMC would be "useful" for trial monitoring and what procedures and practices should be considered to guide how they work.

· When finalized, this guidance will supersede the final guidance for clinical trial sponsors entitled "Establishment and Operation of Clinical Trial Data Monitoring Committees," issued in March 2006. This draft guidance is not final nor is it in effect at this time.

关键措施：

· 本指南旨在帮助临床试验申办方确定数据监查委员会（DMC，也称为数据和安全性监查委员会[DSMB]、数据和安全性监查委员会[DSMC]或独立数据监查委员会[IDMC]）何时对试验监查有用，以及应考虑哪些程序和实践指导其操作。

· 总体而言，本指南阐述了DMC何时对试验监查“有用”，以及应考虑哪些程序和实践来指导其如何工作。

· 定稿后，本指南将取代2006年3月发布的标题为“临床试验数据监查委员会的建立和运行”的临床试验申办方最终指南。本指南草案不是最终版本，目前尚未生效。

7. EMA Guidance on Remote GCP inspections during Public Health Threats, Political Conflicts, Natural Disasters, or Other Major Disruptions

EMA关于公共卫生威胁、政治冲突、自然灾害或其他重大干扰期间远程GCP检查的指南

Summary:

The EMA has released a Guidance on remote GCP inspections during public health threats, political conflicts, natural disasters, or other major disruptions.  In the context of this guidance, a remote / distant GCP inspection is defined as "the process of conducting inspections at a distance / virtually, supported by technology for communicating, sharing, reviewing, and developing documents and accessing systems, without the inspectors being physically present at the sites where the activities subject to an inspection have taken place / where the inspection would routinely be hosted".

总结：

EMA发布了关于在公共卫生威胁、政治冲突、自然灾害或其他重大干扰期间进行远程GCP检查的指南。在本指南的背景下，远程/远程GCP检查被定义为“在沟通、共享、审阅和开发文件和访问系统的技术支持下，以远程/虚拟方式进行检查的过程，而检查员没有实际出现在实施检查的场所/常规检查的现场”。

Key Takeaways:

· This document is intended to provide guidance on the steps to be followed during remote good clinical practice (GCP) inspections which may be conducted during public health threats, political conflicts, natural disasters, or other major disruptions.

· This document replaces the 'Guidance on remote inspections during COVID19 pandemic' published on 10 June 2020. 

· The document is largely unchanged from the previous version with biggest changes being replacing COVID 19 with public health threats, political conflicts, natural disasters, or other major disruptions.

关键信息：

· 本文件旨在为可能在公共卫生威胁、政治冲突、自然灾害或其他重大干扰期间进行的远程药物临床试验质量管理规范(GCP)检查提供所需遵循步骤的指南。

· 本文件取代2020年6月10日发布的“COVID-19大流行期间远程检查指南”。

· 该文件与前一版本相比基本没有变化，最大的变化是用公共卫生威胁、政治冲突、自然灾害或其他重大干扰取代COVID-19。

8. US FDA Issues Final Guidance: Human Gene Therapy Products Incorporating Human Genome Editing

美国FDA发布最终指南：结合人类基因组编辑的人类基因治疗产品

Summary:

In this final guidance, USFDA is providing recommendations to sponsors developing human gene therapy products incorporating genome editing (GE) of human somatic cells. 

总结：

在最终指南中，USFDA  在为申办方开发结合人类体细胞基因组编辑(GE)的人类基因治疗产品提供了建议。

Key Takeaways:

· This guidance provides recommendations regarding information that should be provided in an Investigational New Drug (IND) application in order to assess the safety and quality of the investigational GE product, as required in Title 21 of the Code of Federal Regulations 312.23 (21 CFR 312.23). 

· This guidance includes information on product design, product manufacturing and testing, nonclinical safety assessment, and clinical trial design. 

关键信息：

· 本指南根据美国联邦法规第21章第312.23款(21 CFR 312.23)的要求，提供了关于试验用新药(IND)申请中应提供的信息建议，以评估试验用基因组编辑产品的安全性和质量。

· 本指南包括有关产品设计、产品生产和检测、非临床安全性评估和临床试验设计的信息。

9. Final Guidance Issued: US FDA Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products

发布最终指南：美国FDA关于研发嵌合抗原受体(CAR)T细胞产品的考虑事项

Summary:

The USFDA has issued the final guidance entitled “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products”. The guidance is intended to assist sponsors, including industry and academic sponsors, developing ex vivo-manufactured CAR T cell products. 

总结：

USFDA发布了标题为“研发嵌合抗原受体(CAR)T细胞产品的考虑因素”的最终指南。本指南旨在帮助申办方（包括行业和学术申办方）开发体外制造的CAR T细胞产品。

Key Takeaways:

· The guidance provides CAR T cell specific recommendations regarding chemistry, manufacturing, and control (CMC), pharmacology and toxicology, and design of clinical studies for oncology indications (including hematologic malignancies and solid tumors).

· The guidance announced in this notice finalizes the draft guidance of the same title dated March 2022.

关键信息：

· 本指南提供了关于化学、生产和控制(CMC)、药理学和毒理学以及肿瘤适应症（包括血液恶性肿瘤和实体瘤）临床研究设计的CAR T细胞特异性建议。

· 本通知所载指南是2022年3月的同一标题指南草案的最终版。

10. FDA Office of Compliance Annual Report for Fiscal Year 2023 - BIMO Analysis

FDA合规办公室2023财年年度报告——BIMO分析

Summary:

The FDA has released its Office of Compliance Annual Report for Fiscal Year 2023.  Below is the key information presented about the Bioresearch Monitoring Program.

· 32 pre-notice of noncompliance letters issued for ClinicalTrials.gov violations

· 100% of clinical inspection summaries issued by agreed-upon goal dates for new drug applications and biologics license applications under the Prescription Drug User Fee Amendments (PDUFA) and Biosimilar User Fee Amendments (BSUFA)

· 600 BIMO inspections and RRAs

· 400 inspections to assess the reliability of data submitted in support of marketing applications.

· 128 clinical inspection summaries to support the review of marketing applications.

o 71 priority and 57 standards

o 83 original and 45 supplements

o 48 BLA; 79 NDA; 1 EUA

· 11 Warning Letters (6 clinical investigators; 4 sponsor investigators; 1 IRB)

总结：

FDA已发布其合规办公室2023财年年度报告。以下是关于生物研究监测项目的关键信息。

· 32份针对违反ClinicalTrials.gov要求发出的不合规通知

· 根据处方药使用者费用修订案(PDUFA)和生物仿制药使用者费用修订案(BSUFA)，在商定的新药申请和生物制品许可证申请目标日期前发布的100%临床检查摘要

· 600 BIMO检查和远程监管评估

· 400次检查，以评估为支持上市申请而提交的数据的可靠性。

· 128项支持上市申请审评的临床检查总结。

o 71项优先级和57项标准级别

o 83份首次和45份增补

o 48个生物制剂上市申报；79个新药上市申报；1个紧急使用授权

· 11份警告信（6份临床研究者；4份申办方研究者；1份IRB）

11. US FDA Final Guidance on Real World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products

US FDA关于真实世界数据的最终指南：评估注册登记以支持药品和生物制品的监管决策

Summary:

The US FDA has released a final guidance titled: Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products. FDA is issuing this guidance as part of its RWE Program and to satisfy, in part, the mandate under section 505F of the FD&C Act to issue guidance on the use of RWE in regulatory decision-making. A registry is defined as an organized system that collects clinical and other data in a standardized format for a population defined by a particular disease, condition, or drug exposure.

总结：

美国FDA发布了标题为：真实世界数据：评估注册以支持药品和生物制品的监管决策的最终指南。FDA发布本指南作为真实世界证据(RWE)计划的一部分，并部分满足FD&C法案第505F节规定的发布RWE用于监管决策指南的要求。注册登记定义为以标准化格式收集特定疾病、状况或药物暴露定义人群的临床和其他数据的有组织的系统。

Key Takeaways:

· Sponsors should consider both the strengths and limitations of using registries as a source of data to generate evidence for regulatory decision-making.

· When considering whether to use an existing registry for regulatory purposes, a sponsor's overall assessment of the relevance of the registry data should ensure that the registry is adequate for evaluating the scientific objectives.

· When a registry does not capture all the necessary information to answer the question of interest in an interventional or non-interventional study, sponsors may consider obtaining supplemental information from another source.

· Sponsors interested in using a specific registry as a data source for a study intended to support a regulatory decision by the FDA should meet with the relevant FDA review division before conducting the study.

关键信息：

· 申办方应考虑使用注册登记作为数据来源以生成监管决策证据的优势和局限性。

· 在考虑是否将现有注册登记用于注册目的时，申办方对注册登记数据相关性的总体评估应确保注册登记足以评价科学目标。

· 如果注册登记中未收集回答干预性或非干预性研究中关注问题的所有必要信息，则申办方可考虑从其他来源获得补充信息。

· 有兴趣使用特定登记研究作为预期支持FDA监管决策的研究的数据源的申办方应在进行研究之前与相关的FDA审查部门进行会议。

12. US FDA Final Guidance on Digital Health Technologies for Remote Data Acquisition in Clinical Investigations

美国FDA关于临床研究中远程数据采集的数字健康技术的最终指南

Summary:

The US FDA has released a final guidance titled: Digital Health Technologies (DHT) for Remote Data Acquisition in Clinical Investigations. A digital health technology is a system that uses computing platforms, connectivity, software, and/or sensors, for health care and related uses.  The use of DHTs as recommended in this guidance may improve the efficiency of clinical trials for sponsors, investigators, and other stakeholders, and may increase the opportunities for individuals to participate in research and make participation more convenient.

总结：

美国FDA发布了一份最终指南，标题为：临床研究中远程数据采集的数字健康技术(DHT)。数字健康技术是将计算平台、连通性、软件和/或传感器用于医疗保健和相关用途的系统。按照本指南的建议使用DHTs可以提高申办方、研究者和其他利益相关者临床试验的效率，并可能增加个人参与研究的机会，使参与更加方便。

Key Takeaways:

· This guidance provides recommendations on the use of digital health technologies (DHTs) to acquire data remotely from participants in clinical investigations that evaluate medical products. 

· DHTs for remote data acquisition in clinical investigations can include hardware and/or software to perform one or more functions. 

· The use of DHTs as recommended in this guidance may improve the efficiency of clinical trials for sponsors, investigators, and other stakeholders and may increase the opportunities for individuals to participate in research and make participation more convenient.

关键信息：

· 本指南提供了关于使用数字健康技术(DHTs)远程获取临床研究参与者数据评价医疗产品的建议。

· 临床研究中用于远程数据采集的DHTs可包括执行一项或多项功能的硬件和/或软件。

· 按照本指南的建议使用DHTs可以提高申办方、研究者和其他利益相关者临床试验的效率，并可能增加个人参与研究的机会，使参与更加方便。

13. US FDA Issues Final Rule: IRB Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations

US FDA发布最终规则：IRB豁免或变更最低风险临床研究的知情同意书

Summary:

The US FDA has issued a final rule titled: Institutional Review Board Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations.  The rule provides an exception from the requirement to obtain informed consent when a clinical investigation poses no more than minimal risk to the people participating in the research, and the research includes appropriate safeguards to protect the rights, safety and welfare of participants.  This could include studies comparing the effectiveness of approved products to determine which option works best for certain patients.

· The final rule permits an institutional review board (IRB) to waive or alter certain elements of informed consent, or to waive the requirement to obtain informed consent entirely, under limited conditions, for certain FDA-regulated clinical investigations that pose no more than minimal risk to trial participants.

· The rule continues to protect the rights, safety and welfare of research participants and enables minimal risk clinical investigations that may facilitate medical advances and promote public health.

总结：

美国FDA发布了标题为：机构审查委员会豁免或变更最低风险临床研究知情同意书的最终规则。当临床研究对参与研究的人员造成的风险不超过最低限度时，该规则规定了获得知情同意的要求的例外情况，研究包括保护受试者权利、安全和福利的适当保障。这可能包括比较获批产品有效性的研究，以确定哪种选择对某些患者最有效。

· 最终规则允许机构审查委员会(IRB)在特定的FDA监管的、对试验参与者的风险不超过最低限度的临床研究，免除或改变知情同意的某些要素，或者在限定条件下完全免除知情同意。

· 该规则继续保护研究受试者的权利、安全和福利，并使最低风险的临床研究成为可能，这可促进医学进步和促进公共卫生。

Key Takeaways:

· This regulation will permit an Institutional Review Board (IRB) to waive informed consent under certain conditions for minimal risk clinical investigations.

· This will facilitate certain minimal risk clinical investigations to support the development of new products to diagnose or treat disease and will harmonize with the HHS Common Rule waiver provision that has been adopted and successfully employed by other agencies.

· This regulation is intended to aid patient access to new products by facilitating investigators' ability to conduct studies that may contribute substantially to the development of products to diagnose or treat conditions, or address unmet medical needs.

关键信息：

· 该法规将允许机构审查委员会(IRB)在特定条件下豁免最低风险临床研究的知情同意。

· 这将促进某些最低风险的临床研究，以支持开发新的诊断或治疗疾病的产品，并将与其他机构采用并成功使用的卫生与公众服务部的通用规则豁免条款保持一致。

本规定旨在帮助患者获得新产品，通过促进研究人员进行可能对诊断或治疗疾病的产品开发做出重大贡献的研究，或解决未满足的医疗需求。