1.     EMA Rvised Guideline on Quality, Non-Clinical and Clinical Aspects of Medicinal Products Containing Genetically Modified Cells_Effective on 1 Jun. 2021

EMA修订《含有转基因细胞的药品质量、非临床和临床指导原则》_生效日期：2021年6月1日

Summary:

The EMA has released a revised the Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells.  The original guideline was developed in 2010-2011, before the first gene therapy medicinal product based on genetically modified cells was authorised. The revision of the guideline reflects the experience gained since then with the approval of this type of gene therapy products. Additionally, science has moved on rapidly, and novel technologies that were not yet at the horizon in 2010 are now commonplace: these include CAR-T cells, induced pluripotent stem cells and genome editing. The revision does also incorporate guidance of genetically modified cells developed using these novel technologies.

 EMA发布了修订后的《含有转基因细胞的药品质量、非临床和临床指导原则》。  该指导原则首版于2010-2011年制定，在第一个基于转基因细胞的基因治疗药品获得许可之前。指导原则的修订反映了这类基因治疗产品获批以来积累的经验。此外，科学飞速发展，对于2010年尚未出现的新技术，现在已经司空见惯：包括CAR-T细胞、诱导多能干细胞和基因组编辑。该修订版还纳入了使用这些新技术开发转基因细胞的指导建议。

The guideline provides recommendations covering the quality, non-clinical, and clinical aspects, as well as pharmacovigilance and environmental risk assessment related to medicines with genetically modified cells.  The revisions are based on the agency’s experience with novel technologies, including CAR T-cells, induced pluripotent stem cells, and genome editing.

 本指导原则提供的建议涵盖了质量、非临床和临床方面，以及与含有转基因细胞的药品相关的药物警戒和环境风险评估。  修订是基于监管机构对新技术的经验，包括CAR T-细胞、诱导多能干细胞和基因组编辑。

They include:

·       The quality section of the guideline was updated to include information related to starting materials, comparability, and validation.

·       Current thinking on requirements for conducting non-clinical studies, as well as the scientific principles for CAR T-cell and T-cells with engineered T-cell receptors.

·       Recommends that exploratory pharmacokinetic clinical studies should characterize CAR T-cell levels, as well as their expansion and persistence in blood and target tissues, at various time points.

·       Dose-finding studies should be conducted to examine safety, toxicity, and anti-tumor activity at different dose levels and to define the recommended dose or dose range for phase 2 studies.

·       Conventional drug-drug interaction studies and renal/hepatic impairment studies are less likely to be applicable to CAR T-cells and should be considered on a case-by-case basis.

·       For efficacy of CAR T-cells, dose-selection and timing of response assessment should be based on the results of exploratory trials.

·       In planning confirmatory trials, they recommend adhering to the intention-to-treat (ITT) principle in assessing efficacy. The agency suggests defining the ITT population as all patients enrolled in the trial, including the CAR T-cell and the comparator arm.

·       A randomized controlled trial design is preferred and comparison to best supportive care or investigator’s choice treatment is preferred to single-arm trials.

·       For safety evaluation of CAR T-cell products, EMA advises that drug developers assess the cause of adverse events from the CAR T-cell product and related procedures, such as the lymphodepleting regimen or the apheresis procedure.

·       Sponsors should consider defining expected and unexpected adverse events, choosing an algorithm for detecting and treating potential life-threatening toxicities, and planning a study duration that allows for the detection of late toxicities.

包括：

• 更新了指导原则的质量章节，以纳入与起始物料、可比性和验证相关的信息。

• 目前关于开展非临床研究要求的想法，以及CAR T细胞和T细胞与工程T细胞受体的科学原理。

• 建议探索性药代动力学临床研究应在不同时间点描述CAR T细胞水平，以及其在血液和靶组织中的扩增和持续存在。

• 应进行剂量探索研究，以考察不同剂量水平下的安全性、毒性和抗肿瘤活性，并确定II期研究的推荐剂量或剂量范围。

• 传统的药物间相互作用研究和肾/肝功能不全研究不太可能适用CAR      T细胞，应根据具体情况具体分析。

• 对于CAR T细胞的疗效，剂量选择和缓解评估时间选择应基于探索性试验的结果。

• 在计划验证性试验时，建议在评估疗效时坚持意向治疗(ITT)原则。监管机构建议将ITT人群定义为所有入组试验的患者，包括CAR T细胞组和对照组。

• 首选随机对照试验设计，与最佳支持治疗或研究者选择的治疗进行比较优于单臂试验。

• 对于CAR T细胞产品的安全性评价，EMA建议药物研发人员评估CAR      T细胞产品和相关程序（如淋巴细胞清除方案或单采程序）引起的不良事件的原因。

• 申办方应考虑定义预期和非预期不良事件，选择一种检测和治疗潜在危及生命毒性的算法，并计划允许检测晚期毒性的研究持续时间。

Key Takeaways:

·       The EMA has updated its guidance to industry on the development of new medicines with genetically modified cells, including a special section on considerations for developing chimeric antigen receptor (CAR) T-cell therapies.

·       It is recognized that this is an area under constant development and the guideline should be applied to any novel product as appropriate.

·       The EMA is seeking alignment with the FDA on this topic whenever possible.

关键信息：

• EMA已经更新了其关于转基因细胞新药开发行业指南，包括关于开发嵌合抗原受体(CAR)T细胞疗法的注意事项的特殊章节。

• 众所周知，这是一个正在不断发展的领域，该指导原则应适用于任何适用的新产品。

• EMA正在尽可能就该主题寻求与FDA保持一致。

2.     EMA Updates Q&A: Good clinical practice (GCP) - Nov 2020

EMA更新问答：药物临床试验质量管理规范(GCP) - 2020年11月

Summary:

The EMA has updated their Q&A: Good clinical practice (GCP).  There is now an additional question.

EMA已更新其问答：药物临床试验质量管理规范(GCP)。  目前还有一个额外的问题。

Does the sponsor of a clinical trial have the right to audit the manufacturer of the IMP even if the manufacturer has been subcontracted by a CRO involved in the clinical trial?

临床试验申办方是否有权对IMP生产商进行稽查，即使生产商是参与临床试验的CRO的分包商？

This question touches the scope of Good Clinical Practice (GCP) as well as the scope of Good Manufacturing Practice (GMP).

这个问题涉及到药物临床试验质量管理规范(GCP)的范围以及药品生产质量管理规范(GMP)的范围。

For clinical trials, sponsor oversight is required according to ICH GCP (R2), section 5.2.1: (‘A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor’). This oversight applies not only to duties and functions executed by sponsor staff, but also to duties and functions, which have been transferred to a CRO, or which were even further subcontracted by the CRO to another party; also see section 5.2.2 (addendum) (‘The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s)’).

 对于临床试验，根据ICH GCP(R2)第5.2.1节要求申办方进行监督：（“申办方可以将申办方的任何或所有试验相关职责和职能转移给CRO，但试验数据的质量和完整性的最终责任始终由申办方承担”）。这种监督不仅适用于申办方工作人员执行的职责和职能，也适用于已转移给CRO或由CRO进一步分包给另一方的职责和职能；另请参见第5.2.2节（附录）（“申办方应确保监督代表其执行的任何试验相关职责和职能，包括由申办方合同CRO分包给另一方的试验相关职责和职能”）。

Furthermore, ICH GCP (R2) 5.13.1 and 2.12 stipulate that the sponsor ensures that the IMP is manufactured according to GMP and local regulations. The sponsor can only meet this requirement if he has the possibility to perform an audit at the manufacturing site.

 此外，ICH GCP(R2)5.13.1和2.12规定申办方确保IMP是根据GMP和当地法规生产的。申办方只有在有可能对生产场地进行稽查的情况下才能满足这一要求。

Approaching this question from a GMP perspective, one comes to the same conclusion. According to Annex 13, the sponsor is responsible for the quality of the IMP and for implementation of an effective Quality Management System:

 从GMP的角度来探讨这个问题，人们得出了相同的结论。根据附录13，申办方负责IMP的质量并实施有效的质量管理体系：

(‘Co-operation is required with trial sponsors who undertake the ultimate responsibility for all aspects of the clinical trial including the quality of investigational medicinal products. The increased complexity in manufacturing operations requires a highly effective quality system.’)

 （“需要与对临床试验的所有方面（包括试验用药品的质量）承担最终责任的试验申办方合作。生产操作日益复杂，需要一个高效的质量体系。”）

Moreover, GMP Volume 4, Chapter 7, section 7.17 explicitly states that audits at contractors and subcontractors should be made possible:

 此外，《药品生产质量管理规范》第4卷第7章第7.17节明确规定，应对承包商和分包商进行稽查：

(‘The contract should permit the contract giver to audit outsourced activities performed by the contract acceptor or his mutually agreed subcontractors’).

（“合同应当允许委托方对受托方或其双方同意的分包商执行的外包活动进行稽查”）。

In particular ‘For cause’ audits by the sponsor in relation to a complaint or a quality defect (e.g. quality, packaging, labelling, etc.) can be of great importance, if patient safety or well-being could be affected or even endangered by the issue/defect. Regarding the contracts, no matter which contractual constellation is planned or exists (contract: sponsor – CRO; CRO – subcontractor; sponsor – subcontractor), it is concluded from a GCP- and GMP- perspective that the contracts between the involved parties should permit that the sponsor of the clinical trial audits both, the CRO(s) and the subcontractor(s) (ICH GCP (R2), 5.2.1 and 5.2.2 Addendum and GMP Vol 4, Chapter 7).

 尤其是申办方对某一投诉或质量缺陷（例如，质量、包装、标签等）进行的“有因”稽查，如果该问题/缺陷可能会影响患者的安全或健康，甚至危及患者的安全或健康，则该稽查具有重要意义。关于合同，无论计划或存在哪种合同系列（合同：申办方-CRO；CRO–分包商；申办方–分包商），从GCP和GMP的角度得出结论，相关方之间的合同应允许临床试验的申办方对CRO和分包商进行稽查（ICH GCP(R2)，5.2.1和5.2.2附录和GMP第4卷，第7章）。

Key Takeaways:

·       The main aspects of the above question are, whether sponsor oversight, as defined in ICH GCP E6 (R2) also extends to the manufacturing area, i.e. a GMP area and whether the contract between the CRO and subcontractors should include (or implicitly permit) that a sponsor audit is possible not only at the CRO, but also at the subcontractor.

·       The contract should permit the contract giver to audit outsourced activities performed by the contract acceptor or his mutually agreed subcontractors’.

关键信息：

• 上述问题的主要方面是，ICH      GCP E6(R2)中定义的申办方监督是否也延伸到生产区域，即GMP区域，以及CRO和分包商之间的合同是否应包括（或隐含允许）申办方不仅可对CRO进行稽查，也可对分包商进行稽查。

• 合同应当允许委托方对受托方或其双方同意的分包商进行的外包活动进行稽查。

3.     EMA Revises Guideline on Remote Pharmacovigilance Inspections of MAHs During a Crisis Situation

EMA修订危机情况下MAH远程药物警戒检查指南

Summary:

The EMA has revised its guideline on Remote Pharmacovigilance Inspections of MAHs During a Crisis Situation - Points to Consider.   The document was originally release in 2012.

 EMA修订了《危机情况下MAH远程药物警戒检查指南-考虑要点》。该文件最初于2012年发布。

The main revisions are:

·       Change of the wording from distant/virtual pharmacovigilance inspections to remote pharmacovigilance inspections, in the title and in the text.

·       Clarifications on the necessity to assess before the inspection whether the inspectee meets the technical requirements to provide remote access to electronic systems and maintain communication with and support to inspectors.

·       Further guidance on the documentation preparation and the conduct preparation.

o   Several bullets of the documentation preparation section, covering pre-inspection documentation requests and translation, have been removed.

o   The document now says that inspectorates should decide the extent of the documentation to be reviewed in advance and that further requests for documentation are not precluded.

·       The section on conduct preparation has been completely revised to focus on the importance of video conferencing, IT support and having a detailed inspection agenda. Previously, the section addressed obtaining inspection findings and documentation from past inspections, the process for obtaining documents during the inspection and potential language barriers.

主要修订内容为：

·       将标题和正文中的措辞从远程/虚拟药物警戒检查变更为远程药物警戒检查。

·       阐明在检查前评估被检查方是否符合提供远程电子系统访问以及与检查员保持沟通和支持的技术要求的必要性。

·       文件准备和实施准备的进一步指南。

o   删除了文件准备章节的几个要点，包括检查前文件要求和翻译。

o   目前该文件说明检查机构应当事先决定文件的审查范围，并不排除对文件的进一步要求。

·       对实施准备一节进行了全面修订，重点放在视频会议、信息技术支持和详细检查议程的重要性上。之前，本章节讨论了从过去检查中获得检查结果和文件、检查期间获得文件的过程和潜在的语言障碍。

Key Takeaways:

·       The purpose of this document is to outline the specificities of remote PV inspections by identifying the points that should be considered during the preparation, conduct and reporting of such PV inspections of marketing authorisation holders (MAHs) with centrally authorized products (CAPs) and national authorised products (NAPs).

·       The revisions to the document are minor and mostly relate to the preparation phase ahead of a pharmacovigilance inspection when an on-site inspection would not be feasible due to a crisis.

关键信息：

·       本文件的目的是通过确定在准备、实施和报告对集中授权产品(CAP)和国家授权产品(NAP)的上市许可持有人(MAH)进行此类PV检查时应考虑的要点，概述远程PV检查的特殊性。

·       对文件的修订较小，主要涉及由于危机而无法开展现场检查时，药物警戒检查前的准备阶段。

4.     FDA Issues Final Guidance on Clinical Trial Diversity

FDA发布临床试验多样性最终指南

Summary:

The US FDA has issued a final guidance on Enhancing the Diversity of Clinical Trial Populations Eligibility Criteria, Enrollment Practices, and Trial Designs.

美国FDA发布了关于增强临床试验人群入选标准、入组规范和试验设计多样性的最终指南。

 Some of the main items this guidance discusses are:

·       Broadening eligibility criteria and avoiding unnecessary exclusions for clinical trials.

o   The FDA suggested employing inclusive trial practices, such as considering each exclusion criterion individually to determine if it is necessary to ensure safety and achieve the study objectives.

o   Sponsors should consider eliminating or modifying certain exclusion criteria as a clinical trial moves to phase 3, rather than simply transferring protocols from the phase 2 trial.

o   Sponsors should enroll participants who reflect the characteristics of clinically relevant populations with regard to age, sex, race, and ethnicity.

o   Consider using an adaptive clinical trial design that would allow for pre-specified trial design changes during the trial when data become available, including altering the trial population

o   Consider a broader pediatric development program early.

·       Study Design And Conduct Considerations For Improving Enrollment

o   Make Trial Participation Less Burdensome for Participants

o   Flexible visit windows and/or reduced Frequency of visits

o   Consider use of mobile health professionals

o   Use of phone visits or digital health tools

·       Adopt Enrollment and Retention Practices That Enhance Inclusiveness

o   Implement more inclusive strategies for public outreach and education.

o   Consider fostering community engagement

o   Consider using real-world data to promote more efficient recruitment of a diverse population

·       Applying the recommendations for broadening eligibility criteria to clinical trials of drugs intended to treat rare diseases or conditions.

o   Consider re-enrollment of participants in early-phase trials into later-phase randomized trials when studying the effectiveness of treatments for rare diseases.

o   Make available an open-label extension study with broader inclusion criteria after early-phase studies to encourage participation by ensuring that all study participants, including those who received placebo, will ultimately have access to the investigational treatment.

本指南讨论的部分主要内容包括：

·       放宽入选标准，避免不必要的临床试验排除标准。

o   FDA建议采用包容性试验规范，例如单独考虑每项排除标准，以确定该标准对于确保安全性并达到研究目的是否有必要。

o   申办方应考虑在临床试验进入III期时删除或修改某些排除标准，而不是简单地从II期试验照搬方案。

o   申办方应招募在年龄、性别、人种和种族方面反映临床相关人群特征的受试者。

o   当数据可用时，考虑采用适应性临床试验设计，允许在试验期间进行预先规定的试验设计变更，包括改变试验人群

o   尽早考虑更广泛的儿科研发计划。

·       改善入组情况的研究设计和实施考虑

o   减轻受试者参与试验的负担

o   访视时间窗灵活和/或访视频率降低

o   考虑使用移动医疗专业人员

o   使用电话访视或数字健康工具

·       采用增强包容性的入组和保留方法

o   实施更广泛的公众外联和教育战略。

o   考虑促进社区参与

o   考虑使用真实世界数据来促进更有效地招募不同人群

·       将扩大入排标准的建议应用于治疗罕见疾病或病症的药物临床试验。

o   在研究罕见病治疗的有效性时，考虑将早期试验的参与者再次招募到后期随机试验中。

o   在早期研究后提供具有更广泛入选标准的开放性延长期研究以鼓励参与研究，确保所有研究参与者，包括接受安慰剂的参与者，最终都能获得研究治疗。

Key Takeaways:

·       The FDA is encouraging drug and biologics sponsors to broaden enrollment criteria and to avoid unnecessarily excluding participants in a final guidance document aimed at increasing the diversity of clinical trial participants.

·       Broadening eligibility criteria and adopting more-inclusive enrollment practices should improve the quality of studies by ensuring that the study population is more representative of the population that will use the drug if the drug is approved

关键信息：

·        FDA鼓励药物和生物制剂申办方扩大招募标准，并避免在旨在增加临床试验参与者多样性的最终指南文件中不必要地排除参与者。

·       扩大入排标准和采用更具包容性的入组实践，应通过确保研究人群更能代表药物获批后将使用该药物的人群来提高研究质量