Dear reader,
It's time to launch the 2nd version of "Regulatory Express", subjects including: Gene Therapy Medicinal Products, use of Electronic Health Record (EHR) Data, GCP Q&A updates, MHRA Changes Rules, Sponsor Oversight and Clinical Trial Reporting Compliance Metrics, etc. Details see following content.
致读者：
第二期“法规速递”和大家见面了，本期主题涵盖：基因治疗药品、健康记录（EHR）数据的使用、GCP中的问题和答案更新、申办方的监督、遵守临床试验报告的指标等。详见下文。
Guideline on the Quality, Non-clinical and Clinical Aspects of Gene Therapy Medicinal Products
基因治疗药品质量、非临床和临床研究指导原则
(EMA, Updated 22 Mar 2018)
Summary:
The EMA has finalized a Guideline on the Quality, Non-clinical and Clinical Aspects of Gene Therapy Medicinal Products. This guideline is a revision of the Note for Guidance on the Quality, Preclinical and Clinical aspects of gene transfer medicinal products (CPMP/BWP/3088/99), which was published in 2001. It defines scientific principles and provides guidance for the development and evaluation of Gene Therapy Medicinal Products (GTMPs) intended for use in humans and presented for Marketing Authorization Application (MAA). Its focus is on the quality, safety and efficacy requirements of GTMPs.
摘要：
欧盟委员会（EMA）已经完成了“基因治疗药品质量，非临床和临床研究指导原则”的终稿。该指导原则是对2001年出版的基因转移药品质量、临床前和临床方面的指导说明（CPMP/BWP/3088/99）的修订。它界定了科学原理，对拟用于人类并提交上市许可申请（MAA）的基因治疗药品（GTMS）的开发和评估提供指导。其重点是对GTMPs的质量、安全性和有效性要求。
The revision addresses the issues identified from marketing authorizations, scientific advice and clinical experience with GTMPs. The revised guideline also takes in account the legal and technical requirements as laid down respectively in Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products and the Commission Directive 2009/120/EC amending Annex I Part IV of Directive 2001/83/EC. Because of the new GTMP definition, this revision no longer includes guidance for DNA vaccines (against infectious diseases). Also, guidance for genetically modified cells is no longer included.
该修订涉及了与GTMPs有关的上市许可、科学建议和临床经验中发现的问题。修订版也考虑到了在法规No 1394/2007中有关先进治疗药物产品和委员会指令 2009/120/EC有关指令2001/83/EC附录1第4部分修正中提出的法规和技术要求。由于GTMP新的定义，这版修订版中不再包括关于DNA疫苗（针对感染类疾病）的指南。同样的，基因修饰细胞的指导也不再包括在本修订版中。
The non-clinical section addresses the non-clinical studies required to support a marketing authorization application.
Non-clinical studies should aim to generate information to select the dose for the clinical trials and to support the route of administration and the application schedule.
They should also demonstrate that the observed effects are attributable to the GTMP.
Provides extended guidance on the selection and development of non-clinical in vitro and in vivo (animal) models.
非临床章节涉及支持上市许可申请所需的非临床研究：
· 非临床研究应旨在获得信息以选择临床试验的剂量，并支持给药途径和申请时间表
· 它们还应该证明观察到的效应可归因于GTMP
· 提供了关于非临床体外和体内（动物）模型的选择和开发的扩展指导
The clinical section addresses the requirements for studying, as far as possible, the pharmacological properties of the GTMP itself and the transgene product.
The requirements for efficacy studies emphasize that the same principles apply as for the clinical development of any other medicinal product, especially those of current guidelines relating to specific therapeutic areas.
Further addresses the safety evaluation of the product as well as the principles for follow up and the pharmacovigilance requirements.
In the revision, the guidance on pharmacological, efficacy and safety studies has been updated, e.g. amending the requirements for biodistribution and shedding studies of the vector, introduction of specific requirements for pharmacokinetics studies of the transgene product, expanding the requirements for efficacy studies and focusing on clinical safety endpoints rather than description of the vector biology leading to safety concerns.
临床部分针对GTMP本身和转基因产物的药理学性质的研究的有关要求：
有效性研究的要求强调，相同的原则适用于任何其他药品的临床开发，特别是与特定治疗领域相关的现行指导方针
进一步阐述了产品的安全性评价以及随访原则和药物警戒要求
在修订中，关于药理学、药效和安全性研究的指导已经更新，例如：
修改生物分布和载体的脱落研究的要求，引入转基因产品的药代动力学研究的具体要求，扩展功效研究的要求，并集中于临床安全终点，而不是导致安全性问题的载体生物学的描述
Key Takeaways:
The final guideline discusses the quality, preclinical and clinical aspects of developing and manufacturing gene therapies.
The guideline has been updated to include changes that have occurred in the area of gene therapy since initial release of the guidance back in 2001.
Several groups have called for global harmonization on this topic. However, given the EU and United States have very different legal and regulatory frameworks for gene therapies, EMA thinks it is impossible to harmonize requirements through guidelines.
关键信息：
终版指南讨论了基因治疗的开发和生产的质量、临床前和临床相关方面
更新后的指导原则包括自2001年首次发布指南以来基因治疗领域发生的变化
几个小组呼吁在这一主题上进行全球协调。然而，鉴于欧盟和美国对于基因治疗具有非常不同的法律和监管框架，EMA认为不可能通过指南协调要求
Use of Electronic Health Record (EHR) Data in Clinical Investigations
(FDA, issued in Jul 2018)
Summary:
The US FDA has released a final guidance on Use of Electronic Health Record (EHR) Data in Clinical Investigations. This guidance is intended to assist sponsors, clinical investigators, contract research organizations, institutional review boards (IRBs), and other interested parties on the use of electronic health record data in FDA-regulated clinical investigations. The recommendations outlined in this guidance apply to the use of EHR data in clinical investigations of human drugs and biological products, medical devices, and combination products, including clinical investigations conducted in clinical practice settings. For the purposes of this guidance, an electronic health record (EHR) is an individual patient record contained within the EHR system. This guidance uses broad definitions of EHRs and EHR systems to be inclusive of many different types of EHRs and EHR systems.
摘要：
美国FDA已经发布了关于在临床研究中使用电子健康记录（EHR）数据的最终指南。本指南旨在协助申办方、临床研究者、合同研究组织、机构审查委员会（IRBs）和其他有关各方在FDA监管的临床研究中使用电子健康记录数据。本指南中概述的建议适用于在人类药物和生物制品，医疗器械和组合产品的临床研究中使用EHR数据，包括在临床实践环境中进行的临床研究。为了本指导的目的，电子健康记录（EHR）是包含在EHR系统内的个体患者记录。本指南使用EHRs和EHRs系统的广泛定义，包括许多不同类型的EHRs和EHRs系统。
This guidance provides recommendations on:
Deciding whether and how to use EHRs as a source of data in clinical investigations
Using EHR systems that are interoperable with electronic data capture (EDC) systems in clinical investigations
Ensuring the quality and integrity of EHR data collected and used as electronic source data in clinical investigations
Ensuring that the use of EHR data collected and used as electronic source data in clinical investigations meets FDA’s inspection, recordkeeping, and record retention requirements
本指导原则对以下方面提出建议：
决定是否以及如何在临床研究中使用EHRs作为数据来源
使用在临床研究中与电子数据捕获（EDC）系统可以互操作的EHR系统
确保收集的EHR数据的质量和完整性，并在临床研究中用作电子源数据
确保在临床研究中使用收集和用作电子源数据的EHR数据符合FDA的检查，记录和记录保留要求
Inspection Readiness:
All relevant information in the EHR pertaining to the clinical investigation must be made available to FDA for review upon request. This information should be made available and viewable to FDA as original records in the EHR or as certified copies.
During an inspection, FDA may also request other paper or electronic records to support data in the eCRF (e.g., case histories, other data pertaining to the clinical investigation).
In addition, FDA may request to review the EHR audit trail information during inspection.
检查准备：
EHR中与临床研究有关的所有相关信息必须根据要求提供给FDA进行审查。此信息应作为EHR中的原始记录或作为认证副本供FDA查看。
在检查期间，FDA还可能要求提供其他文件或电子记录，以支持eCRF中的数据（例如，病史、与临床研究有关的其他数据）。
此外，FDA可能要求在检查期间审查EHR稽查轨迹。
Key Takeaways:
In an effort to modernize and streamline clinical investigations, the goals of this guidance are to facilitate the use of EHR data in clinical investigations and promote the interoperability of EHR and EDC systems.
The use of EHRs as a source of data in clinical investigations may involve additional considerations, planning, and management as described in this guideline
关键信息：
为了使临床研究现代化和简化，本指南的目标是促进在临床研究中使用EHR数据，并促进EHR和EDC系统的互操作性。
在临床研究中使用EHRs作为数据来源可能涉及本指南所述的额外考虑，规划和管理。
Questions and Answers on Good Clinical Practice (GCP)
(EMA, updated in June)
Summary:
The EMA has updated their Questions and Answers on Good Clinical Practice (GCP). The most recent version includes Question #9: "What is the level of validation/qualification needed to be performed by a sponsor when using an electronic system previously qualified by a provider? What documentation is required to be available for inspections?"
摘要：
EMA对药物临床试验质量管理规范（GCP）的问题和回答进行了更新。最新版本包含问题＃9：“当使用由供应商预先认证的电子系统时，申办方需要执行的验证/资格水平是什么？检查需要什么文件？”
EMA refers to ICH E6 (R2) 5.2.1., which states the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor, and according to ICH E6 (R2) 5.5.3.a, the sponsor should ensure and document that the electronic data processing system(s) conforms to the sponsors established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation). They also refer to section 1.65, Validation of Computerized Systems is a process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled from design until decommissioning of the system or transition to a new system.
EMA参考ICH E6(R2)5.2.1，指出申办方对试验数据的质量和完整性负有最终责任，并根据ICH E6（R2）5.5. 3a规定申办方应当确保并记录电子数据处理系统符合申办方所确立的完整性、准确性、可靠性和一致性的预期性能的要求（如：验证）。此外还参考了第1.65节，计算机系统的验证是建立和记录计算机系统能够一贯满足从设计直到系统的退役或过渡到新系统的过程。
The sponsor is ultimately responsible for the validation of the clinical trial processes which is supported by electronic systems. The sponsor may rely on qualification documentation provided by the vendor if the qualification activities performed by the vendor have been assessed as adequate, but may also have to perform additional qualification/validation activities based on a documented risk assessment.
申办方最终负责验证由电子系统支持的临床试验流程。如果供应商进行的确认活动已被评估为充分，申办方可能依赖于供应商提供的验证文件，但也可能需要根据记录的风险评估进行额外的确认/验证活动。
The conditions for a sponsor to use the vendor’s qualification documentation include, but are not limited to, the following:
The sponsor has a thorough knowledge about the vendor’s quality system and qualification activities, which will usually be obtained through an in-depth assessment/audit;
An assessment/audit has been performed by qualified staff, with sufficient time spent on the activities and with cooperation from the vendor;
An assessment/audit has gone sufficiently deep into the activities and that a suitable number of examples for relevant activities have been looked at (and documented);
The assessment/audit report has documented the vendor’s qualification documentation to be satisfactory or that shortcomings can be mitigated by the sponsor – e.g. that the sponsor is performing part of the qualification;
The sponsor, or where applicable the CRO performing these activities for the sponsor, has a detailed knowledge about the qualification documentation and can navigate in it and explain the activities as if they had performed the activities themselves;
When required during an inspection, the qualification documentation is made available to the inspectors in a timely manner irrespective of whether it is provided by the sponsor, CRO or the vendor.
Both the sponsor and the vendor establish full configuration management for qualification and production environments and that the sponsor can fully account for any differences between the vendor’s validation environment and the sponsor’s production environment and subsequently, justify any differences that are considered insignificant. If not, the qualification effort potentially does not justify the use of the system.
The sponsor has performed an Installation Qualification/Performance Qualification where the system depends on trained users.
申办方使用供应商资格证明文件的条件包括但不限于以下内容：
申办方对供应商的质量体系和确认活动有透彻的了解，通常可通过深入评估/审核获得
由合格的工作人员进行了评估/稽查，有足够的时间用于评估及和供应商的合作
对这些活动进行了充分深入的评估/稽查，并对有关活动进行了适当数量的抽样评估（并记录在案）
评估/稽查报告记录了供应商的资格证明是令人满意的，或者可由申办方弥补不足，如由申办方履行部分资格
申办方或在适当的情况下为申办方进行这些活动的CRO，对确认文件有详细的了解，找到正确的文件并对内容进行解释，就好像他们自己开展了这些活动
检查期间需要时，可及时向检查人员提供验证文件，无论提供方是申办方、CRO或供应商
申办方和供应商均需对确认和生产环境进行全面的配置管理，申办方可以充分考虑供应商验证环境与申办方生产环境之间的任何差异，并在随后证明存在的任何差异是微小或不重要的。如果没有，将被认为资质方面的努力无法证明使用该系统的合理性
如果系统依赖于经过培训的使用者，申办方进行了安装确认/性能确认
Key Takeaways:
Sponsors and vendors should be aware that if the electronic systems are used for generating/handling relevant clinical trial data or maintain control and oversight of clinical trial processes, during GCP inspections documentation regarding the qualification process and any other relevant documentation on the e-system maintained at the sponsor level, as well as on the vendor level, could be inspected.
Documentation regarding the validation of processes and qualification of systems is considered essential by inspectors and it is likely to be requested during inspections.
关键信息：
申办方和供应商应注意，如果电子系统用于生成/处理相关临床试验数据或保持对临床试验过程的控制和监督，在GCP检查期间，保存在申办方和供应商处的有关确认过程的文件和其他任何维护电子系统的相关文件，都可能被检查；
检查员认为有关程序验证和确认系统的文件是必不可少的，在检查过程中很可能被检查。
FDA Announces Complex Innovative Trial Design (CID) Pilot Meeting Program
FDA发布复杂创新试验设计（CID）试点会议计划
(FDA 29 Aug 2018)
Summary:
The FDA is conducting a Complex Innovative Trial Design (CID) Pilot Meeting Program to support the goal of facilitating and advancing the use of complex adaptive, Bayesian, and other novel clinical trial designs. This pilot meeting program offers sponsors whose meeting requests are granted the opportunity for increased interaction with FDA staff to discuss their proposed CID approach. Meetings will be conducted by FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) during fiscal years 2019 to 2022. To promote innovation in this area, trial designs developed through the pilot meeting program may be presented by FDA (e.g., in a guidance or public workshop) as case studies, including trial designs for medical products that have not yet been approved by FDA.
摘要：
FDA正在进行复杂的创新试验设计（CID）试点会议计划，以支持促进和推进使用复杂的适应性，贝叶斯和其他新型临床试验设计的目标。 这个试点会议计划向那些会议请求已被批准的申办者提供与FDA工作人员更多互动的机会，以讨论他们提出的CID方法。会议将由FDA药物评估和研究中心（CDER）和生物制剂评估和研究中心（CBER）在2019-2022财政年度进行。为了促进这一领域的创新，通过试点会议计划开发的试验设计可以由FDA（例如，在指导或公共研讨会中）作为案例研究提出，包括尚未被FDA批准的医疗产品的试验设计。
As a condition of participation in the pilot, FDA will be able to publicly present trial designs, and “generally” intends to include information such as study endpoints, target population, sample size and power determination. The agency stresses that it does not intend to make public the sponsor’s or product’s name, nor a complete description of study eligibility criteria. FDA makes clear that sponsors who want to participate in the pilot program need to provide a rationale for withholding any aspects of design/analysis that they consider non-disclosable. They also emphasize that participation in the program is voluntary, and sponsors that do not want public disclosures can use other existing channels.
作为参与试点计划的条件，FDA将能够公开呈现试验设计，并且“通常”意图包括诸如研究终点，目标群体，样本大小和效力（效能）测定的信息。 FDA强调，它不打算公开申办者或产品的名称，也不需要完整地描述研究合格性标准。 FDA明确指出，希望参与试点计划的申办者需要提供他们认为不可公开的设计/分析的任何方面的理由。 他们还强调，参与该计划是自愿的，不希望公开披露的申办者可以使用其他现有渠道。
Goals of the CID Pilot Meeting Program
Facilitate the use of CID approaches in late-stage drug development.
Promote innovation by allowing FDA to publicly discuss the trial designs considered through the pilot program, including trial designs for medical products that have not yet been approved by FDA.
CID试点会议计划的目标
· 促进CID方法在晚期药物开发中的应用
· 通过允许FDA公开讨论通过试点计划考虑的试验设计，包括尚未被FDA批准的医疗产品的试验设计，促进创新
Key Takeaways:
The new program is aimed at helping to solidify the science used to support these novel approaches and promote their adoption in drug development programs where these trial constructs can advance innovation.
In meetings granted under this pilot program, FDA staff across disciplines within the CDER and CBER will provide advice and direction on how a proposed CID approach can be used in a specific drug development program.
关键信息：
· 新计划旨在帮助巩固用于支持这些新方法的科学，并促进它们在药物开发计划中的采用以推进创新
· 在根据这个试点计划召开的会议中，CDER和CBER内的跨学科的FDA工作人员将提供关于如何在特定药物开发计划中使用拟议的CID方法的建议和指导
MHRA Changes Rules to Allow Patients With Prior ATMP Therapy to Participate in Clinical Trials under Certain Conditions
MHRA改变规则，允许先前ATMP治疗的患者在某些条件下参与临床试验
（MHRA 29 Aug 2018）
Summary:
The UK Medicines and Healthcare products Regulatory Agency (MHRA) has issued guidance explaining when it may be appropriate for clinical trials to include patients previously treated with an advanced therapy medicinal product (ATMP). In the past, prior treatment with a cell therapy or other ATMP (ex. CAR-T) prohibited a patient from participating in clinical trials. The MHRA has now relaxed it’s prior position, however the revised guidance still places limitations on when patients who relapse or progress following treatment with ATMPs can be enrolled in clinical trials. While these patients have few options, the UK is only willing to let them enroll in trials if certain criteria are met.
摘要：
英国药品和保健产品监管机构（MHRA）发布了指导，解释何时可以在临床试验中纳入既往接受过先进治疗药物（ATMP）治疗的患者。 在过去，禁止曾接受细胞疗法或其他ATMP（例如， CAR-T）治疗的患者参加临床试验。 MHRA现在已经放松了它之前的立场，然而修订的指导仍然限制那些接受ATMPs治疗后复发或进展的患者参加临床试验。 虽然这些患者几乎没有其他选择，但只有满足某些标准，英国才愿意让他们参加试验。
The MHRA guideline outlines several factors that sponsors should consider when seeking permission to conduct a clinical trial with an IMP that is to be administered to patients with previous ATMP use.
Trial Rationale
Trial Population
New IMP Characteristics
Risk Mitigation Strategies
Careful Benefit-Risk Assessment
Scientific Validity of the Trial
Blood Sample Collection
Ethical Issues
MHRA指南概述了申办方在寻求允许对先前使用ATMP的患者进行IMP的临床试验时应该考虑的几个因素。
研究原理
试验人群
新的IMP特性
风险控制策略
谨慎的获益-风险评估
试验的科学有效性
血样采集
伦理学问题
Key Takeaways:
· The new UK guidance outlines points to consider when planning clinical trials in patients previously treated with an advanced therapy medicinal product.
· As ATMPs come to occupy more slots in treatment pathways, previously-treated patients will represent a growing, important subpopulation.
关键信息：
· 新英国指南概述了在曾接受先进治疗药物治疗的患者中计划开展临床试验时需要考虑的要点
· 由于ATMPs在治疗途径中占据越来越多的位置，曾接受治疗的患者将代表不断增加的，重要的亚群。
References:
UK Changes Approach To Trials In Patients With Prior ATMP Therapy – Pink Sheet
UK Clears People Previously Treated With Advanced Therapies to Participate in Trials - RAPS
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