1. MHRA and FDA Joint Paper “Data Integrity in Global Clinical Trials”
1. MRHA和FDA联合论文《全球临床试验中的数据完整性》
Summary:
The MHRA has posted a blog on : MHRA and FDA Joint Paper 'Data Integrity in Global Clinical Trials. It discusses a paper published in the Journal of Clinical Pharmacology and Therapeutics regarding both Agencies’ perspectives on how to ensure Data Integrity in clinical trials. The paper talks about the need for robust processes to manage data, throughout its Lifecyle, using a risk-based approach. Data integrity also relies on organizations having an open culture with regards to reporting any issues, with proportionate management of those failures. A common thread among various data integrity guidance documents is an emphasis on risk-based approach to data management, specifically targeting data and study procedures that are critical and have the greatest impact on maintaining subject safety and determining product efficacy. Despite the importance of data quality in clinical trials, until recently quality measures within the clinical trial enterprise have been largely reactive rather than proactive.
MRHA发布名为“MHRA和FDA联和论文《全球临床试验中的数据完整性》”的博客，围绕两个机构如何确保临床试验中数据完整性的观点，讨论了发表在《临床药理学和治疗学杂志》上的这篇文章。该文章阐述了在数据的全生命周期管理中，采用基于风险的方法、构建稳健流程的必要性。数据完整性还依赖于组织具有开放的文化上报任何问题及对这些问题进行适当管理。各种数据完整性指导文件的一个共同点是强调基于风险的数据管理方法，特别是对维护受试者安全和确定产品疗效有最大影响的关键数据和研究程序。尽管数据质量在临床试验中很重要，但直到最近，临床试验企业内部的质量措施在很大程度上仍是被动而非主动的。
Consequences of not maintaining data integrity:
· Rejection of data for marketing applications
· Need to conduct additional studies
· Reputational damage
· Pose Significant subject safety risks
未保持数据完整性的后果：
· 上市申请的数据被拒绝
· 需要进行额外的研究
· 名誉受损
· 对受试者造成重大安全风险
The paper discusses some specific areas where Regulators have seen issues that impact data integrity, such as:
· Audit trails
· Maintaining the study blind
· General data management practices
本文讨论了监管方发现影响数据完整性问题的一些特定领域，例如：
· 稽查轨迹
· 保持研究盲态
· 一般数据管理实践
Differences in approach to Data Integrity during inspections
· EMA: focused on GCP systems and processes in clinical trials and also grade each finding and cite ICH E6 (R2) on GCP noncompliance.
· FDA: take an outcome-focused approach, focusing on data line listings to verify data provided in marketing applications and cite 21 CFR.
检查过程中评估数据完整性的方法差异
· EMA：重点关注临床试验中的GCP系统和流程，也对每项发现进行分级，并引用ICH E6(R2)中的GCP不依从性。
· FDA：采用侧重结果的方法，重点关注数据行列表，以验证上市申请中提供的数据，并引用21 CFR。
MHRA and FDA GCP Inspectors enjoy close collaboration.
· They share information relating to non-compliances, they have observed at each other’s inspections and are working towards a program of collaborative and joint inspections.
· They have quarterly teleconferences and annual face to face meetings, where discuss issues of interest to both agencies and how might want to approach them.
MHRA和FDA GCP检查员紧密合作。
· 共享与不合规有关的信息，观察彼此的检查工作，并正在努力制定一个合作和联合检查的方案。
· 召开季度电话会议和年度面对面会议，在会上讨论两个机构感兴趣的问题，以及如何处理这些问题。
Noted emerging areas related to data integrity:
· Sponsor oversight of electronic systems and electronic health records used at sites
· Electronic source data
· Protocol deviations and management of these deviations
· Novel clinical trial designs and the challenges in ensuring the quality and reliability of study data.
注意与数据完整性相关的新兴领域：
· 申办方对研究中心使用的电子系统和电子健康记录的监督
· 电子源数据
· 方案偏离和对这些偏离的管理
· 新的临床试验设计和确保研究数据质量和可靠性的挑战
The article also contains tables on:
1. Different types of Types of GCP Inspections – EMA, MHRA and FDA
2. Factors to consider for ensuring a robustly blinded study
该文章还包含以下表格：
1. 不同类型的GCP检查-EMA、MHRA和FDA
2. 确保可靠设盲研究需要考虑的因素
Key Takeaways:
· Concerns with audit trails, blinding and data management overall have been presented as well as potential measures to prevent or mitigate the impact of the data integrity concerns.
· The ability to share information among regulatory agencies bolsters the effectiveness of the regulatory authorities, and also aids in process improvement to better guide resource allocation for inspection coverage and align best practices.
关键信息：
· 关注稽查轨迹、设盲和总体数据管理，以及能防止或减轻影响数据完整性问题的潜在措施。
· 监管机构之间共享信息的能力增强了监管机构的有效性，也有助于流程改进，以更好地指导检查范围的资源分配，并使最佳实践保持一致。
2. US FDA Revises Guidance on Risk Evaluation and Mitigation Strategies: Modifications and Reviews
2. US FDA修订《风险评估和缓解策略指南：修改和审查》
Summary:
The FDA has issued a revised guidance: Risk Evaluation and Mitigation Strategies: Modifications and Reviews. This guidance provides information on how the FDA defines the types of changes to approved risk evaluation and mitigation strategies (REMS), how application holders should submit changes to an approved REMS, and how the FDA will process submissions from application holders for changes to REMS. It revises an earlier version released in July 2019.
摘要：
FDA发布了修订版《风险评估和缓解策略：修改和审查》本指南提供了关于FDA如何定义已批准风险评估和缓解策略(REMS)的变更类型，申请持有人应如何提交已批准REMS的变更，以及FDA将如何处理申请持有人提交的REMS变更申请的信息。其修订了2019年7月发布的早期版本。
Some changes to the document include:
文件的一些变更包括：
Page 2: ADDED: to minimize the burden on the health care delivery system of complying with the REMS, or to accommodate different, comparable aspects of the elements to assure safe use (ETASU) for a drug that is the subject of an application under section 505(j), and the applicable listed drug, the FDA has the authority to require that the application holder submit a proposed modification to a REMS under section 505-1(g) of the FD&C Act.
第2页：添加内容：为了最大限度地降低因遵守REMS而给医疗保健提供系统带来的负担，或者为了确保第505(j)节所述药物以及适用的列名药物的安全使用(ETASU)，FDA有权要求申请持有人根据FD&C法案第505-1(g)节提交对REMS的拟议修改。
Page 5: ADDED: example to the table: Addition of an authorized generic for a drug in a shared system (SS) REMS when product-specific information is not included in the REMS document and/or REMS materials.
第5页：添加内容：表格示例：当产品特定信息未包含在REMS文件和/或REMS材料中时，为共享系统(SS)REMS中的药物添加授权仿制药。
Page 6: ADDED to table:
· Addition of an authorized generic to a single drug REMS
· Addition of an authorized generic for a drug in a shared system (SS) REMS when product-specific information is in the REMS document and/or REMS materials.
第6页：添加至表格：
· 在单个药物REMS中增加授权的仿制药
· 当产品特定信息在REMS文件和/或REMS材料中时，为共享系统(SS)REMS中的药物添加授权仿制药。
Key Takeaways:
The guidance lays out FDA’s policies for REMS modifications and revisions, including what types of changes the agency will consider and the processes and procedures for submitting those changes to the agency.
Tables in the guidance provide examples of REMS revisions and minor and major REMS modifications. These tables are intended to be a representative, rather than comprehensive, list of examples.
关键信息：
· 该指南阐述了FDA对REMS修改和修订的政策，包括该机构纳入考虑的变更类型以及向该机构提交这些变更的流程和程序。
· 指南中的表格提供了REMS修订以及微小和重大REMS修改的示例。这些表格旨在成为代表性而非综合性示例列表。
3. CDER Issues New MAPP on Determination of the Need for and Review of a New REMS （June 2020）
3. CDER发布关于确定新REMS需求和审查的新政策和程序手册 (MAPP)
Summary:
The US FDA’s CDER Office has issued a Manual of Policies and Procedures (MAPP) on the procedures the center will use to Determination of the Need for and Review of a New REMS.
摘要：
美国FDA CDER办公室发布了一份关于该中心将用于确定需求和审查新REMS的政策和程序手册(MAPP)。
The purpose is to:
· Determine whether a risk evaluation and mitigation strategy (REMS) for a prescription drug product marketed under a new drug application (NDA) or biologics license application (BLA) is necessary to ensure that the benefits of the drug product outweigh its risks
· Review a proposed-REMS submission developed by an applicant for an NDA or BLA to determine if it is acceptable
目的是：
· 确定是否有必要对新药申请(NDA)或生物制品许可申请(BLA)上市的处方药产品实施风险评估和缓解策略(REMS)，以确保药品的获益大于风险
· 审查申请人针对NDA或BLA提出的REMS申请，以确定其是否可接受
The document describes:
· Responsibilities of the different roles in the process
· The pre-approval REMS Determination and Review
o Pre-submission activities
o Application Submission
o Determining the Need for a REMS
o Review of Proposed REMS
o Prepare to Act on the Application
o Review of Resubmission of an Application
· Post Approval REMS Determination and Review
o Determining the Need for a REMS
o Review of Proposed REMS
o Prepare to Act on the FINAL REMS Supplement
本文件描述了：
· 过程中不同角色的职责
· 预批准REMS的评估和审查
o 申报前活动
o 申请递交
o 确定是否需要REMS
o 拟定REMS的审查
o 准备处理申请
o 重新提交申请的审查
· 批准后REMS的评估和审查
o 确定是否需要REMS
o 拟定REMS的审查
o 制定最终REMS补充方案
The CDER Office of Surveillance and Epidemiology and Office of New Drugs will jointly determine the need for and the components of the REMS for a drug approved under an NDA or BLA.
CDER监测和流行病学办公室和新药办公室将共同确定NDA或BLA批准药物的REMS需求和组成部分。
Key Takeaways:
· The MAPP describes the procedure for reviewing a proposed REMS submission developed by an NDA or BLA applicant to determine if it is necessary and acceptable.
· The MAPP applies to a new REMS being developed at either the preapproval or post approval stage.
· It does not pertain to a shared system REMS developed by multiple applicants for NDAs, ANDAs, and BLAs, and also does not apply to modifications to an approved REMS.
关键信息：
· MAPP描述了审查由NDA或BLA申请人提交的REMS申请的程序，以确定其必要性和可接受性。
· MAPP适用于在批准前或批准后阶段开发的新REMS。
· 它与NDA、ANDA和BLA多个申请人开发的共享系统REMS无关，也不适用于对已批准REMS的修改。
4. FDA Issues Final Guidance on Patient-Focused Drug Development: Collecting Comprehensive and Representative Input
4. FDA发布以患者为中心的药物研发终版指南：收集全面的、具有代表性的信息
Summary:
The FDA has released a final guidance entitled Patient-Focused Drug Development (PFDD): Collecting Comprehensive and Representative Input. This guidance finalizes the draft guidance of the same title issued on June 13, 2018.
摘要：
FDA发布了标题“以患者为中心的药物开发(PFDD)：收集综合和代表性信息”的终版指南。本指南最终确定了2018年6月13日发布的同一标题指南草案。
Changes from the draft to the final guidance include:
1. Removing most of the section and appendix on methods for collecting and analyzing patient experience data since that information will be covered in later guidances in the series.
2. Editorial changes were made to improve clarity
从草案到终版指南的变更包括：
1. 删除大部分关于收集和分析患者体验数据方法的章节和附录，因为该信息将在本系列后续指南中介绍。
2. 进行了编辑性变更，以提高清晰度
This guidance:
1. Presents methods for collecting information on the patient experience that is representative of the intended population to inform the development and evaluation of medical products throughout their lifecycle.
2. Discusses methods on how to operationalize and standardize the collection, analysis, and dissemination of patient experience data.
3. Includes a glossary of terms that will be used in one or more of the series of four guidance documents.
4. Provides a general overview of the relationship between potential research question(s) and method(s) when deciding from whom to get input.
5. Provides hypothetical case examples
本指南：
1. 介绍了收集患者体验信息的方法，这些信息代表预期人群，以便为医疗产品在其整个生命周期内的开发和评价提供信息。
2. 讨论如何操作和规范患者体验数据的收集、分析和传播的方法。
3. 包括将在四个指南文件系列中的一个或多个文件中使用的术语表。
4. 在决定从谁那里获得信息时，提供潜在研究问题和方法之间关系的一般概述。
5. 提供假设案例示例
This guidance is the first of a series of four guidance documents that FDA committed to develop to address in a stepwise manner how stakeholders can collect and submit information on the patient experience for medical product development and regulatory decision making. This series of guidance documents is intended to facilitate the advancement and use of systematic approaches to collect and use robust and meaningful patient and caregiver input that can more consistently inform medical product development and regulatory decision making.
本指南是FDA致力于开发的、旨在逐步解决利益相关者如何收集和提交患者体验信息，以供医疗产品开发和监管决策的，4个系列指南文件中的第一份。本系列指南文件旨在促进系统方法的进步和使用，以收集和使用可靠且有意义的患者和护理人员的输入信息，从而更一致地为医疗产品开发和监管决策提供信息。
The other guidance documents expected in the series include:
1. Guidance 2: Methods to Identify What is Important to Patients
2. Guidance 3: Selecting Developing or Modifying Fit for Purpose Clinical Outcomes Assessments
3. Guidance 4: Incorporating Clinical Outcome Assessments into Endpoints for Regulatory Decision Making
预期本系列的其他指南文件包括：
1. 指南2：识别患者重要事项的方法
2. 指南3：选择开发或修改符合目的的临床结果评估
3. 指南4：将临床结局评估纳入监管决策的终点
Key Takeaways:
1. This guidance is the first of a series of four methodological guidance documents that FDA committed to develop to address in a stepwise manner how to collect and submit information from patients and caregivers for medical product development and regulatory decision making.
2. The 21st Century Cures Act includes requirements for PFDD, and the guidance also meets one of the commitments made by the agency under the most recent Prescription Drug User Fee Act (PDUFA VI).
关键信息·：
1. 本指南是FDA致力于开发的、旨在逐步解决如何从患者和护理人员处收集和提交信息，以供医疗产品开发和监管决策的，一系列4个方法学指南文件中的第一个。
2. 21世纪治愈法案包括PFDD的要求，该指南也符合该机构根据最新处方药使用者付费法案(PDUFA VI)所做的承诺之一。
5. EMA GCP Remote Inspection Guidance
5. EMA GCP 远程检查指南
Summary:
The EMA has posted a guidance on Remote Good Clinical Practice Inspection Procedures during the COVID-19 Pandemic explaining how remote good clinical practice (GCP) inspections should be conducted amid the coronavirus disease (COVID-19) pandemic. Remote inspections should follow the applicable procedures that already exist for coordinating, preparing and conducting GCP inspections requested by the CHMP, but should also take into consideration the limitations imposed by using a remote process and recognize that such a remote process cannot completely replace on-site GCP inspections. They will require early contact with the sponsor or applicant to determine the feasibility of a remote inspection.
摘要：
EMA发布了一份“关于COVID-19大流行期间远程药物临床试验质量管理规范检查程序”的指南，解释了在冠状病毒病(COVID-19)大流行期间应如何进行远程药物临床试验质量管理规范(GCP)检查。远程检查应遵循现有的有关协调、准备和执行CHMP要求的GCP检查的适用程序，但也应考虑到使用远程过程所带来的局限性，并认识到这种远程过程不能完全取代现场GCP检查。 他们将需要尽早与申办方或申请人联系，以确定远程检查的可行性。
Sponsor Inspection Remote Feasibility determination:
1. For this phase, the standard procedure for preparing GCP inspections requested by the EMA (INS-GCP-2) is applicable.
2. It is fundamental to assess whether the inspectee meets the technical requirements to provide remote access to electronic systems and maintain communication with and support to inspectors.
3. The team will take into account the type of site, the scope and nature of the inspection, the activities delegated to CROs and service providers and inspection history of the inspectee, may decide that the requested inspection could be conducted remotely instead.
4. If the remote inspection is considered feasible, the remote inspection will be conducted and EMA should formally communicate this decision to the applicant.
申办方远程检查可行性确定：
1. EMA要求的准备GCP检查的标准程序(INS-GCP-2)适用于该阶段。
2. 重要的是要评估被检查人是否满足远程使用电子系统的技术要求，并与检查员保持沟通和支持。
3. 检查组将考虑研究中心的类型、检查的范围和性质、委托给CRO和服务提供商的活动以及被检查方的检查历史，决定对所要求的检查是否可以远程进行。
4. 如果认为远程检查可行，则将进行远程检查，EMA应正式将该决定告知申请人。
Some Expectations of the Sponsor:
对申办者的一些预期要求：
1. The functionality of critical communication pathways should be tested prior to the start of the remote inspection. The inspectors should have read-only access, but not otherwise be limited. The expectations and requirements should be discussed and agreed on between the inspectee and the inspection team during the preparation phase.
应在远程检查开始之前测试关键通信路径的功能。检查员应具有只读访问权限，但不受其他限制。在准备阶段，被检查方和检查小组应当讨论并商定预期和要求。
2. Remote inspections could be longer in duration than on-site inspections given the particularities of this type of inspection and the fact that inspectors may need to control several systems simultaneously when conducting the inspection.
考虑到此类检查的特殊性以及检查员在进行检查时可能需要同时控制几个系统的情况，远程检查的持续时间可能长于现场检查。
3. A host should be assigned by the inspectee to coordinate and manage further requests and queries during the inspection.
被检查方应指定一个主持人，以便在检查期间协调和管理进一步的请求和查询。
4. The inspectee should provide a list of attendees for the opening and closing meeting, as well as any subsequent meeting / session.
被检查方应当提供首次和末次会议以及任何后续会议的与会者名单。
5. Ideally, a video streaming system, embedded video conferencing or interactive tool for managing questions, queries and decisions, document sharing, or intuitive inspectors viewing tool, would facilitate all involved parties’ work and avoid disruptions, overlapping of activities and optimise resources and time invested. A chat / instant-messaging platform should also be considered, in case of sound interferences.
理想情况下，采用嵌入有视频会议或交互式工具的视频系统，管理问题、质询和决策、文档共享或检查员直观的查看工具，将促进所有相关方的工作，避免干扰、活动重叠，并优化资源和所投入的时间。如果存在声音干扰，也应考虑聊天/即时通讯平台。
6. Inspectors should be enabled to use export / save functions to retrieve documents from the eTMF. This could be provided through a sharing document platform or other media like email or a secure system after the applicable Quality Assurance (QA) checks by the document owner / subject matter experts have been performed.
检查员应能够使用导出/保存功能从eTMF中检索文件。在文件所有者/主题专家完成了适用的质量保证(QA)检查后，可通过共享文件平台或其他媒体（如电子邮件）或安全系统提供。
7. It is recommended to use an electronic document request form that can be shared among the inspectee and the inspection team. The inspection team may request the inspectee to keep track of all requests and provide a regular update of the electronic document created.
建议使用电子文件申请表，可供受检方和检查小组共享。检查小组可要求被检查方跟踪所有请求，并定期更新创建的电子文件。
8. It is important that sponsors / CROs provide remote technical support for inspectors, that the eTMF is robust and capable to support a remote inspection even if the eTMF is decentralized and managed from different locations and its content spread across different systems. It is important that inspectors can still gain access to (or via) a centralized system with one or several connected systems.
申办方/CRO为检查员提供远程技术支持非常重要，即使eTMF从不同的地点分散和管理，并且其内容遍及不同的系统，eTMF必须非常稳健，能够支持远程检查。重要的是，检查员仍然可以访问（或通过）有一个或几个连接系统的集中系统。
Remote inspections at investigator sites are not considered to be feasible, because:
1. It is crucial to avoid any additional burden on investigator site staff at this time
2. Inspection of source documents may not be possible due to local legal requirements concerning accessibility and data protection
3. Potential limited access to relevant electronic systems by investigational site staff and / or by inspectors.
在研究中心进行远程检查不可行，因为：
1. 此时避免对研究中心工作人员造成任何额外负担至关重要
2. 由于当地有关可访问性和数据保护的法律要求，可能无法检查源文件
3. 研究中心工作人员和/或检查人员对相关电子系统的访问可能受到限制。
Key Takeaways:
1. This document is intended to provide guidance on the steps to be followed during remote good clinical practice (GCP) inspections.
2. The EMA feels it is indispensable to continue conducting GCP inspections in the context of assessment of marketing authorization applications (MAA) submitted to the EMA, during crises like the COVID-19 pandemic.
3. Remote Inspections at investigators sites are not considered feasible by the EMA.
关键信息：
1. 本文件旨在为远程药物临床试验质量管理规范(GCP)检查期间应遵循的步骤提供指导。
2. EMA认为，在类似COVID-19大流行的危机期间，在评估提交给EMA的上市许可申请(MAA)的背景下，继续进行GCP检查至关重要。
3. EMA认为在研究中心进行远程检查不可行。
Reference:
1: MHRA and FDA Joint Paper 'Data Integrity in Global Clinical Trials.
2: Risk Evaluation and Mitigation Strategies: Modifications and Reviews.
3. Determination of the Need for and Review of a New REMS
4-1. Patient-Focused Drug Development (PFDD): Collecting Comprehensive and Representative Input
4-2. FDA’s first patient-focused drug development guidance now final
5-1. EMA issues guidance on remote GCP inspections
5-2. Remote Good Clinical Practice Inspection Procedures during the COVID-19 Pandemic
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