Regulatory Express_Q3 2022

1. EMA根据GCP和GMP发布申办者在人用IMP处理和运输方面的职责指南（2022年3月）

EMA Releases Guideline on the Responsibilities of the Sponsor with regard to Handling and Shipping of IMP for Human Use in accordance with GCP and GMP (Mar-2022)

总结：

EMA发布一份指南：申办者根据《药物临床试验质量管理规范》和《药品生产质量管理规范》处理和运输人用试验药品的职责。

Summary:

The EMA posted a document titled: Guideline on the responsibilities of the sponsor with regard to handling and shipping of investigational medicinal products for human use in accordance with Good Clinical Practice and Good Manufacturing Practice.

关键信息：

· 指南阐述了在GCP规范下的临床试验中管理试验用药品的原则，既是GCP与GMP的衔接，也是对GMP的补充。

· 指南描述了试验用药品的放行程序、运输和合同安排或技术协议。

Key Takeaways:

· The guideline lays down the principles for management of the investigational medicinal products by the sponsor for use in a clinical trial and in accordance with Good Clinical Practice (GCP) which are at the interface with, and complementary to, Good Manufacturing Practice (GMP).

· The guidance describes investigational medicinal product (IMP) release procedure, shipping and contractual arrangement or technical agreements.

2. EMA启动临床试验原始数据分析试点项目（2022年7月）

EMA Launches Pilot Project on Analysis of Raw Data from Clinical Trials (Jul-2022)

总结：

EMA已经启动了一个试点项目，评估监管机构对来自临床试验的“原始数据”分析是否能改善对新药上市许可申请(MAA)以及许可后申请的评价，并探索提交和分析此类数据的切实可行的方法。

Summary:

EMA has launched a pilot project to assess whether the analysis of 'raw data' from clinical trials by regulatory authorities improves the evaluation of marketing authorization applications (MAAs) for new medicines as well as post-authorization applications and to explore the practical aspects of the submission and analysis of such data.

关键信息：

· 对于某些监管程序，监管机构可能受益于在药品评估过程中访问原始数据。获取原始数据有助于监管机构理解提交的证据，从而为监管机构有关产品获益-风险平衡的决策提供信息。

· 联合大数据工作组建议进行这个概念性验证的试点，以研究可视化和分析原始数据的益处，以支持药品的科学评估，并确定相关的操作、资源和技术需求。

Key Takeaways:

· For certain regulatory procedures, regulators may benefit from having access to raw data during the assessment of the medicinal product. Access to raw can assist regulators in understanding the submitted evidence and therefore inform the regulatory decisions on the benefit-risk balance of the product.

· The joint Big Data Task Force recommended conducting a PoC pilot to investigate the benefits of visualising and analysing raw data to support the scientific assessment of medicinal products and to identify the associated operational, resource and technological needs.

3. US FDA指南草案：以患者为中心的药物开发：选择、开发或调整适合目的的临床结局评估（2022年6月）

US FDA Draft Guidance: Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments (Jun-2022)

总结：

FDA发布了指南草案《以患者为中心的药物开发：选择、开发或调整适合目的的临床结局评估》。

· 这是4个以患者为中心的药物研发方法学指南系列中的第3个指南，这些指南描述了患者、护理人员、研究人员、医疗产品开发人员和其他利益相关者如何收集并提交患者体验数据和其他来自患者和护理人员的相关信息，以用于医疗产品开发和监管决策。

· 本文件包括选择、调整、开发和验证临床结局评估(COA)的方法，以测量临床试验中患者的重要结局。

Summary:

FDA has published a draft guidance, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments.

· This is the third in a series of four methodological patient-focused drug development guidances that describe how stakeholders such as patients, caregivers, researchers, medical product developers, and others, can collect and submit patient experience data and other relevant information from patients and caregivers to be used for medical product development and regulatory decision-making.

· This document includes approaches to selecting, modifying, developing, and validating clinical outcome assessments (COAs) to measure outcomes of importance to patients in clinical trials.

4. FDA发布远程监管评估指南草案（2022年7月）

FDA Releases Draft Guidance on Remote Regulatory Assessments (Jul-2022)

FDA已经以Q&A的形式发布了关于执行远程监管评估(RRA)的指南草案。

FDA has released draft guidance, in the form of a Q&A, on Conducting Remote Regulatory Assessments (RRAs).

关键信息：

· RRA是对FDA监管的机构和/或其记录以完全远程的方式进行审查，以评估是否符合适用的FDA要求。审查方式包括收集记录、虚拟会议和实时或预录视频。

· 在制定本指南时，FDA的目的是提高在大规模流行病期间和大规模流行病之后采用RRA情况的透明度，并促进RRA实施方式的更大一致性。

· RRA可用于促进上市申请的更快批准，减少检查员在FDA监管的机构花费的时间，支持监管行动，并有助于基于风险的检查安排。

Key Takeaways:

· An RRA is an examination of an FDA-regulated establishment and/or its records, conducted entirely remotely, to evaluate compliance with applicable FDA requirements. Examples include records' requests, virtual meetings, and livestream or pre-recorded video.

· In developing this guidance, FDA's intention is to provide more transparency about the circumstances in which RRAs may be used both during and beyond the pandemic, and to promote greater consistency in the way RRAs are conducted.

· RRAs may be used, for example, to promote faster approvals of marketing submissions, reduce the amount of time an investigator spends at an FDA-regulated facility, support regulatory actions, and contribute to risk-based scheduling of inspections.

5. FDA生物研究监查技术符合性指南（第3版）（2022年8月）

FDA Bioresearch Monitoring Technical Conformance Guide (Version 3) (Aug-2022)

总结：

FDA发布了生物研究监查技术符合性指南修订版（第3版）。

本指南提供了当前的FDA质量标准、建议以及准备和提交以下内容的一般考虑：

· 临床研究层面信息

· 按临床研究中心列出的受试者层面数据行列表

· 临床研究中心数据集摘要

v.3中的主要变更：

· 将BIMO审查指南重命名为BIMO数据审查指南

· 将TRTEFFR重命名为TRTEFFR1

· 增加EFFPOP、TRTEFFR2和CENSOR2变量

· 删除了对TRTEFFS的要求

· 将ISO代码的使用说明变更为使用地缘政治实体、名称和代码(GENC)代码列表

· 微小的编辑性变更

Summary:

The FDA has released a revised Bioresearch Monitoring Technical Conformance Guide (Version 3). 

This Guide provides current FDA specifications, recommendations, and general considerations for preparing and submitting:

· Clinical Study-Level Information

· Subject-Level Data Line Listings by Clinical Site

· Summary-Level Clinical Site Dataset

Key changes in v.3 :

· Rename BIMO Review Guide to BIMO Data Review Guide

· Renamed TRTEFFR to TRTEFFR1

· Added EFFPOP, TRTEFFR2, and CENSOR2 Variables

· Deleted request for TRTEFFS

· Change instructions for use of ISO codes to use of Geopolitical Entities, Names and Codes (GENC) code list

· Minor editorial changes

关键信息：

· 药品评价和研究中心(CDER)使用该数据以电子格式对新药上市申请(NDA)、生物制品许可申请(BLA)和包含由CDER监管的临床数据的NDA或BLA补充申请制定生物研究监查(BIMO)检查计划。

· 这同样适用于在计划的NDA、BLA或补充提交之前根据某些研究性新药临床试验申请(IND)提交的数据和信息。

Key Takeaways:

· This data is used by the Center for Drug Evaluation and Research (CDER) for the planning of Bioresearch Monitoring (BIMO) inspections in electronic format for new drug applications (NDAs), biologics license applications (BLAs), and NDA or BLA supplemental applications containing clinical data that are regulated by CDER.

· It also applies when these data and information are submitted under certain investigational new drug applications (INDs) in advance of a planned NDA, BLA, or supplemental submission.

6. 关于使用真实世界数据和真实世界证据提交文件的FDA最终指南（2022年9月）

FDA Final Guidance on Submitting Documents Using Real-World Data and Real-World Evidence (Sep-2022)

总结：

美国FDA发布了一份最终指南，标题为：使用真实世界数据和真实世界证据向FDA提交关于药品和生物制品的文件。RWD的可用性以及不断发展的用于生成RWE的分析技术，使研究和医学界对使用RWD/RWE来加强临床研究和支持监管决策产生了兴趣。本指南适用于包含RWD/RWE的研究性新药临床试验申请(IND)、新药上市申请(NDA)和生物制品许可申请(BLA)，旨在支持有关产品安全性和/或有效性的监管决策。

Summary:

The US FDA has released a final guidance titled: Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products.   The availability of RWD and evolving analytic techniques to generate RWE have created interest within the research and medical communities in the use of RWD/RWE to enhance clinical research and support regulatory decision-making.  This guidance applies to submissions for investigational new drug applications (INDs), new drug applications (NDAs), and biologics license applications (BLAs) that contain RWD/RWE intended to support a regulatory decision regarding product safety and/or effectiveness.

关键信息：

· 为了便于FDA对向FDA提交的包含真实世界数据(RWD)和真实世界证据(RWE)的申请进行内部跟踪，本指南鼓励申办者和申请者在其申请函中明确RWD/RWE的特定用途。本指南不涉及FDA对作为FDA标准审评程序一部分提交的RWD/RWE的实质性审评。

· 通过提高FDA对为支持监管决策而提交的RWD和RWE的范围和使用的理解，按照本指南中所述对此类提交进行内部跟踪可以根据《FD&C法案》第505F节为FDA的RWE计划提供信息。

Key Takeaways:

· To facilitate FDA's internal tracking of submissions to the Agency that include real-world data (RWD) and real-world evidence (RWE), this guidance encourages sponsors and applicants to identify in their submission cover letters certain uses of RWD/RWE. This guidance does not address FDA's substantive review of the RWD/RWE submitted as part of the Agency's standard review process.

· By enhancing FDA's understanding of the scope and use of RWD and RWE submitted to support regulatory decisions, internally tracking these submissions as described in this guidance can inform FDA's RWE program under section 505F of the FD&C Act.

7. 美国FDA生产和质量体系软件的计算机软件保证指南草案（2022年9月）

US FDA DRAFT Guidance Computer Software Assurance for Production and Quality System Software (Sep-2022)

指南参考CFR820，适用于医疗器械生产或质量体系中的计算机系统。指南中提及的概念可借鉴于制药和消费品领域中的计算机系统。

The guidance only makes reference to CFR 820 focusing on Med Tech systems used as part of production or quality system, however, the concepts could be applicable to a larger set of systems in Pharm or Consumer.

总结：

FDA发布本指南草案的目的是为作为医疗器械生产或质量体系组成部分的计算机和自动化数据处理系统提供计算机软件保证建议。本指南草案旨在：

· 将“计算机软件保证”描述为一种基于风险的方法，用于建立生产或质量体系自动化的置信度，并确定可能需要额外严格度的地方；以及

· 描述确定保证活动（包括测试）的各种基于风险的方法，这些方法可能用于建立与医疗器械或过程风险相称的计算机软件保证，并满足法规要求，例如21 CFR第820部分（第820部分）。

· 本指南包括一些具体示例（例如：不合格项管理系统、学习管理系统和商业智能应用程序），这些示例有助于概述文档所述原则在各种软件保证情况下的可能应用。

· 本指南定稿后将补充FDA指南《软件验证的一般原则》（《软件验证指南》），但本指南将取代《软件确认指南》的第6节（“自动化过程设备和质量体系软件的验证”）。

Summary: 

FDA is issuing this draft guidance to provide recommendations on computer software assurance for computers and automated data processing systems used as part of medical device production or the quality system. This draft guidance is intended to:

· Describe "computer software assurance" as a risk-based approach to establish confidence in the automation used for production or quality systems, and identify where additional rigor may be appropriate; and

· Describe various risk-based methods for determination of assurance activities (including testing) that may be applied to establish computer software assurance commensurate with the medical device or process risk, and fulfill regulatory requirements, such as in 21 CFR part 820 (Part 820).

· The guidance includes some specific examples (e.g. Nonconformance Management System, Learning Management System and Business Intelligence Applications) that help outline possible application of the principles described within the document to various software assurance situation cases.

· When final, this guidance will supplement FDA's guidance, "General Principles of Software Validation" ("Software Validation guidance") except this guidance will supersede Section 6 ("Validation of Automated Process Equipment and Quality System Software") of the Software Validation guidance.

8. MHRA博客：创新、质量和透明度——合规团队视角（2022年8月）

MHRA Blog: Innovation, Quality & Transparency – a Compliance Team Perspective (Aug-2022)

总结：

在英国MHRA的博客中，GxP专家圈的Paula Walker和Jason Wakelin-Smith反映了该行业对创新的关注，以及传统的“质量”活动和专业人员在该领域的定位。

Summary:

In a blog for the UK's MHRA, Paula Walker and Jason Wakelin-Smith of GxP Expert Circle reflected on the industry's focus on innovation, as well as where the traditional "quality" activities and professionals fit into the space. 

关键信息：

· 传统的质量保证长期采用的一个方法，即在产品生命周期内计划年度稽查计划，以确保遵守法规。正如检查是监管机构工具包的一部分一样，稽查也是申办者工具包中的工具，既可以作为审查内容的快照，也可以作为确认问题的快照。

· 从MHRA的角度来看，需要将质量投入纳入风险评估，并将此细节透明地发布给监管机构，以支持创新。

预期未来会更新人用药品（临床试验）法规，并将风险适应推向临床试验计划和管理的前沿。

Key Takeaways:

· Traditional quality assurance has a long-standing approach of planning an annual audit schedule across the product life cycle to ensure regulatory compliance. Just as inspections serve as part of a regulator's toolkit, audits are a tool in a sponsor's toolkit, with both serving as a snapshot of things reviewed and issues acknowledged.

· From the MHRA's perspective, quality input built into risk assessments and transparent release of this detail to regulators is needed to support innovation.

· Expect future updates to the Medicines for Human Use (Clinical Trials) Regulations and look to push risk adaptation into the forefront of planning and managing clinical trials.