Regulatory Express_Q3 2019

1.      EU Revises Draft Q&A Document on Regulation No 536/2014 (EU CTR)

（EU June 2019）

欧盟修订了第536/2014号法规（EU CTR）的Q&A文件草案

（EU2019年6月）

Summary:

A revised draft guidance document on the EU Clinical Trials Regulation Questions and Answers has been released.  All updates to this questions and answers document are presented and discussed within the “Expert group on clinical trials” and reflects the view of the group. This group is chaired by the Commission and is composed of representatives of all EU Member States and EEA contracting parties.

摘要：

一份关于欧盟临床试验法规的Q&A的指导文件的修订稿已经发布。本Q&A文件的所有更新均在“临床试验专家组”中介绍和讨论，并反映了专家组的观点。该小组由欧盟委员会担任主席，由所有欧盟成员国和欧洲经委会缔约方的代表组成。

What has changed?

修订内容

·        This version adds Chapter 7 on “Safety Reporting” drafted by the Clinical Trials Facilitation and Coordination Group of the Heads of Medicines Agency and endorsed by the Expert Group on Clinical Trials of the European Commission. 

o   The section contains 47 questions on requirements for reporting safety issues in clinical trials.

本版增加了第七章“安全报告”，由临床试验促进和协调小组的药品管理负责人起草，并得到欧盟委员会临床试验专家组的认可。

o   该部分包含的47个问题是关于临床试验中报告安全性问题的要求。

·        They have also revised the following Q&As

o   1.15: Can a study be considered as clinical trial within the scope of Regulation (EU) No 536/2014 if it starts after administration/exposure of the investigational medicinal product has finished?

o   3.1: How "substantial modification" is defined?

o   5.2: How responsibilities are shared in case of cosponsorship?

o   5.7: What are the requirements for the legal representative of a non EEA-sponsor in view of article 74 of Regulation (EU) No 536/2014?

o   10.10: How is "early termination" defined?

其他修订的Q&As如下：

o   1.15 : 如果一项研究是在研究药物给药/暴露结束后开始的，是否可以认为它是在欧盟（EU）第536/2014号法规规定范围内的临床试验呢？

o   3.1：如何定义“实质性修改”？

o   5.2：共同申办者如何分担责任？

o   5.7：根据第536/2014号法规（EU）第74条的规定，对非EEA申办者的法定代表有哪些要求？

o   10.10：如何定义“提前终止”？

Key Takeaways:

·        Certain Q&As and a section of this document are still being discussed within the expert group on clinical trials and are therefore not yet included. Updated versions of the Q&A will be published progressively.

关键信息：

·        某些Q&As和本文件的一部分仍在临床试验专家组内讨论，因此尚未包括在内。Q&A的更新版本将陆续出版。

References:

EU Explains Safety Reporting Under New Clinical Trial Regs – Pink Sheet

2.      Meeting on Risk Based Monitoring Approaches of Clinical Investigations

(Jul 2019)

基于风险的临床研究的监查方法的会议

(2019年7月）

Summary:

The FDA recently co-sponsored a meeting titled: Improving the Implementation of Risk-Based Monitoring Approaches of Clinical Investigations.  During the meeting US and EU officials explained what their respective regulatory agencies look for in clinical trial risk-based monitoring (RBM).  Pharmaceutical companies and industry groups presented on their experiences with using RBM.

摘要：

FDA近期联合主办了一次题为“改进基于风险的临床研究监查方法的实施”的会议。在会议期间，美国和欧盟官员解释了他们各自的监管机构在临床试验基于风险的监查（RBM）中的要求。制药公司和行业团体介绍了他们使用RBM的经验。

Agenda Topics:

·        Regulatory Foundation for Risk-Based Monitoring (FDA and EMA)

·        Experiences with Implementation of Risk-Based Monitoring Approaches

·        Analytical Tools and Methods to Support Risk-Based Monitoring

·        Identifying Enablers to Support Implementation of Risk-Based Monitoring

·        Measuring the Impact of Risk-Based Monitoring Approaches

·        Synthesis and Next Steps

议题：

·        基于风险监查的监管基础（FDA和EMA）

·        实施基于风险监查方法的经验

·        支持基于风险监查的分析工具和方法

·        确定支持实施基于风险监查的驱动力

·        衡量基于风险监查方法的影响

·        汇总和后续步骤

Highlights from Regulatory Foundation for Risk-Based Monitoring (FDA and EMA) Session

基于风险监查监管基础（FDA和EMA）的议题重点

FDA

Office of Scientific Investigations (OSI) Director David Burrow represented FDA

He stated they expect a three-part system of risk-based quality management which includes:

1.      Risk assessment (pre-study and ongoing)

2.      A well-designed and articulated protocol and investigation plan

3.      A risk-based monitoring plan.

“It’s the whole system of risk-based quality management, not just the last component of monitoring,” he explained.  Burrow placed emphasis on including a plan that specifies the intent of an RBM system as FDA would not otherwise consider it to be “true RBM.” If a sponsor has no RBM plan, it could result in application delays following complete response letters or requests for additional information.

FDA

科学调查办公室（OSI）主任David Burrow代表FDA发言

他表示，他们期望建立一个基于风险的质量管理体系，包括三部分内容：

1.      风险评估（研究前和研究进行中）

2.      精心设计和清晰的方案和研究计划

3.      基于风险的监查计划

“这是基于风险的质量管理体系，而不仅仅是监查的最后一个组成部分” ，他解释道。Burrow强调应包括一个明确RBM系统意图的计划，否则FDA不会认为它是“真正的RBM”。如果申办者没有RBM计划，可能会因被要求提供完整答复或提供更多信息而导致申请延迟。

EMA 

Scientific Administrator Camelia Mihaescu represented EMA.  She stressed:

·        Risk adapted monitoring should be embedded in a risk-based quality management approach.

·        There should always be a connection between a monitoring plan and a risk assessment and mitigation plan.

·        Implementation of a study specific quality management strategy and a multi-disciplinary approach to study design are key features of good quality clinical trials.

EMA

科学管理员Camelia Mihaescu 代表EMA发言。她强调：

·        风险适应性监查应纳入基于风险的质量管理方法

·        监查计划与风险评估和管控计划之间应始终存在联系

·        执行研究特定的质量管理策略和多学科的研究设计方法是高质量临床试验的关键特征

EMA highlighted some points to consider in relation to GCP inspections

·        Is monitoring planned and implemented in parallel with the protocol and CRF design, contractual agreements, training activities etc. ?

·        Does the risk-based approach take into account trial specific risks or is it using generic parameters only to define scope/content/frequency of visits/SDV sample size?

·        Is remote monitoring used for SDV of subject-related data ?

·        Is the documentation of monitoring results (on-site as well as centralized) sufficiently detailed to allow verification of compliance with the monitoring plan?

·        Is a periodic risk review and monitoring strategy review performed?

·        Is risk-based monitoring focusing on critical to quality factors and on aspects of the trial that are not routine clinical practice and that require additional training?

EMA强调了与GCP检查有关的一些需要考虑的问题

·        监查是否与研究方案和CRF设计、合同协议、培训活动等同时计划和实施?

·        基于风险的方法是否考虑了试验特定的风险，还是仅使用通用参数来定义访视范围/内容/频率/SDV样本量？

·        是否使用了远程监查对受试者相关数据进行SDV？

·        监查结果的记录（现场和中央）是否足够详细，以验证是否符合监查计划？

·        是否进行定期风险评估和监查策略评估？

·        基于风险的监查是否侧重于质量因素中的关键项，以及非常规临床实践并且需要额外培训的试验方面？

Key Takeaways:

·        FDA acknowledges there is continuing uncertainty among sponsors on how to adopt risk-based monitoring of clinical trials, and the agency has signaling its willingness to refine guidance on RBM.

·        Risk Based monitoring activities should include a pre-specified plan, based on appropriate assessments, with mitigation, escalation and remediation strategies.

关键信息：

·        FDA承认申办者在如何采用基于风险的临床试验监查方面仍存在不确定性，表示有意完善RBM指南。

·        基于风险的监查活动应包括基于适当评估的预先指定的计划，以及管控，升级和补救策略。

References:

Link to Meeting Slides

3.      Analysis of FDA and EMA New Drug Approval Metrics

(Jul 2019)

FDA和EMA新药审批指标分析

(2019年7月）

Summary:

According to a new study the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) concur more than 90% of the time in their decisions to approve new drugs.  The study conducted by EMA and FDA officials looked at 107 new drug applications from 2014 to 2016.

摘要：

根据一项新的研究，欧洲药品管理局（EMA）和美国食品和药物管理局（FDA）在批准新药的决定中，90%以上的决定是一致的。EMA和FDA官员进行的这项研究观察了2014年至2016年间的107个新药申请。

·        FDA and EMA decisions on whether to approve a product for marketing upon first submission and review were concordant (both agencies had the same regulatory outcome) for 92% (98/107) of the applications.

·        In 8 of the 107 applications, FDA initially declined to approve a new drug or biologic while EMA approved it, although in all eight of those cases, FDA ended up approving that drug or biologic.

·        In 1 case, FDA approved the treatment and EMA initially did not, but later did.

·        对于首次提交和复审时是否批准产品上市的申请， FDA和EMA的决定92%（98/107）的是一致的(两个机构具有相同的监管结果）。

·        在107个申请中的8个新药或生物制剂申请中，FDA最初拒绝批准，而EMA批准了它们，但所有这些案例，FDA最终予以批准。

·        在1例中，FDA批准了治疗，EMA最初没有后来予以批准。

The study also found EMA had a higher rate of first-cycle approvals than FDA, and the researchers “observed remarkable similarity in the basic scientific and data interpretation issues raised by the FDA and the EMA during reviews of the same applications. Specifically, most of the FDA's second cycle approvals (i.e., approvals after resubmission of the applications) were based on submission by the sponsor of the same additional data that EMA had received during its initial review either from the start or following request after clock‐stops.”

该研究还发现EMA的第一轮的批准率高于FDA，研究人员“发现FDA和EMA在审查相同申请过程中，提出的基础科学和数据解释问题有显著的相似性。具体而言，FDA的第二轮批准（即重新提交申请后的批准）大部分是基于申办者提交的额外数据，这些数据与EMA在初始审查期间收到的数据或之后要求提交的数据相同。“

·        Overall, taking account of the resubmitted and reexamined applications, the EMA and the FDA had final differing marketing authorization decisions for only 2 drugs bringing concordance to 98%, both were approved by EMA and not FDA.

·        总体而言，考虑到重新提交和重新审查的申请，EMA和FDA最终只对2种药物的上市许可做出了不同的决定，使一致性达到了98%，而这两种药都得到了EMA的批准，但未获FDA批准。

For the 98 drugs approved:

·        15 had differences in marketing authorization type

·        21 had notable differences in labeled indications

·        8 drugs differed in both indication and marketing authorization

对于批准的98种药物：

·        15个上市许可类型存在差异

·        21个在药品标签适应症方面有显着差异

·        8种药物在适应症和上市许可方面存在差异

The only therapeutic areas that stood out in terms of outcome divergence overall were oncology and hematology.

·        In these areas, submissions to the EMA often were later than to the FDA and often included additional clinical trials or more mature data from the same clinical trial than were submitted to the FDA.

·        In those instances, the EMA was more likely than the FDA to grant standard approval (whereas the FDA issued accelerated approval) or a broader indication.

整体结果差异突出的治疗领域是肿瘤学和血液学。

·        在这些领域，提交给EMA的时间往往晚于提交给FDA的时间，并且与提交给FDA的数据相比，通常包括额外的临床试验或来自同一临床试验的成熟数据。

·        在这些情况下，EMA比FDA更有可能予以标准批准（而FDA予以加速批准）或批准更广泛的适应症。

Key Takeaways:

·        This is the first effort by the EMA and the FDA to compare the agencies’ decisions related to marketing applications and the reasons for any differences.

·        Both agencies agree that ongoing scientific cooperation and collaboration efforts have contributed to the trend toward drug approval alignment between the agencies.

关键信息：

·        这是EMA和FDA首次努力比较两家机构在上市申请相关的决定以及产生差异的原因。

·        两个机构都同意，正在进行的科学合作和共同努力，促进了机构之间药物批准一致性的趋势。

References:

EMA/FDA analysis shows high degree of alignment in marketing application decisions between EU and US – EMA website

FDA and EMA on the Same Page for Most Drug Approval Decisions, Analysis Shows – FDANews

FDA/EMA Study Examines Drug Approval ‘Concordance’ – FDAWebview

EMA and FDA Historically Agree on Just About Every New Drug Approval, but is That Slowly Changing? -Regulatory Focus

4.      MHRA Posts Blog on Inspection Findings Related to EHR Systems

(MHRA Jul 2019)

MHRA发布与EHR系统相关的视察结果的博客

(MHRA 2019年7月）

Summary:

In a recent blog, MHRA inspectors discuss the importance of a GCP complaint Electronic Health Records (EHR) System.  The MHRA published a position statement in 2015 on the expectations for an EHR that would be GCP compliant.  In this blog they provide 17 examples of inspection findings related to EHR that did not meet the requirements of being GCP Compliant.

摘要：

在最近的一个博客中，MHRA检查员讨论了电子健康记录（EHR）系统GCP合规的重要性。MHRA在2015年发布了一份立场声明，提出了EHR将符合GCP的期待。在这个博客中，他们提供17例与EHR相关，且不符合GCP要求的检查结果。

Some examples of the issues MHRA has identified are listed below.  Read the full blog to see all 17 examples.

·        Access & security - The source data printouts did not contain all the relevant source data. For example, it was advised that the arm in which the vaccination was given was not recorded in the EHR, so this was documented in a paper source worksheet. However, on direct review of the EHR during inspection, the vaccination arm had been recorded, but there was no ability to print this EHR source data. On comparison of the EHR and source worksheet there were a number of discrepancies in the recorded vaccination arm.

·        Scanning & certified copies - There was a lack of quality control (QC) of scanning and upload to the EHR to ensure it was a certified copy of the original. As a result, there were pages that were unreadable due to: poor quality, missing parts of the page, black and white scanning resulting in loss of associated metadata, or loss of source data in the transfer of electronic data to the EHR.

·        Audit trails - Entries into the EHRs could be deleted and amended. The EHR audit trails had not been reviewed and the audit trail provided post inspection for the EHR was deficient as it did not show what type of changes were being made, such as if the entries were new, deletions or amendments. Due to these deficiencies, integrity of the data could not be confirmed.

·        Medical oversight - The audit trail showed that non-medically or non-clinically qualified personnel had been making entries in the EHR on behalf of the medics. The administration staff used the medics’ dictated notes to make the EHR entries and there was no documented evidence by the investigator to verify that the entries were correct.

下面列出了MHRA发现的一些问题的例子。阅读完整的博客可以看到所有17个例子。

·        访问和安全- 打印的源数据未包含所有相关源数据。例如，有人建议，接种疫苗的手臂不记录在EHR中，所以这被记录在纸质工作表中。然而，在检查中直接审查EHR时，发现EHR中已经记录了疫苗接种的手臂，但无法打印此EHR源数据。在比较EHR和源工作表时，记录的疫苗接种的手臂存在一些差异。

·        扫描和核证副本- 缺乏扫描和上传至EHR的质量控制（QC），以确保它是原始的核证副本。结果，有些页面由于质量差，页面部分缺失，黑白扫描导致相关源数据丢失，或在将电子数据传输到EHR时丢失源数据而无法读取。

·        稽查轨迹- 录入EHRs中的内容可以被删除和修改。EHR稽查轨迹未经过审查，检查后提供的EHR稽查轨迹存在缺陷，因为它没有显示修改的类型，例如否为新录入的内容，抑或有删除或修改。由于这些缺陷，数据的完整性无法得到证实。

·        医疗监督- 稽查轨迹显示，非医学或没有临床资质的人员代表医疗人员在EHR中进行录入。管理人员基于·医疗人员的口述记录录入·EHR，并且没有研究者的书面记录以确认录入内容的正确性。

Here are some considerations that may help in ensuring your EHR system is as compliant as possible: Read the full blog to see all suggestions.

·        In cases where the electronic systems cannot provide evidence of the review of data (i.e. lab results) other ways of documenting the review need to be implemented by sponsors, and this needs to be determined and agreed with the site prior to the trial starting

·        Ensure you know what the “true” source data is - for example, patient scan results may be a report in the EHR that the monitor has used for SDV, but the true source data is held in radiology, as it is the scanned image with the measurements annotated on it - these are not routinely being looked at

·        Have a source data agreement between the sponsor and the investigator site - this would help in identifying all the places the source data is collected (in other words, where the data is FIRST collected) so everyone is clear what needs to be accessed and how access will be granted

·        If you must use printouts of the EHR, ensure that these are comprehensive and certified copies, also, give consideration as to how they will be retained and archived so there is evidence of what the monitor reviewed and when.

以下是一些可能有助于确保您的EHR系统尽可能符合要求的考虑因素：阅读完整的博客以查看所有建议。

·        当电子系统无法提供审查数据的证据时（如实验室检查结果），则需要由申办者采用其他记录审查的方法，这需要在试验开始前确定并与研究中心达成一致

·        确保您知道什么是“真正”的源数据-例如，患者扫描结果可能是在EHR中的一份报告，监查员用它来进行原始数据核对，，但真正的源数据保存在放射科，因为它是带有标注测量值的扫描图像-这些并不是例行监查项目

·        在申办者和研究中心之间达成源数据协议-这将有助于确定源数据收集的所有地点（换句话说，数据首次被记录在哪里），因此每个人都清楚需要审阅哪些文件以及如何获得审阅权限

·        如果您必须使用EHR的打印件，请确保这些打印件是全面的和经过核证的副本，同时考虑到文件的保留和存档，以便有证据表明监查员何时审查以及审查了哪些内容。

Key Takeaways:

·        Although progress has been made, the MHRA continues to see significant issues with EHRs on their investigator site inspections.

·        For sponsors it is important to address and identify the source data and EHR as early as possible during the site set up phase and while the contracts are being drafted.

·        The ideal scenario for inspectors and sponsor representatives (monitors and auditors) is to have read-only access of EHR restricted to the trial patients.

关键信息：

·        虽然取得了进展，但MHRA在现场检查仍不断发现EHR的重大问题。

·        对于申办者来说，重要的是在研究中心启动阶段和合同起草期间尽早处理和识别源数据和EHR。

·        理想情况是检查员和申办者代表（监查员和稽查员）获得EHR的只读权限，并仅可访问试验受试者的数据。