Regulatory Express_Sep. 2018

MHRA Posts Blog on Sponsor Oversight

MHRA博客发帖：申办方的监督

Sponsor Oversight Part 1 - MHRA Blog

（MHRA，26 July 2018）

Summary:

The MHRA has posted a blog about Sponsor oversight.  They state that there is a clear requirement in the regulations that the sponsor retains all responsibility for the conduct and reporting of clinical trials (SI 2004/1031 Regulation 3). Therefore, it is imperative that the sponsor has systems and procedures in place to ensure adequate oversight of the management of clinical trials both conducted in-house and those outsourced to vendors.

摘要：

MHRA在其博客上发布了关于申办方监督的博客。他们指出，在法规中有明确的要求，申办方对临床试验的实施和报告承担全部责任（SI 2004/1031第3条）。 因此，申办方必须有系统和程序，以确保对内部和外包给供应商管理的临床试验进行充分监督。

Contracts and Agreements

One of the main issues seen on inspection in this area is with the lack of information and documentation in the form of contracts and agreements with vendors. These are used to delegate activities to vendors by sponsors.

• It should be clear in the agreement that compliance      with the protocol and regulations is required which would supersede any      internal processes and procedures.

• Subcontracting should be mentioned in the contract and      how the sponsor maintains oversight of any further subcontracting      performed.

• The delegation of duties should be clearly documented      and there are no gaps or ambiguity which may lead to non-adherence with      regulatory requirements.

• It is often seen on inspection that key legislative      requirements are missing from contracts such as reporting of urgent safety      measures and serious breaches, which can lead to non-compliance as the      roles and responsibilities have not been clearly defined.

合同和协议：

在这一领域的检查中看到的主要问题之一是在与供应商签订的合同和协议中缺乏信息和记录。这些信息和记录用于描述申办方委托给供应商的活动。

• 在协议中应当明确，需要遵守方案和法规，以取代任何内部流程和程序

• 合同中应提及分包，以及申办方如何维护对任何进一步分包的监督

• 职责委托应明确记录，不存在可能导致不遵守监管要求的差距或含义不明确的表述

• 在检查中经常看到，合同中缺少关键的法规要求，例如报告紧急安全事件的方法和严重违约，这可能导致不合规，因为未明确定义角色和责任

Mechanisms of Oversight:   

There are several methods which could be used for oversight of vendors and it is recommended that a risk-based approach is taken regarding this decision. When assessing the level of risk, it is important to consider what activities will be undertaken and their potential impact on patient safety and data integrity.

Some examples of oversight mechanisms include:

• Vendor Assessment - Document the      assessment and outcome.  It is expected that the sponsor documents      their decision on whether to use or continue using the vendor.

• Project Plans - it is recommended      that a communication plan is created along with any other plans which      clearly identify the processes and procedures to be followed by each party      and the mechanisms of communication.

• Performance Reviews: Feedback at the end of      the trial to evaluate the vendor’s performance can be a useful tool in      deciding whether to continue using the vendor or not.

• Project Meetings/ Update (Metrics) Reports: It is      recommended that where meetings are held there is a clear agenda and      minutes documented. Where actions arise, it should be clear who the action      has been assigned to and when it is due to be completed. Where status      reports are received, it is important to know what to do with them, what      the review entails and how issues are followed up and resolved.

• Document Review: Oversight by the      sponsor can also be demonstrated by the review and approval of      documentation for the trial (e.g. Monitoring Visit Reports (MVRs),      Statistical Analysis Plans, review of deviation logs, audit trails etc.).      It should be clear within the sponsor’s QMS which documents are required      to be reviewed by the sponsor and what the review entails.

• Co-Monitoring Visits: There should be clear      documentation of the co-monitoring visit by the person performing the      visit. This is in addition to the MVR written by the CRA. It should be      clear what activities were performed and any issues identified, with an      appropriate Corrective and Preventative Action Plan (CAPA).

• Issue Escalation: There should be      processes and procedures in place to ensure that the sponsor is promptly      notified of issues so that appropriate action can be taken.

• Trial Master File: The sponsor should be      able to demonstrate their oversight of trial activities

监督机制：

有几种方法可用于监督供应商，并建议对这一决定采取基于风险的方法。 在评估风险水平时，重要的是要考虑将进行什么活动及其对患者安全和数据完整性的潜在影响。

监督机制的一些例子包括：

• 供应商评估 - 记录评估和结果。 希望申办方就是否使用或继续使用供应商的决定予以记录

• 项目计划 - 建议制定其他计划的同时制定一个沟通计划，明确每个缔约方应遵循的流程和程序以及沟通机制

• 绩效评估：试验结束时对的供应商的绩效进行反馈评估可能是决定是否继续使用供应商的有用工具

• 项目会议/更新（指标）报告：建议举行会议时有明确的议程和会议记录。 当需要采取行动时，应当明确由谁负责和何时完成这项行动。 在收到状态报告的情况下，重要的是要知道如何处理，需要审查什么，以及如何跟进和解决问题

• 文件审查：申办方的监督也可以通过审查和批准试验文件来体现（例如， 监查访视报告（MVRs），统计分析计划，偏差记录审查，稽查轨迹等）。 申办方应在QMS内明确要求申办方对哪些文件进行审查以及需要审查的内容

• 协同访视：除外CRA撰写的监查报告（MVR）以外，进行协同访视的人员应明确记录协同访视。应明确记录开展哪些活动，发现的任何问题，并制定适当的纠正和预防措施计划（CAPA）

• 问题上报： 应该有流程和程序，以确保及时将问题上报申办方，以便采取适当的行动

• 试验必需文件：申办者应当能够证明其对试验活动的监督

Key Takeaways:

• It is important to remember that it is not just      external vendors which require oversight, but also investigator sites and      contractors working in-house.

• Ensure sponsor oversight activities are clearly defined      within the QMS and retain documentation and evidence of oversight in the      TMF.

• Sponsor oversight is not just the initial vendor      assessment process, it should be demonstrated throughout the trial.

关键信息：

• 重要的是要记住，不仅是外部供应商需要监督，还应包括对研究中心以及在内部工作的承包商的监督

• 确保申办方监督活动在QMS中明确定义，并在TMF中保留监督文件和证据

• 申办方的监督不仅仅是最初的供应商评价过程，而是应在整个试验期间予以证实

AllTrials Releases Metrics on EU Compliance with Clinical Trial Reporting

AllTrials发布了欧盟遵守临床试验报告的指标

（Sep 2018）

Summary:

The AllTrials organization has released a second tracking tool to highlight clinical trial sponsors who fail to publish clinical trial results.  (In February they released FDAAA.TrialsTracker.net which highlights compliance with US requirements due to FDA Amendments Act of 2007 (FDAAA)). (Link to Feb RIKI Communication)  The AllTrials mission is for all past and present clinical trials to be registered and their full methods and summary results reported.

摘要：

AllTrials组织发布了第二个跟踪工具，以突出未能发布临床试验结果的临床试验申办方。 （2月他们发布了FDAAA.TrialsTracker.net ，以显示2007年FDA修正案（FDAAA）的遵循情况。(Link to Feb RIKI Communication) AllTrials旨在要求所有过去和现在的临床试验都进行注册，包括完整的方法和结果报告概述。

The new EU trials tracker shows compliance rates with the European Commission’s requirement that all trials on the EU Clinical Trials Register (EUCTR) post results to the registry within 12 months of completion (final compliance date 21 December 2016).  The website is highlighted by an accompanying paper in The BMJ led by one of the AllTrials founders, Dr. Ben Goldacre.

新的欧盟试验跟踪显示了对于欧盟委员会要求所有注册于欧盟临床试验注册（EUCTR）的试验在完成后12个月内提交结果（最终合规日期2016年12月21日）的遵循情况。 该网站上转载了AllTrials创始人之一Ben Goldacre博士主笔发表在BMJ上的一篇相关文章。

The EU Trials Tracker shows that only 51.1% of clinical trials have reported results.  Breaking down the data further shows that 68% of company-sponsored trials have reported results against just 11% of academic trials.

欧盟的试验跟踪显示，只有51.1%的临床试验报告了结果。 对数据进一步分解显示由公司发起的研究中，68％报告了结果，而仅有11％的学术试验上报了结果。

Key Takeaways:

• Compliance with the EC reporting guideline has been      poor with only half of all due trials reporting results. However, sponsors      conducting a large number of trials, and pharmaceutical companies, show      higher rates of compliance.

• This is an example of the continued trend to increase      transparency and the resulting scrutiny of publicly available      information. 

• The owners of this tracking system hope that making      this data public will prompt institutions to prioritize trial      reporting. 

关键信息：

• 遵守EC报告指南的情况不尽人意，只有一半的临床试验报告了结果。 然而，开展大量试验的申办方和制药公司表现出更高的合规率。

• 这是增加透明度的持续趋势的一个例子，以及由此产生的对公开信息的监督。

• 这个跟踪系统的所有者希望通过公开这些数据促进机构优先考虑试验报告。

References:

Half of European studies fail to report results: BMJ -  FierceBiotech

Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource - BMJ