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Regulatory Express_Q2 2019

2019-06-24 11:36:14

4. FDA Releases Draft Guidance on A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers

FDA就“基于风险的临床试验监查方法的问与答”发布指导草案

(FDA Mar 2019)

Summary:

The FDA has released a draft guidance titled: A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers Guidance for Industry. FDA’s experience suggests that additional guidance would be beneficial to better understand their 2013 guidance document on Oversight of Clinical Investigations--A Risk-Based Approach to Monitoring. The following questions and answers are intended to assist sponsors in planning and conducting risk-based approaches to monitoring.

FDA发布了标题为“基于风险的临床试验监查方法问与答行业指南” 的草案。FDA的经验表明，额外的指导将有利于更好地理解他们2013年的指导文件临床试验的监督-基于风险的监查方法。以下问题和答案旨在帮助申办者规划和实施基于风险的监查方法。

Questions addressed in the document are noted below:

1. What is the purpose of the risk assessment and should sponsors document their methodologies and activities for assessing risk?

2. Should sponsors monitor only risks that are important and likely to occur?

3. What factors should sponsors consider when determining the timing, types, frequency, and extent of monitoring activities?

4. How can a risk-based approach to monitoring that includes centralized monitoring help minimize missing data, protocol violations, or protocol deviations?

5. Should the risk-based monitoring approach include processes to ensure that appropriate blinding is maintained?

6. What elements should sponsors include in monitoring plans?

7. How should sponsors follow up on significant issues identified through monitoring, including communication of such issues?

8. How should centralized monitoring activities and the results of these activities be documented and shared with those involved in the investigation?

文件中提到的问题如下所述：

1. 风险评估的目的是什么，申办者应该记录评估风险的方法和活动吗？

2. 申办者应只监查重要且可能发生的风险吗？

3. 申办者在确定监查活动的时间、类型、频率和范围时应考虑哪些因素？

4. 包括中央化监查在内的基于风险的监查方法如何帮助最大限度地减少数据缺失、方案违背或方案偏离？

5. 基于风险的监查方法是否应包括确保维持适当盲法的程序？

6. 申办者在监查计划中应包括哪些要素？

7. 申办者应该如何跟踪通过监查确定的重大问题，包括这些问题的通报？

8. 应该如何记录中央化监查活动和这些活动的结果，并与参与试验的人员分享？

Key Takeaways:

· FDA believes risk-based monitoring is an important tool to allow sponsors to identify and address issues during the conduct of clinical investigations.

· The document provides additional guidance on planning a monitoring approach, developing the content of monitoring plans and addressing and communicating monitoring results.

· FDA commissioner Scott Gottlieb says this is one of several new guidances released intended to drive sponsors and clinical research organizations to modernize the clinical trial process.

关键信息：

· FDA认为基于风险的监查是一个重要的工具，帮助申办者在临床研究过程中发现并解决问题。

· 该文件为计划监查方法、制定监查计划的内容以及处理和传达监查结果提供了更多指导。

· FDA专员Scott Gottilieb说，这是几个新发布的指南之一，旨在推动申办者和临床研究机构实现临床试验过程的现代化。

5. MHRA Posts Blog on GCP Perspective related to GXP Data Integrity Guidance

MHRA发布与GXP数据完整性指导相关的GCP视角的博客

(MHRA Mar 2019)

Summary:

The MHRA has posted a blog post, “MHRA GXP Data Integrity Guidance: Part 1 – A GCP Perspective” which provides clarification on the interpretation and implementation of the GXP Data Integrity guidance in the clinical trial setting.

MHRA发布了一篇名为“MHRA GXP数据完整性指南：第1部分–GCP视角“的博文，其中澄清了在临床试验环境中对于GXP数据完整性指南的解释和执行情况。

Audit Trail - The guidance describes the need for a documented audit trail review, where the need for and extent of such evaluation is identified in the trial risk assessment, performed prior to the trial commencing.

· Sponsors do not need to develop a generic audit trail review SOP that covers all clinical trials as part of their quality system. It is not mandated by the guidance or expected by GCP inspectors. The risk assessment for data integrity can be incorporated into the standard trial risk assessment and does not necessitate a separate document/duplicate of information already contained within the overall trial risk assessment.

稽查轨迹 - 指导原则描述了记录稽查轨迹审评的必要性，即：当在试验开始前进行的试验风险评估中确定了对稽查轨迹进行评估的必要性和程度时。

· 申办者不需要制定作为其质量体系一部分、涵盖所有临床试验的对稽查轨迹进行审评的SOP。指导原则对此没有强制要求，GCP检查员对此没有预期。数据完整性的风险评估可以纳入标准试验风险评估，不需要以单独文件的形式或重复在总体试验风险评估中已涵盖的内容。

Recording of Patient Data - Section 5.2 of the DI guidance states that ‘recording by the second person should be contemporaneous with the task being performed, and the records should identify both the person performing the task and the person completing the record’

· In standard clinical situations occurring in clinical trials, this can absolutely be the same person performing the task and completing the clinical trial record. A second person would only be needed if, from a clinical perspective, it is not practical for one person to both perform the clinical tasks and record the data.

记录患者数据- DI指南的第5.2节指出，“当记录是由非操作人员完成时，记录应与操作同步进行，并且在记录中应该标注操作人员和记录者”

· 当临床试验是在标准临床情况下，这绝对可以由同一人进行操作并完成临床试验记录。只有从临床角度来看，由同一人进行临床操作和完成记录不可行时，才需要第二人。

Amount and Resolution of Data to be Collected - section 6.7 of the DI guidance describes collecting data that ‘allows the full reconstruction of activities, the amount and the resolution (degree of detail).

· Determining the amount and resolution of the data to be collected is an integral part of clinical trial quality/data management as defined by ICH E6(R2). The precision, accuracy and timing of clinical measurements are determined by the authorised clinical trial protocol and are commonly addressed and documented as part of an organisation’s overall quality management planning, rather than specifically in relation to any ‘separate’ DI considerations. Therefore, it is up to organisations to determine the best way to approach this as per their quality system, and there is no statutory requirement to have a stand-alone SOP.

待收集数据的数量和解析 - DI指南第6.7节描述收集“允许全面重建活动，数量和分辨率（细节程度）的数据“。

· 确定待收集数据的质量和分辨率是ICH E6 （R2）定义的临床试验质量/数据管理的组成部分。临床测量的精确度，准确性和时间由临床试验方案决定，并且通常作为组织整体质量管理计划的一部分进行阐述和记录，而不是专门针对“单独的DI”考虑。因此，各组织应根据其质量体系确定处理这一问题的最佳方法，没有法规要求需要制定一个单独的SOP。

Key Takeaways:

· Overall, the important message of this post is that the GXP DI Guidance introduces no new statutory requirements for clinical trials, or specific requirements for mandatory SOPs.

· How the guidance is implemented should be determined by an organisation’s existing quality system, the need for additional procedures determined by the requirements of an individual trial or scope of work, and should not require duplication of existing SOPs or ways of working simply to fulfil the perceived needs of the DI guidance.

关键信息：

· 总的来说，这篇文章的重要信息是GXP DI 指南并没有引入新的临床试验法规要求或强制性SOP的特定要求。

· 如何实施该指南应由一个组织现有的质量体系决定，需要根据具体试验的要求或工作范围确定是否需要额外的程序，并且不应要求重复现有的SOP或以简单工作的方式来满足DI指南的要求。

References:

EMA Discusses Pivotal Role Of RWE For Six Drugs - RAPS

Pfizer uses real-world data to score Ibrance breast cancer nod in males -Fierce Pharma

Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drugs and Biologics - FDA

Link to ICH E8 (R1) Guidance

ICH Drafts Revised Guideline on General Considerations for Clinical Studies – Regulatory Focus

ICH Plans Revamp Of Guidance On Clinical Trial Data Quality – Pink Sheet

Optimisation of Safety Data Collection

A Risk-Based Approach to Monitoring of Clinical Investigations Q&A