在明媚的阳光中，迎来2022年第一期Regulatory Express, 想和您分享以下话题，欢迎点击正文链接，查看详情。
· 风险管理：
ICH Q9(R1) （Article 1）
风险调整方法 (Article 3)
· 申办方的监督和监查(Article 2)
· RWD/RWE (Article 4, 5)
· 远程数据采集(Article 6)
· PV检查指标 (Article 7, 8)
1.ICH Q9(R1)草案扩展了质量风险管理原则，纳入产品可用性相关内容
1. ICH Q9(R1) Draft Expands the Principles of Quality Risk Management to Include Product Availability
总结：
ICH Q9(R1)质量风险管理目前公开征求意见。
Summary:
ICH Q9(R1) Quality Risk Management is currently available for Public Comment.
关键信息：
· 这是ICH Q9质量风险管理（QRM）的第一次修订。
· 修订的目的是：
o 进一步阐明风险管理中的主观性及其可能的驱动因素
o 增加了风险评估形式的说明，特别是形式是一个连续统一的状态，而不是二元状态
o 介绍基于风险的决策(RBDM)术语及其如何整合到所有QRM活动中
o 修订QRM原则，将产品可用性纳入其中，并在“供应链控制“中增加阐述QRM的附录
· 专家工作组目前正在根据案例研究编写培训材料，以进一步举例说明修订中阐述的概念。
Key Takeaways
· This is the first revision of ICH Q9 Quality Risk Management.
· The purpose of the revision is to:
o Add clarity about subjectivity within risk management and what may drive it
o Add clarity about formality of risk assessment specifically that formality is a continuum not a binary state
o Introduce the term of Risk Based Decision Making (RBDM) and how it integrates in all QRM activities
o Amend the principles of QRM to include product availability and a new annex addressing QRM as part of Supply Chain Control
· The Expert Working Group is currently developing training materials based on case studies to further exemplify the concepts elaborated in the revision
2. MHRA发布药物临床试验监督和监查指南
2. MHRA Issues Guidance on Oversight and Monitoring of Investigational Medical Product Trials
总结：
MHRA发布了药物临床试验监督和监查的指南。申办方的监督和监查可被视为申办方在试验实施期间进行的所有活动，以确保受试者的权利和健康得到保护、试验数据以及试验结果的可靠性，确保临床试验遵守法规要求。是申办方用于检查试验方案、程序、培训等是否已实施的“安全网”。
Summary:
The MHRA has issued a guidance on Oversight and Monitoring of Investigational Medical Product Trials. The sponsor's oversight and monitoring can be regarded to encompass all the activities undertaken by the sponsor during the conduct of the trial that are there to ensure the participants' rights and well being are protected, the reliability of the trial data, and hence the trial results and that the trial is conducted in accordance with the legislation. It is the sponsor's "safety net" to check that the trial protocol, procedures, training etc. that have been implemented.
关键信息：
· 本指南旨在帮助申办方和开展试验的人员对药物临床试验实施充分的监督和监查过程。
· MHRA网站还提供了一个示例，在某项临床试验的中心化统计监查中发现了错误校准的温度计。
Key Takeaways:
· This guidance is meant to assist sponsors and those conducting trials on implementing adequate oversight and monitoring processes for trials of investigational medical products.
· The MHRA website also provides an example where Centralised Statistical Monitoring detected miscalibrated thermometers in a clinical trial.
3. MHRA发布了临床试验和风险评估的风险调整方法的最终指导原则
3. MHRA Releases Final Guidance on Risk-Adapted Approach to Clinical Trials and Risk Assessments
总结：
MHRA发布了题为“临床试验和风险评估的风险调整方法”的最终指导原则。
Summary:
The MHRA has released a final guideline titled: Risk-Adapted Approach to Clinical Trials and Risk Assessments.
关键信息：
· 建议对所有临床试验进行风险评估。
· 强烈建议风险评估作为一个单独的文件，并进行权限和版本控制。
· 本文件提供了风险评估的示例，组织可以使用这些示例来帮助建立自己的风险评估过程。
Key Takeaways:
· It is recommended that a risk assessment be undertaken for all clinical trials.
· It is strongly recommended that the risk assessment is a separate document in its own right and version controlled.
· The document provides examples of what risk assessments may look like and organisations may use the examples to help develop their own risk assessment processes.
4. MHRA 发布了2个临床试验中使用真实世界数据的指南文件
4. MHRA Posts 2 Guidance Documents on the Use of Real-World Data in Clinical Studies
总结：
MHRA发布了2个与使用真实世界数据(RWD)相关的指南。指南中，RWD是指在临床试验之外采集的与患者健康状况或医疗保健提供相关的数据。使用RWD进行试验的许多优点与减轻患者和医疗保健专业人员的负担相关。因此，在监管决策方面，使用RWD来源的随机试验可能最常用于已获批产品的说明书变更，包括药物的新适应症，这种情况下减少监查可能是合理的。但是，也有可能使用RWD支持更广泛的试验目的，包括研究新产品。
Summary:
The MHRA has released 2 guidelines related to use of Real World Data (RWD). For the purposes of these guidelines, RWD is defined as data relating to patient health status or delivery of health care collected outside of a clinical study. Many of the advantages of running a trial using RWD are related to reductions in patient and healthcare professional burden. Therefore, in terms of regulatory decision making, randomised trials using a RWD source may be most commonly used for label changes for already approved products, including drug repurposing, where reduced monitoring may be possible to justify. However, the use of RWD in support of a wider range of trial objectives, including the investigation of new products, may also be possible.
Randomized Controlled Trials Using Real-World Data to Support Regulatory Decisions
Guidance on the Use of Real-World Data in Clinical Studies to Support Regulatory Decisions
关键信息：
· MHRA正在制定一系列指南，为计划使用RWD进行临床试验的申办方提供总体考虑要点，以支持监管决策。
· 本指导原则提供的信息，有助于设计旨在提供证据支持监管决策的研究。
· MHRA声明：原则上，如果，通常认为使用RWD来源的随机对照试验(RCT)生成的证据，对于监管决策的价值等同于数据质量可靠，并且设计良好的RCT的证据。
Key Takeaways:
· The MHRA is producing a series of guidelines to provide general points to consider for sponsors planning to conduct clinical research using RWD to support regulatory decision making.
· The guidelines provide information to aid the design of studies aiming to provide evidence suitable for supporting regulatory decisions.
· The MHRA states In principle, evidence generated from randomised controlled trials (RCTs) using a RWD source is not generally considered of more or less value for regulatory decision making than evidence from traditional RCTs provided the data quality is robust and the trial is well-designed.
5. US FDA指南草案：使用真实世界数据和真实世界证据支持监管决策的考虑
5. US FDA Draft Guidance: Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making
总结：
美国FDA发布了一份题为“使用真实世界数据和真实世界证据支持药品和生物制品监管决策的考虑事项”的指南草案。本指南讨论了312部分（21 CFR第312部分）下FDA新药临床试验申请（IND）法规对使用RWD的各种临床试验设计的适用性。本指南还阐明了临床试验中使用RWD以支持关于药物有效性和安全性的监管决策（例如：作为新药申请（NDA）或生物制品许可申请（BLA）的一部分）时，FDA对此类临床试验的预期，前提是此类研究不受第312部分的约束。本指南主要关注非干预性临床试验设计。
Summary:
The US FDA has released a draft guidance titled: Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and Biological Products. This guidance discusses the applicability of FDA's investigational new drug application (IND) regulations under part 312 (21 CFR part 312) to various clinical study designs that utilize RWD. The guidance also clarifies the Agency's expectations concerning clinical studies using RWD submitted to FDA in support of a regulatory decision regarding the effectiveness and safety of a drug (e.g., as part of a new drug application (NDA) or biologics license application (BLA)) when such studies are not subject to part 312. This guidance focuses primarily on clinical study designs that are non-interventional.
关键信息：
· FDA已经发布了关于真实世界数据（RWD）如何用于临床试验以及如何将其纳入非干预性试验设计的行业指南草案。
· 作为监管决策中使用真实世界证据的框架的一部分，这是FDA一系列指南中的最新内容。
Key Takeaways:
· The FDA has issued draft guidance to industry on how real-world data (RWD) could be used in clinical trials and how it could be incorporated into the design of non-interventional studies.
· This is the latest in a series of guidance from FDA as part of its framework for using Real-World Evidence in regulatory decisions.
6. US FDA指南草案：临床试验中远程数据采集的数字健康技术
6. US FDA Draft Guidance: Digital Health Technologies for Remote Data Acquisition in Clinical Investigations
总结：
美国FDA发布了题为“临床试验中远程数据采集的数字健康技术”的指南草案。数字健康技术（DHT）是将计算平台、连通性、软件和/或传感器用于医疗保健和相关用途的系统。用于远程数据采集的DHTs在医疗保健中发挥着越来越大的作用，并为临床试验提供了重要的机会。与间断性试验访视相比，使用DHTs远程收集试验受试者的数据可允许连续性或更频繁的数据收集。远程传输数据的能力增加了患者在远离研究者研究中心的地点参与临床试验的机会（分散临床试验）。
Summary:
The US FDA has released draft guidance titled: Digital Health Technologies for Remote Data Acquisition in Clinical Investigations. A digital health technology (DHT) is a system that uses computing platforms, connectivity, software, and/or sensors, for healthcare and related uses. DHTs used for remote data acquisition are playing a growing role in health care and offer important opportunities in clinical research. Compared to intermittent trial visits, the use of DHTs to remotely collect data from trial participants may allow for continuous or more frequent data collection. The ability to transmit data remotely increases opportunities for patients to participate in clinical investigations at locations remote from the investigator's site (decentralized clinical trials).
关键信息：
· 本指南概述了促进DHTs在临床试验中使用的建议，适用于医疗产品的评价。
· 这些建议涉及申办方计划使用一种或多种DHTs开展新药临床试验申请（IND）或研究性器械豁免申请（IDE）或包括此类临床试验的上市申请中应包含的部分信息。
· 本指南中的一些考虑，也可能有助于DHTs在“远程收集数据来评价临床试验中的终点”之外的使用（例如富集策略）。
Key Takeaways:
· This guidance outlines recommendations intended to facilitate the use of DHTs in a clinical investigation as appropriate for the evaluation of medical products.
· These recommendations address some of the information that should be contained in an investigational new drug application (IND) or an investigational device exemption (IDE) application for a clinical investigation in which the sponsor plans to use one or more DHTs or in a marketing application that includes such a clinical investigation.
· Some of the considerations in this guidance may also be helpful for uses of DHTs other than remote collection of data to evaluate endpoints in a clinical investigation (e.g., enrichment strategies).
7. EMA发布2019年和2020年PV检查指标
7. EMA Releases PV Inspection Metrics for 2019 and 2020
总结：
EMA药物警戒检查员工作组（PhV IWG）最近发布了2019年和2020年年度报告。对于欧盟集中许可的产品（CAPs），常规药物警戒检查通常由国家监管机构开展，以检查上市许可持有人是否具有执行所需药物警戒活动的人员、系统和设施。EMA人用药品委员会（CHMP）也在某些情况下启动药物警戒检查请求，包括“有因”检查或检查全球药物警戒中心。这些检查的优先级取决于对公共卫生的潜在风险、产品的性质、使用范围、MAH在欧洲经济区（EEA）市场的产品数量和其他风险因素。
Summary:
The EMA's Pharmacovigilance Inspectors Working Group (PhV IWG) recently released their 2019 & 2020 Annual Report. For centrally authorized products (CAPs) in the EU, routine pharmacovigilance inspections are typically carried out by national regulators to check that marketing authorization holders have the personnel, systems and facilities in place to perform required pharmacovigilance activities. EMA's Committee for Medicinal Products for Human Use (CHMP) also initiates requests for pharmacovigilance inspections in certain situations, including "for cause" inspections or to inspect a global pharmacovigilance site. These inspections are prioritized based on the potential risk to public health, the nature of the products, the extent of use, the number of products that the MAH has in the European Economic Area (EEA) markets, and other risk factors.
关键信息：
· 2019年最常发现问题的3个领域为：
o 不良事件快速报告(ICSR)
o 药物警戒系统主文件
o QPPV职能
· 2020年最常发现问题的3个领域是：
o 不良事件快速报告(ICSR)
o 药物警戒活动计算机化系统
o 质量管理体系
Key Takeaways:
· The three most common areas with findings in 2019 were:
o Adverse Event Expedited Reporting (ICSRs)
o Pharmacovigilance System Master File
o QPPV Function
· The three most common areas with findings in 2020 were:
o Adverse Event Expedited Reporting (ICSRs)
o Computerized System for Pharmacovigilance activities
o Quality Management System
8. MHRA年度PV检查指标报告（2020年4月2021年3月）
8. MHRA Annual PV Inspections Metrics Report (Apr 2020-Mar 2021)
总结：
MHRA已发布其年度PV检查指标。这些检查的目的是检查现行欧盟和国家药物警戒法规和指南的合规性。自2019年以来，GPvP检查模式一直在不断发展。使用修订后的基于风险的方法对选择的上市许可持有人（MAH）进行检查，该方法旨在提高最高风险产品和药物警戒系统的检查覆盖率。
在2020年4月1日至2021年3月31日期间，GPvP检查机构对上市许可持有人（MAH）进行了37次检查。
Summary:
The MHRA has released their annual PV inspection metrics. The purpose of these inspections is to examine compliance with existing EU and national pharmacovigilance regulations and guidelines. The GPvP inspection model has been evolving since 2019. MAHs are selected for inspection using a revised risk-based methodology that aims to increase inspection coverage for the highest risk products and pharmacovigilance systems.
During the period 01 April 2020 to 31 March 2021, the GPvP Inspectorate conducted 37 inspections of marketing authorisation holders (MAHs).
关键信息：
· 按主题领域细分检查结果，无论分级如何，与质量管理体系相关的发现项比例最高，占28%，或140个结果中的39个。其次是风险管理，报告的所有发现项中有22%（31/140），21%（29/140）是持续安全性评价。2019/20年，这三个主题领域的发现项比例也最高。
· 风险管理仍然是总体上报告最多严重发现项的领域。2020/21年期间报告的与该领域相关的两个严重发现项与安全性参考信息的维持和额外风险最小化措施(aRMM)相关。这与最近的三个报告期的结果一致，在这些风险管理子主题中也报告了严重发现项。
· 持续安全性评价是过去经常报告严重发现项的另一个主题领域，2020/21年期间报告的两个严重发现项在该领域。在本报告期内，还报告了药物不良反应(ADR)管理的严重发现项-自2015/16年以来，该领域首次报告了严重问题。
· 2020/21年度每次检查报告的重大发现数量减少，原因可能是，在此期间进行的检查更有针对性的目标且范围缩小，这源于以下原因：
o GPvP检查模式的变化，有助于以药物警戒系统的不同方面为重点的检查活动提供更有针对性的检查方法。
o COVID-19大流行导致优先考虑特定原因检查，以及根据MHRA药物警戒和风险管理部门的优先次序和2020年4月引入的监管灵活性进行的高风险常规检查。
Key Takeaways:
· Breaking down the inspection findings by topic area, the highest proportion of findings regardless of grading were in relation to the quality management system, comprising 28%, or 39 of 140 findings. This was followed by risk management with 22% (31 out of 140) of all findings reported, and ongoing safety evaluation with 21% (29 out of 140). These three topics also had the highest proportion of findings in 2019/20.
· Risk management remains the topic for which the largest number of critical findings has been reported overall. The two critical findings associated with this topic reported during 2020/21 related to the maintenance of reference safety information and additional risk minimisation measures (aRMMs). This is consistent with the last three reporting periods where critical findings were also raised against these risk management subtopics.
· Ongoing safety evaluation is another topic where critical findings have frequently been reported in the past, and two of the critical findings reported during 2020/21 were in this area. For this reporting period, a critical finding was also reported against management of adverse drug reactions (ADRs) - the first time a critical was reported in this area since 2015/16.
· The decrease in the number of major findings reported per inspection in 2020/21 could be attributed to the fact that the inspections conducted during this period had more targeted objectives and a reduced scope, which was as a result of the following:
o A change in the GPvP inspection model, which facilitates a more targeted approach to inspection activity focused on different aspects of the pharmacovigilance system.
o The COVID-19 pandemic, which resulted in the prioritization of specific for cause inspections, as well as high-risk routine inspections conducted in line with the priorities of the MHRA's Vigilance and Risk Management of Medicines division and the regulatory flexibilities that were introduced in April 2020.
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