3      MHRA Posts Blog on Reference Safety Information (RSI) for Clinical Trials (February 2021)

MHRA关于临床试验安全性参考信息(RSI)的博客（2021年2月）

Summary:

The MHRA has posted a blog titled: Reference Safety Information (RSI) for Clinical Trials- Part III.  Below are some highlights.  See the full blog for more details.

总结：

MHRA发布了标题为“临床试验安全参考性信息(RSI)-第III部分”的博客。以下是一些要点。更多详情参见完整博客。

MHRA Common Inspection Findings:

·       Clinical Trials Facilitation and co-ordination Group(CTFG)Q&A Impact Assessment not completed on time

·       Onset Date incorrect

·       Comparator IMPs SUSARs not reported

·       Fatal and Life-Threatening (LT) SARs should not be considered expected (unless explicitly stated in the RSI and approved by the national competent authorities NCA)

·       RSI Implementation Date (should not be implemented prior to competent authority approval)

·       RSI for a licensed product (it is not acceptable to copy and paste section 4.8 of the Summary of Product Characteristics (SmPC) into the RSI section of an IB)

·       Lack of efficacy & disease progression. SARs due to lack of efficacy or disease progression should not be considered expected, unless this has been approved as part of the protocol or is in the RSI.

·       Death (fatal events are to be considered unexpected unless explicitly stated in the RSI and approved by the competent authority)

·       MedDRA terms and updates.  When assessing the expectedness of a SAR, the sponsor needs to refer to the specific MedDRA Preferred Terms (PTs) included in the RSI. In addition, a process must be in place to assess whether MedDRA updates have an impact on the RSI (and this assessment should be documented).

·       Drug Safety Update Reports (DSURs): If the RSI was updated during the reporting period, approved, and implemented for expedited reporting, then sponsors need to assess the impact of this change on their DSUR line listings.

·       Causality: The sponsor should be actively following up with investigators to obtain a causality assessment before the reporting deadline.

·       Frequency of expected SARs: A frequency of ‘not known’ is not deemed acceptable because it does not allow assessment of whether the new SAR report represents an increased frequency and therefore is unexpected. If the frequency cannot be calculated, the number of serious adverse reactions should be provided.

·       RSI for biosimilar/ generics : As a general rule, all SARs caused by a biological medicinal product whose biosimilarity to the reference product has not been proved should be considered unexpected.

 MHRA常见检查结果：

·       未按时完成临床试验促进和协调小组（CTFG）Q&A影响评估

·       发生日期不正确

·       未报告对照药物IMP SUSAR

·       致死性和危及生命(LT)的SAR不应视为预期事件（除非RSI中明确说明并获得国家主管部门（NCA）批准）

·       RSI实施日期（在主管部门批准之前不得实施）

·       许可产品的RSI（不允许将产品特性概要（SmPC）的第4.8节复制和粘贴到IB的RSI章节）

·       缺乏疗效和疾病进展。因缺乏疗效或疾病进展导致的SAR不应视为预期事件，除非已在研究方案中获批或列在RSI中。

·       死亡（除非RSI中明确说明并经主管部门批准，否则致死性事件应视为非预期事件）

·       MedDRA术语和更新。评估SAR的预期性时，申办方需要参考RSI中包含的特定MedDRA首选术语(PT)。此外，必须有程序评估MedDRA更新是否影响RSI（该评估应记录）。

·       药物安全性更新报告(DSUR)：如果RSI在报告期间更新、批准并实施快速报告，则申办方需要评估该变更对其DSUR行列表的影响。

·       因果关系：申办方应在报告截止日期前积极跟进研究者以获得因果关系评估。

·       预期SAR的频率：“未知”频率被视为不可接受，因为其无法评估新SAR报告是否代表频率增加而成为非预期事件。如果无法计算频率，应提供严重不良反应的数量。

·       生物仿制药/仿制药的RSI：作为一般规则，由尚未证实与参比制剂生物相似性的生物药品引起的所有SAR均应视为非预期SAR。

Tips to Improve Compliance

·       Submission of RSI Updates -consider submitting the RSI update as a substantial amendment for all trials conducted in the UK at one time.

·       Tracking of RSI updates - Have a clear change control procedure and green light for when an RSI update can be implemented.

·       Perform an impact assessment - Assess the impact of CTFG Q&A on RSI on the quality system and on the clinical trial safety data to determine if there has been any under-reporting of SUSARs.

·       Compliance reviews/metrics - It is recommended that clinical trial safety reporting metrics, including review of submissions to Research Ethics Committees (RECs), are included in the compliance reviews/oversight mechanisms.

·       DSUR Review - Quality control and review of the listings in the DSUR to ensure that they are in accordance with the RSI at the start of the reporting period.

·       Investigator Brochures - Remember that by waiting for RSI approval before sending an IB to investigators, sponsors are not withholding urgent safety information from them.

·       Trial Specific RSI - It is possible to have a trial-specific RSI, which can be particularly useful when there are multiple IMPs.

提高依从性的建议

·       提交RSI更新-考虑提交RSI更新，作为一次在英国进行的所有试验的实质性修正案。

·       跟踪RSI更新-当可以实施RSI更新时，具有明确的变更控制程序和许可程序。

·       进行影响评估-评估临床试验促进和协调小组（CTFG） Q&A对RSI质量体系和临床试验安全性数据的影响，以确定是否存在任何SUSAR漏报。

·       依从性审查/指标-建议在依从性审查/监督机制中纳入临床试验安全性报告指标，包括审查向研究伦理委员会（REC）提交的文件。

·       DSUR审查-对DSUR中的列表进行质量控制和审查，以确保其在报告期开始时符合RSI。

·       研究者手册-请记住，在向研究者发送IB之前等待RSI批准，申办方不会向他们隐瞒紧急安全性信息。

·       试验特定RSI-可能有试验特定RSI，当有多种IMP时，可能特别有用。

Key Takeaways:

·       There continues to be non-compliance when it comes to RSI for clinical trials seen in MHRA Inspections.

·       They are still seeing unreported suspected unexpected serious adverse reactions (SUSARs) and absence of adequate risk mitigation measures due to incorrect use of the RSI.

·       The MHRA hopes that by following the recommendations in this post, safety reporting compliance will improve so both the regulator and sponsor can fulfill their obligations to protect patients.

关键信息：

·       在MHRA检查中观察到的临床试验的RSI方面，仍然存在不合规情况。

·       仍然发现未报告的可疑非预期严重不良反应(SUSAR)，并且由于不正确使用RSI而没有适当的风险缓解措施。

·       MHRA希望通过遵循本指南中的建议，提高安全性报告的依从性，以便监管机构和申办方履行其保护患者的义务。

4.      MHRA Annual GCP Inspections Metrics Report (Apr 2018-Mar 2019) (February 2021)

MHRA年度GCP检查指标报告（2018年4月至2019年3月）（2021年2月）

The MHRA has released its annual GCP Inspections Metrics Report (Apr 2018-Mar 2019).

 MHRA发布了年度GCP检查指标报告（2018年4月至2019年3月）。

*Described in more detail below 

Key Takeaways for Commercial Sponsors:

·       Commercial Sponsor inspections have decreased by about a third from the prior reporting period.

·       The number of critical observations has increased from the prior reporting period despite there being a lower number of total inspections.

·       Pharmacovigilance observations continue to be among the most frequent Critical observations along with Record-Keeping/ Essential Documents.

The PV trend is consistent with the last 2 years’ findings and the MHRA’s focus on Reference Safety Information (RSI) during Pharmacovigilance Inspections.

·       The average number of major observations per inspection remained about the same as the prior year.

·       Of the 8 Commercial Sponsor inspections, 6 were systems inspections, and 2 were triggered inspections. (there were no triggered inspections the previous year)

·       4 (50%) had at least one Critical finding and all (100 %) had at least one Major and/or Critical finding. 

 针对商业申办方的关键信息：

·       商业申办方的检查较上一报告期减少了约三分之一。

·       尽管检查总数较少，但严重发现项的数量较上一报告期有所增加。

·       药物警戒发现项以及记录保存/必备文件仍然是最常见的严重发现项之一。

药物警戒趋势与最近2年的发现结果以及药物警戒检查期间MHRA对安全性参考信息(RSI)的关注一致。

·       每次检查的平均主要缺陷数量与前一年大致相同。

·       在8次商业申办方检查中，6次为系统检查，2次为触发检查（前一年无触发检查）

·       4例(50%)至少有一个严重发现项，所有(100%)至少有一个重大和/或严重发现。

Commercial Sponsors (Routine Systems, Study Specific, and Triggered Inspections)

商业申办方（常规系统、研究特定和触发检查）

The breakdown of Critical Findings:  7 Critical findings from 4 organizations are summarized below.   See the report for full details regarding these critical findings. (Suggest “Commercial Sponsors”)

·       (2) Pharmacovigilance

·       (2) Record Keeping/ Essential Documents

·       (1) Clinical Trial Authorization

·       (1) Protocol Compliance

·       (1) Data Integrity

严重发现分类：  来自4个组织的7项严重发现总结如下。有关这些严重发现的完整详细信息，请参见报告。（建议“商业申办方”）

·       (2)药物警戒

·       (2)记录保存/必备文件

·       (1)临床试验授权

·       (1)方案依从性

·       (1)数据完整性

Critical Finding 1 and 5: Pharmacovigilance

·       There was no process in place to ensure the RSI had been approved by the MHRA prior to implementation and use.

·       The version of the RSI used to assess the expectedness of SARS was not documented.

·       The company procedures did not require that the RSI used at the onset of an event should be used to evaluate the case throughout the follow-up period.

·       There was a lack of tracking to determine when the last approval for the RSI was obtained.

·       Where the RSI had been submitted for multiple trials, there was a lack of tracking to ensure that this could be implemented at a trial level.

·       CAPA was not implemented following a critical finding from a previous inspection.

严重发现项1和5：药物警戒

·       没有适当的程序确保RSI在实施和使用前已获得MHRA的批准。

·       未记录用于评估SARS预期性的RSI版本。

·       公司流程未要求事件发生时使用的RSI，应用于该病例的整个随访期的评价。

·       缺乏跟踪以确定何时获得RSI末次批准。

·       如果已提交多项试验的RSI，则缺乏跟踪以确保可在试验水平实施。

·       在之前检查中的严重发现项未实施CAPA。

Critical Finding 2 and 7: Record Keeping/ Essential Documents

·       The TMF selected were incomplete and direct access was not readily provided to all document repositories comprising the TMF.

·       Essential documents were not defined in the SOP nor was there any clear policy or process to ensure accurate completion of the TMF.

·       Documents not uploaded in a timely manner.

·       There was a failure to define the TMF within the quality system.

·       There was a lack of effective oversight QC of the eTMF by the sponsor.

 严重发现项2和7：记录保存/必备文件

·       抽检的TMF不完整，不容易直接访问组成TMF的所有文档存储库。

·       SOP中未定义必备文件，也没有任何明确的政策或流程来确保TMF的准确完成。

·       未及时上传文件。

·       未在质量体系内定义TMF。

·       申办方对eTMF缺乏有效的QC监督。

Critical Finding 3: Clinical Trial Authorization

·       Another regulatory authority had put the trial on hold, but the sponsor failed to notify the MHRA in a timely manner.

·       The Sponsor failed to inform the Principal Investigator of the MHRA instruction to not continue dosing prior to the PI actually dosing the patient.

严重发现项3：临床试验授权

·       另一监管机构已暂停试验，但申办方未及时通知MHRA。

·       申办方未能在PI给患者用药前告知其MHRA关于停止继续用药的建议。

Critical Observation 4: Protocol Compliance

·       Deliberate protocol waivers had been implemented and a process existed where waivers of eligibility criteria could be granted by the sponsor.

·       The sponsor had purposely recruited trial patients from outside the UK to the trial knowing that the requirements for the long-term follow-up of these patients could not be met.

 严重发现项4：方案合规性

·       实施了有意的方案豁免，存在申办方允许豁免入选标准的程序。

·       申办方已知无法满足这些患者的长期随访要求，有意从英国以外招募试验患者。

Critical Observation 6: Data Integrity

·       The organization permitted unplanned reviews of unblinded clinical trial data for business decision purposes which had a significant potential to introduce bias into the trial.

·       In another trial, there was a lack of contemporaneous documentation of the actions taken following accidental unblinding within the trial to demonstrate how any potential bias was minimized.

·       There was no process for ensuring that any inadvertent unblinding was documented in the CSR.

 严重发现项6：数据完整性

·       该组织允许出于商业决策目的对揭盲的临床试验数据进行计划外审查，这可能会在试验中引入偏倚。

·       在另一项试验中，缺乏试验内意外揭盲后采取的措施的同期记录，以证明如何将任何潜在偏倚降至最低。

·       没有程序确保任何意外揭盲均记录在CSR中。

Key Takeaways for Investigator Sites:

·       A total of 21 investigator sites were inspected and all were as an associated site with a sponsor/CRO/non-commercial/Clinical Trial Unit (CTU) inspection.

·       As associated sites, the emphasis of the inspection was on how the investigator site had been overseen by the sponsor/contracted CRO.

·       1 (4.8%) had critical findings and 13 (62%) had at least one major findings.

·       The largest number of major findings for Investigator Sites were in the category of CRF Data/Source Data Category (more than 50 percent more than any other category), this is similar to findings in the prior reporting period.

 针对研究中心的关键信息：

·       共检查了21家研究中心，所有研究中心均与申办方/CRO/非商业/临床试验单位(CTU)检查相关。

·       作为相关研究中心，检查的重点是申办方/合同CRO如何监督研究中心。

·       1例(4.8%)有严重发现项，13例(62%)至少有一个重大发现项。

·       研究中心的重大发现数量最多的是CRF数据/源数据类别（比任何其他类别多50%以上），这与上一报告期的结果相似。

Investigator Sites (as part of Commercial/Non-Commercial /CTU/CRO (Routine Systems, Study Specific and Triggered)

研究中心（作为商业/非商业/CTU/CRO的一部分（常规系统、研究特定和触发）

Critical Findings: Clinical Trial Authorization and Protocol Compliance

·       These findings directly correlate with critical findings in the commercial sponsor section

·       The investigator site and the sponsor are both responsible for protocol compliance and informing the relevant regulatory authorities when new information that may affect the benefit/risk management of a trial has been discovered. As a result of non-compliance with such legislation, these findings were attributed to both the Commercial Sponsor and this Investigator Site.

 严重发现项：临床试验授权和方案依从性

·       这些发现与商业申办方章节中的严重发现项直接相关

·       当出现可能影响试验获益/风险管理的新信息时，研究中心和申办方共同负责方案依从性并通知相关监管机构。由于不遵守此类法规，这些发现归因于商业申办方和该研究中心。