1. Reimbursement of exceptional expense
EMA
• If, in order to implement urgent measures for the protection of participants involved in a clinical trial, expenses may arise which may be borne initially by the participants, these should typically be compensated subsequently by the sponsor via the investigator
归纳总结
特殊费用的报销
• 出于保护受试者的目的而采取的紧急保护措施所产生的先由受试者自行支付的费用，应由申办者通过研究者给予受试者补偿
2. Safety reporting & Safety report submission
EMA
• It is important that the investigator continue collecting adverse events from the participant through alternative means , e.g. by phone
• Sponsors are expected to continue safety reporting in adherence to EU and national legal frameworks
MHRA
• SAE reporting: Deviation from protocol defined timelines in this case does not require a substantial amendment to MHRA
• Particular attention should be paid to timely reporting of suspected unexpected serious adverse reactions (SUSARs) which put participant safety at risk on a trial or have the potential to impact participants of other trials. Every effort should be made to notify MHRA in this case
归纳总结
安全报告和安全报告的提交
• 研究者应采用其他方式，如电话，继续收集受试者的不良事件信息
• 申办方应继续遵循相关法规进行安全报告
• 因疫情造成SAE上报时限超出方案规定的时限，不需要作为实质性修正上报MHRA
• 可能影响受试者安全的SUSAR应及时上报MHRA
3. Risk Assessment & Documentation
EMA
• It is expected that the sponsor performs a risk assessment of each individual ongoing trial and the investigator of each individual participant and implements measures which prioritise subject safety and data validity. In case these two conflict, subject safety always prevails
• It is important that sponsors in their risk assessment consider prioritisation of critical tasks in the clinical trial and how these are best maintained
• These risk assessments should be based on relevant parties’ input and should be documented on an ongoing basis
• The sponsor should reassess risks as the situation develops. This reassessment should also be documented
• It is possible that with the escalation of the pandemic, local circumstances lead to a local change in risk assessment, therefore the need to implement additional measures may arise, and an investigator-driven risk assessment might be necessary (and communicated to the sponsor)
• Regarding participants enrolled in ongoing clinical trials who may be determined as being a risk group for COVID-19 or who are in trials involving treatments, which may increase such risk, the potential impact of COVID-19 on these participantgroups should be carefully considered when deciding to start or continue such trials
MHRA
• Brief risk assessment and documentation of the impact of this (refer to changes to the conduct of trials), with consideration of prioritisation of critical activities such as safety reporting
FDA
• Sponsors and clinical investigators should document the reason for any contingency measures implemented
• Sponsors and clinical investigators should document how restrictions related to COVID-19 led to the changes in study conduct and duration of those changes and indicate which trial participants were impacted and how those trial participants were impacted
归纳总结
风险评估和记录要求
• 申办者应对每个正在进行的试验进行风险评估，研究者应对每个受试者进行风险评估。采取的措施优先考虑受试者安全和数据有效性，两者冲突时，以受试者安全为重
• 申办方的风险评估应首先考虑试验的关键任务以及如何最好地得以实施
• 风险评估应基于各方意见，并应持续记录。情况变化时应重新进行评估并记录
• 随着大流行的升级，当地风险评估随当地情况变化而变化，因此可能需要采取额外的措施，也可能需要研究者主导进行风险评估（并于申办者沟通）
• 对于受试者，可能属于疫情下的高危人群，或是正在进行的试验治疗可能增加其感染风险，因此需要仔细考虑COVID-19对这些受试者的影响，决定是否继续试验
• 申办者和研究者针对疫情对试验的影响以及相关调整措施的风险评估应做好记录
• 申办者和研究者应记录疫情导致的调整或变化，以及这些变化持续的时间，哪些受试者受到了影响以及具体的影响是什么
4. CRF & CSR
FDA
• It will be important to capture specific information in the case report form that explains the basis of the missing data, including the relationship to COVID-19 for missing protocol-specified information
• Sponsors should describe in appropriate sections of the clinical study report (or in a separate study specific document)
ₒ Contingency measures implemented to manage study conduct during disruption of the study as a result of COVID-19 control measures
ₒ A listing of all participants affected by the COVID-19 related study disruption by unique subject number identifier and by investigational site, and a description of how the individual’s participation was altered
ₒ Analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., trial participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the study
归纳总结
CRF & CSR
• 应在病例报告表（CRF）中收集具体的信息，以此为基础对缺失的信息进行解释，包括与疫情的关系
• 申办者应在研究总结报告的合适部分或单独的文件中描述：
ₒ 在疫情下针对试验管理而采取的应急措施
ₒ 受到疫情影响的受试者列表，标注所在研究中心，描述每个受试者参与试验中具体哪些方面受到了疫情的影响
ₒ 分析和讨论实施的应急措施（例如，试验参与者终止研究产品和/或研究，用于收集关键安全性和/或有效性数据的替代程序）对研究报告的安全性和有效性结果的影响
5. Communication with sites/IRB/authorities
EMA
• Agreement with and communicate to site:
ₒ Changes to trial conduct should be agreed with and communicated clearly to investigator sites
ₒ Agreements may be documented as e-mail exchange
• In case the risk assessment leads to actions that affect the trial as described below in a) and b), the relevant competent authorities and Ethics Committees must be informed in accordance with the Directive 2001/20/EC and national laws:
ₒ a) When a new event is likely to have a serious effect on the benefit-risk balance of the trial, it is possible that immediate actions are required by the sponsor and investigator to protect the subjects against immediate hazard. These, urgent safety measures may be taken without prior notification, but the information needs to be provided ex post to the National Competent Authority (NCA) and the Ethics Committee as soon as possible (EC 2010/C82/01; 3.9)
ₒ b) If changes are likely to affect the safety or well-being of the participants and/or the scientific value of the trial, but do not require immediate action from sponsor or investigator, it should be possible to submit them as substantial amendment applications
• Even when a trial is put on hold for reasons not linked to participant safety (as covered by a) and b) ), e.g. to avoid unnecessary strain on health care professionals, the sponsor is expected to notify NCAs and Ethics Committees, unless national regulatory guidance instructs otherwise
• The impact of protocol changes on clinical data interpretability needs to be properly assessed by the sponsor and the overall evidence generation package could be subsequently discussed within scientific advice with regulatory authorities. A relevant guidance on the implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trial by the CHMP Biostats working party was published on March 25 2020
FDA
• Sponsors and clinical investigators are encouraged to engage with IRBs/IEC as early as possible when urgent or emergent changes to the protocol or informed consent are anticipated as a result of COVID-19
• Such changes to the protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants (e.g., to limit exposure to COVID-19) may be implemented without IRB approval or before filing an amendment to the IND or IDE, but are required to be reported afterwards. FDA encourages sponsors and investigators to work with their IRBs to prospectively define procedures to prioritize reporting of deviations that may impact the safety of trial participants
• With respect to efficacy assessments, FDA recommends consultation with the appropriate review division regarding protocol modifications for the collection of efficacy endpoints, such as use of virtual assessments, delays in assessments, and alternative collection of research-specific specimens, if feasible
• If changes in the protocol will lead to amending data management and/or statistical analysis plans, the sponsor should consider doing so in consultation with the applicable FDA review division. Prior to locking the database, sponsors should address in the statistical analysis plan how protocol deviations related to COVID-19 will be handled for the prespecified analyses
归纳总结
与研究中心/IRB/官方的沟通
• 疫情下采取的应急措施应与研究者/研究中心沟通、记录并达成一致
• 通过风险评估发现必须采取的措施对受试者的安全和权益或是研究的科学性有所影响，应事先上报监管部门和伦理委员会。除非是为了避免对受试者造成即刻危害而采取的紧急措施，可在采取措施之后尽快上报
• 如果暂停试验的原因并非由于受试者的安全性，如避免对医疗保健专业人员造成不必要的压力，期望申办者告知监管部门和伦理委员会，除非国家法规有另外的规定
• 申办者应评估方案变更对临床数据可解释性的影响，随后可与监管部门讨论和咨询其意见。 2020年3月25日，CHMP Biostats工作组发布了关于冠状病毒病（COVID-19）对正在进行的临床试验的方法学方面的影响的相关指南（参见Reference Link）
• 当预计因疫情影响将对方案或知情同意书进行紧急更改时，建议研究者和申办者尽早与伦理委员会联系
• 鼓励申办者和研究者与伦理委员会合作，事前确定影响受试者安全的方案偏离应采取优先报告的程序
• 对于方案中疗效终点数据收集的相关修改，建议咨询审评部门
• 如果方案变更会导致修订数据管理和/或统计分析计划，申办者应考虑与审评部门协商后修改。 在锁定数据库之前，申办者应在统计分析计划中说明如何在预先规定的分析中处理与疫情相关的方案偏离
6. Develop policies and procedures
FDA
• Sponsors, clinical investigators, and IRBs should consider establishing and implementing policy and procedures, or revise existing policy and procedures, to describe approaches to be used to protect trial participants and manage study conduct during possible disruption of the study as a result of COVID-19 control measures at study sites
• Changes to policy and procedures could address, but not be limited to, impact on the informed consent process, study visits and procedures, data collection, study monitoring, adverse event reporting, and changes in investigator(s), site staff, and/or monitor(s) secondary to travel restrictions, quarantine measures, or COVID-19 illness itself
• Policy and procedures should be compliant with applicable (regional or national) policy for the management and control of COVID-19. Depending upon the nature of the changes described above, a protocol amendment may be required under the applicable regulations
归纳总结
创建政策与流程
• 申办者、研究者和伦理委员会应考虑制定相关政策和程序，或对现行的政策和程序进行修改，以描述疫情下对受试者的保护和研究管理采取的措施
• 需变更的政策和程序包括但不限于知情同意程序、研究访视和程序、数据收集、研究监测、不良事件报告等
• 政策和程序应遵循所在区域或国家发布的疫情下如何管理临床试验的建议和指导原则。根据上述流程变更的性质，可能需要根据适用的法规对方案进行修订
Reference:
EMA:
MHRA
FDA
https://www.fda.gov/media/136238/download
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