FDA issued this Guidance to provide general considerations to sponsors of clinical research to help them ensure the safety of trial participants, maintain compliance with good clinical practice (GCP) and minimize risks to trial integrity during the COVID-19 pandemic. Given this public health emergency, the Guidance is being implemented without prior public comment because FDA has determined that prior public participation is not feasible or appropriate. The Guidance is implemented immediately, but remains subject to comment in accordance with FDA’s good guidance practices.
FDA recognizes that the COVID-19 pandemic may impact the conduct of clinical trials and present challenges that arise, for example, from quarantines, site closures, travel limitations, interruptions to the supply chain for the investigational product, or other considerations if site personnel or trial subjects become infected with COVID-19. These challenges may lead to difficulties in meeting protocol-specified procedures, including administering or using the investigational product or adhering to protocol-mandated visits and laboratory/diagnostic testing.
As a result, FDA recognizes that protocol modifications may be required, and that there may be unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control measures. Although the necessity for, and impact of, COVID-19 control measures on trials will vary depending on many factors, including the nature of the disease under study, the trial design and in what region(s) the study is being conducted, FDA has issued this Guidance to outline general considerations for sponsors to evaluate for clinical studies.
Considerations for Ongoing Trials
- Patient Safety. The safety of trial participants is paramount, and sponsors should consider whether a participant’s safety, welfare and rights are best served by continuing as a study participant in the trial as per the protocol or by discontinuing the administration or use of the investigational product or even participation in the trial. Such decisions will depend on specific circumstances, including the nature of the investigational product, the ability to conduct appropriate safety monitoring, the potential impact on the investigational product supply chain and the nature of the disease under study in the trial.
- Safety Assessments. Sponsors should determine whether in-person visits are necessary to fully ensure the safety of trial participants or whether alternative methods for safety assessments (e.g., phone contact; virtual visit; alternative location for assessment, including local labs or imaging centers) could be implemented and would be sufficient to ensure the safety of trial participants. In making the decision to continue use or administration of the investigational product, the sponsor should consider whether the safety of trial participants can be ensured with the implementation of the altered monitoring approach.
- Additional Safety Monitoring. Sponsors should assess whether trial participants who no longer have access to the investigational product or the investigational site may need additional safety monitoring (e.g., withdrawal of an active investigational treatment).
- New or Modified Processes. Sponsors should assess whether to implement new processes or modify existing processes. For example, this assessment could include consideration of whether it is appropriate to delay some assessments for ongoing trials or, if the study cannot be properly conducted under the existing protocol, whether to stop ongoing recruitment or even withdraw trial participants.
Sponsors and clinical investigators should i) document the reason for any alternative processes implemented, ii) explain how restrictions related to COVID-19 led to the changes in study conduct, and iii) indicate which trial participants were impacted and how those trial participants were impacted.
- Protocol Changes. Sponsors and clinical investigators are encouraged to engage with Investigational Review Boards (IRBs) and Independence Ethics Committees (IECs) 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 limit exposure to COVID-19 may be implemented without IRB approval or before filing a Contains Nonbinding Recommendations amendment to the Investigational New Drug (IND) or Investigational Device Exemption (IDE), but are required to be reported afterward. 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.
- Missing Information. Changes in study visit schedules, missed visits or participant discontinuations may lead to missing information (e.g., for protocol-specified procedures). Sponsors should capture specific information in the case report form that explains the basis of the missing data, including, for missing protocol-specified information, the relationship to COVID-19 (e.g., missed study visits or study discontinuations due to COVID-19).
- Administration. If scheduled visits at clinical sites will be significantly impacted, certain investigational products, such as those that are typically distributed for self-administration, may be amenable to alternative secure delivery methods. For other investigational products that are normally administered in a health care setting, consulting FDA review divisions on plans for alternative administration (e.g., home nursing or alternative sites by trained but non-study personnel) is recommended. In all cases, existing regulatory requirements for maintaining investigational product accountability remain and should be addressed and documented.
- 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. For individual instances where efficacy endpoints are not collected, the reasons for failing to obtain the efficacy assessment should be documented (e.g., identifying the specific limitation imposed by COVID-19 that led to the inability to perform the protocol-specified assessment).
- Data Management. 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.
- On-Site Monitoring. If planned on-site monitoring visits are no longer possible, sponsors should consider optimizing use of central and remote monitoring programs to maintain oversight of clinical sites.
Considerations for All Trials That Are Affected by the COVID-19 Pandemic
Sponsors should describe the following in appropriate sections of the clinical study report (or in a separate, study-specific document):
- Contingency measures implemented to manage study conduct during disruption of the study as a result of COVID-19 control measures.
- 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.
- 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. FDA expects that robust efforts will be maintained to ensure the safety of trial participants and study data integrity, and such efforts should be documented.
As stated above, FDA recognizes that protocol modifications may be required, including unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control measures. Efforts to minimize impacts on trial integrity, and to document the reasons for protocol deviations, will be important.