Conduct of Clinical Trials of Medical Products During COVID-19 Pandemic: Guidance for Industry, Investigators, and Institutional Review Boards

In the Guidance,[1] FDA recognizes the challenges presented by the COVID-19 pandemic on the conduct of clinical trials for medical products.  Such challenges may arise, for example, from quarantines, site closures, travel limitations, and interruptions in the supply chain for the investigational product.  These challenges may, in turn, require modifications to the clinical trial protocol, and may also result in unavoidable protocol deviations due to COVID-19 illness of trial subjects or site personnel and/or COVID-19 control measures.

The FDA Guidance identifies numerous considerations to assist sponsors in addressing these challenges while assuring participant safety, maintaining Good Clinical Practice compliance, and minimizing risk to the trial integrity.

FDA places these considerations in three separate buckets:  (1) considerations for ongoing trials; (2) general considerations and for where policies and procedures are not already in place; and (3) considerations for all trials that are affected by the COVID-19 pandemic.

When these considerations are viewed collectively, the takeaway is that robust efforts to maintain study participant safety and study integrity are expected and should be documented.  Efforts to minimize the impacts on trial integrity, and documentation of the reasons for protocol deviations, will be important.

A summary list of each of FDA’s recommendations is provided below.  For a more detailed discussion, the FDA Guidance should be consulted.
 

Considerations for Ongoing Trials

• Ensuring the safety of the clinical trial participants is paramount.  To this end, Sponsors should consider each circumstance, focus on the potential safety impact, and modify the study conduct accordingly.
• In consultation with the clinical investigators and IRBs/IECs, Sponsors may determine that the participant’s well-being is best served by either continuing that participant in the trial per the protocol or by discontinuing.  The FDA Guidance makes clear that these are fact-based decisions.
• Sponsors should evaluate whether alternative methods (e.g., virtual visit, telephone, alternative location) for safety assessments are feasible in the case of a trial participant being unable to make it to the investigational site for protocol-specified visits.
• Whether additional safety monitoring may be required in the case of a trial participant no longer having access to the investigational product should be considered.
• Whether circumstances are such that new or modified processes should be put into place (e.g., delay assessments, discontinue recruitment, withdraw participants) should be considered.
• Mandated COVID-19 screening procedures do not need to be reported as an amendment to the clinical protocol unless those data collected are to be used as part of a new research objective.
• Sponsors and clinical investigators are encouraged to engage with the IRBs/IEC as early as possible when changes to the protocol or informed consent are anticipated.
• Changes deemed necessary to minimize or eliminate imminent hazards or to protect the life and well-being of trial participants (e.g., limit participant’s exposure to COVID-19) may be implemented without IRB approval or before filing an IND or IDE amendment, but must be submitted subsequently.
• Specific explanatory information should be provided in the case report form as to the basis for any missing data, including the relationship of that missing information to COVID-19 (e.g., missed study visit(s) or study discontinuation).
• Alternative secure delivery methods for, and the setting for administration of, the investigational drug may be considered.  FDA notes, however, in all cases, existing regulatory requirements for maintaining accountability of the investigational product remain in effect and should be addressed and documented.
• FDA recommends consulting with the appropriate FDA Review Division regarding protocol modifications for the collection of efficacy endpoints.  For individual instances where efficacy endpoints are not collected, the reason should be documented.
• Sponsors should consider consulting with the applicable Review Division concerning any protocol modifications that will lead to amending data management and/or the statistical analysis plan (SAP).  FDA further notes that prior to locking the database, Sponsors should ensure that the SAP addresses how protocol deviations related to COVID-19 will be addressed for the pre-specified analyses.
• If on-site monitoring visits are no longer feasible, Sponsors are encouraged to consider optimizing use of central and remote monitoring programs.

In General, and If Policies and Procedures Are Not Already in Place

FDA advises Sponsors, Clinical Investigators, and IRBs to consider establishing and implementing, or revising, policies and procedures, to describe approaches to be used to protect trial participants and manage study conduct during possible disruptions resulting from the applicable COVID-19 control measures at study sites.

For All Trials that Are Affected by the COVID-19 Pandemic

FDA advises Sponsors to describe in the appropriate sections of the clinical study report (or in a separate study-specific document) the following:  implemented contingency measures; a listing of each participant[2] affected by the COVID-19-related study disruption and how that individual’s participation was altered.  In addition, analyses and corresponding discussions that address the impact of implement contingency measures on the reported safety and efficacy study results should be provided.

[1] Consistent with FDA’s good guidance practices, FDA has determined that for this Guidance, prior public participation is not feasible or appropriate due to it being COVID-19 related.  As such, it takes immediate effect but remains subject to public comment. 

[2] Participants should be identified by subject number identifier and by investigational site.