On March 18, 2020, the U.S. Food & Drug Administration (“FDA”) published guidance for clinical trial sponsors, investigators, and institutional review boards (“IRBs”) on conducting clinical trials in the midst of the COVID-19 pandemic. In the guidance, FDA outlines important considerations for assuring the safety of trial participants, maintaining compliance with good clinical practice, and minimizing risks to trial integrity. FDA’s guidance comes at a critical time as sponsors, investigators, and IRBs are grappling with how best to protect the health and safety of trial participants while also providing necessary resources on the clinical side to care for patients with COVID-19.

FDA has recognized that quarantines, clinical trial site closures, travel limitations, interruptions to the supply chain for the investigational product, and possible infection of site personnel or trial subjects may have a near-term impact on the ability to meet protocol-specified procedures and a long-term impact on product development. Accordingly, as further detailed below, the guidance provides considerations for changes to study plans, including certain changes that should be made in consultation with the appropriate FDA division (CDER, CBER, CDRH), as well as reporting and documentation procedures to contextualize data arising from trials conducted during this time.

Considerations for Changes to Study Plans

• Continuing or discontinuing existing participants. Sponsors, in consultation with investigators and IRBs, may determine that the protection of a participant’s safety, welfare, and rights is best served by (1) continuing a study participant in the trial or (2) discontinuing the administration or use of the investigational product or even participation in the trial. Factors to consider include 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.
• Altering safety assessments or increasing safety monitoring. Sponsors should evaluate 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 when necessary and feasible, and whether these measureswould be sufficient to assure the safety of trial participants. Additionally, further safety monitoring may be needed in the case of trial participants who no longer have access to the investigational product orclinical trialsite.
• Switching to central or remote monitoring. If on-site monitoring is no longer possible under the circumstances, sponsors should consider central and remote monitoring options to maintain oversight of clinical trial sites.

Changes to Study Plans that Should be Made in Consultation with FDA

• Altering Administration of Investigational Products. If the study involves investigational products that are administered in health care facilities, FDA recommends considering, in consultation with the applicable FDA review divisions, the possibility of alternative administration methods (e.g., home nursing or alternative sites by trained but non-study personnel). If investigational products may be self-administered during a site visit, alterative secure delivery methods may be possible. (State pharmacy regulations may impact the ability of hospital-based pharmacies to ship these medications across state lines and need to be analyzed in connection with any identified alternative delivery method.)
• Changing efficacy endpoint collection. FDA recommends consultation with the appropriate FDA review division regarding protocol amendments for the collection of efficacy endpoints, such as virtual assessments or delays in assessments. If efficacy assessments cannot be collected in particular situations, the specific COVID-19 limitation should be documented.
• Amending data management or statistical analysis plans. FDA recommends consultation with the appropriate FDA review division if changes in the protocol will lead to amending data management and/or statistical analysis plans. Prior todatabase lock, sponsors should ensure that the statistical analysis plan addresses how protocol deviations related to COVID-19 will be handled for the pre-specified analyses.

Reporting and Documentation Requirements

• COVID-19 screenings. COVID-19 screening procedures that may be mandated by clinical trial sites do not need to be reported as protocol amendments, unless the sponsor is incorporating the data collected as part of a new research objective.
• Other protocol deviations. Changes to the protocol or study 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 develop procedures for prioritizing reporting of deviations that may impact participant safety.
• Efficacy endpoints. As noted above, where efficacy endpoints cannot be collected, sponsors should document the reasons specifically (e.g., identifying the specific limitation imposed by COVID-19 leading to the inability to perform the protocol-specified assessment).
• Statistical analysis plans. As noted above,statistical analysis plans should be updated to address how protocol deviations related to COVID-19 will be handled for the pre-specified analyses.
• Missing data. The guidance highlights the importance of capturing specific information in the case report form that explains missing data (e.g., from missed study visits or study discontinuations due to COVID-19). This information, summarized in the clinical study report, will be helpful to the sponsor and FDA.
• Policies and procedures. Sponsors, clinical investigators, and IRBs should consider establishing and implementing policies and procedures to address the impact of COVID-19 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.
• Clinical study reports. Clinical study reports (or other study-specific documents) should be updated to address:
  • 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 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.

The FDA’s guidance is being immediately implemented without a public comment period given the public health emergency. However, you still may submit an electronic comment here or submit a written comment to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

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