The COVID-19 pandemic has had a significant impact on day-to-day life for all of us in an attempt to “flatten the curve” to slow transmission of the coronavirus (SARS-CoV-2). However, for those of us involved in the development of medical products, quarantines, site closures, travel limitations, interruptions in the supply chain, and infection add an unprecedented set of challenges that make it difficult to conduct clinical trials. In an acknowledgement that protocol modifications may be required and protocol deviations may be unavoidable, FDA’s three medical product centers today issued a Guidance on Conduct of Clinical Trials of Medical Products during COVID-19. Given this public health emergency, this guidance was developed and implemented without prior public comment and is effective immediately.
Considerations That May Result from COVID-19 Pandemic
FDA outlines considerations to assist in assuring the safety of trial participants, maintaining compliance with good clinical practice and minimizing risks to trial integrity during the COVID-19 pandemic. Considerations for sponsors, investigators, and institutional review boards (IRBs) include:
- To ensure the safety of trial participants, consider whether to: (a) continue trial recruitment, (b) continue use of the investigational product for patients already participating in the trial, and (c) change patient monitoring during the trial. The key to this is insuring trial participants are kept informed of any changes to the study or monitoring plans that could impact them.
- If trial participants may not be able to come to the investigational site for protocol-specified visits, consider alternative methods for safety assessments (e.g., phone contact, virtual visit, alternative location). If in-person visits are not possible, and safety of trial participants cannot be assured by alternative means, consider whether to discontinue use of the investigational product (and, if so, whether withdrawal of active investigational treatment requires additional safety monitoring).
- If a trial, as designed, cannot be properly conducted, consider whether it is possible to delay some assessments or whether to stop ongoing recruitment or even withdraw participants.
- If onsite monitoring visits are no longer possible, consider use of central and remote monitoring programs.
Even if these considerations are not yet impacting a clinical trial, FDA requests sponsors, investigators, and IRBs to ensure they have policies and procedures in place to protect participants and manage study conduct during possible disruption as a result of COVID-19.
FDA Guidance on Specific Actions
Outside of these decision-making considerations, FDA provides guidance on other specific actions:
- COVID-19 Screening Procedures: If COVID-19 screening procedures are mandated by the health care system in which the clinical trial is being conducted, these do not need to be reported as an amendment to the protocol, even if done during clinical study visits, unless the sponsor is incorporating the data collected as part of a new research objective.
- Safety-Related Changes to Protocols and Informed Consent: If protocol or informed consent changes are anticipated as a result of COVID-19 that will help minimize or eliminate immediate hazards or to protect the life and well-being of participants (e.g., to limit exposure to COVID-19), these changes may be implemented without IRB approval or before filing an amendment to the IND or IDE (but are required to be reported afterwards), although early engagement with IRBs is encouraged.
- Protocol Deviations: Sponsors and investigators should work with IRBs prospectively define procedures to prioritize reporting of deviations that may impact the safety of trial participants. While alternative processes should be consistent with the protocol to the extent possible, any contingency measures implemented should be documented with the reason taken. It is important to capture specific information in the case report form that explains the basis for missing data (e.g., due to changes in study visits schedules, missed visits, or patient discontinuations), including the relationship to COVID-19.
- Efficacy-Related Changes to Protocol: FDA recommends consultation with the review division, if feasible, regarding protocol modifications for the collection of efficacy endpoints (or other changes that would require changes to the statistical analysis plan (SAP)), such as use of virtual assessments, delays in assessments, and alternative collection of research-specific specimens. Failure to collect an efficacy assessment should be documented by identifying the specific limitation imposed by COVID-19 leading to the inability to perform the protocol-specified assessment. Prior to locking the database for a study, sponsors should address in the SAP how protocol deviations related to COVID-19 will be handled for the prespecified analysis.
As an overarching action item for sponsors, investigators, and IRBS, the draft guidance requests that policies and procedures be put in place 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. The policies and procedures could address, for example, changes to the informed consent process, study visits and procedures, data collection, study monitoring, adverse event reporting, and changes in investigator, site staff, and clinical monitor due to travel restrictions, quarantine measures, or COVID-19 illness itself.
FDA established an email box for receipt of questions on clinical trial conduct during the COVID-19 pandemic: Clinicaltrialconduct-COVID19@fda.hhs.gov.
Documenting Actions Taken in Response
In addition, FDA requests that all actions taken by the sponsor, investigator, and IRB be documented. Specifically, FDA states that the clinical study report or other separate study-specific document provide:
- A description of contingency measures implemented;
- A listing of all participants affected with a description of how participation was altered; and
- Analyses and discussions that address the impact of the implemented measures (e.g., trial participant discontinuation, alternative procedures) on the safety and efficacy results reported.
What Should Sponsors Do Now?
For each protocol, sponsors should evaluate whether new or modified procedures should be in place to protect trial participants and manage study conduct during possible disruption of the study as a result of COVID-19. Sponsors should also prospectively develop plans for addressing different circumstances (e.g., quarantined study site, illness at the site, cancelled study visit) and regulatory responsibilities (e.g., informed consent, product accountability and administration, training and monitoring the sites). Finally, sponsor should ensure that the investigators and study sites involved in their clinical studies are familiar with the recommendations in these new FDA guidelines as soon as possible. Many of the FDA recommendations directly affect the study investigator, such as a need to document the relationship of COVID-19 to the conduct of the study including contingency measures, missing data, or protocol deviations.