On March 18, the Food and Drug Administration issued a guidance for industry, investigators, and Institutional Review Boards on the “Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic.” FDA recognizes that that the COVID-19 pandemic may affect the conduct of clinical trials of investigational human drugs, medical devices, and biological products (e.g., because of quarantines, site closures, travel limitations, supply chain interruptions for the investigational product, site personnel or trial subjects becoming infected with COVID-19). FDA is aware 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.
In issuing this guidance, FDA outlines general considerations for clinical trials to assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP) requirements, and minimizing risks to trial integrity during the COVID-19 pandemic. The guidance is effective immediately.
We will summarize the key points from the guidance in this Bulletin.
Considerations for Ongoing Clinical Trials
- When there is a need to modify study conduct, ensuring the safety of trial participants is paramount. Trial participants should be kept informed of changes to the study and monitoring plans that could affect them.
- Sponsors, in consultation with clinical investigators and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), may determine that the protection of a participant’s safety, welfare, and rights is best served by continuing 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.
- Because trial participants may not be able to come to the study site for protocol- specified visits, sponsors should consider whether alternative methods for safety assessments are appropriate and feasible (e.g., phone contact, virtual visit, alternative locations such as local labs or imaging centers).
- In some cases, trial participants who no longer have access to the investigational product or the study site may need additional safety monitoring (e.g., withdrawal of an active investigational treatment).
- The need to put new processes in place or to modify existing processes will vary by the protocol and local situation (e.g., consideration of whether it is appropriate to delay some assessments, or if the study cannot be properly conducted under the existing protocol, whether to stop trial recruitment or withdraw trial participants).
- COVID-19 screening procedures (if mandated by the health care system in which the trial is being conducted) need not be reported as an amendment to the protocol even if done during study visits, unless the sponsor is incorporating the data collected as part of a new research objective (e.g., a new clinical endpoint concerning the COVID-19 virus).
- Sponsors and clinical investigators should consult with IRBs/IECs as soon as possible when changes to the protocol or informed consent are anticipated as a result of COVID-19. However, changes to the protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of trial participants (e.g., to limit exposure to COVID-19) may be implemented without IRB approval or before filing an amendment to the Investigational New Drug Application (IND) or Investigational Device Exemption (IDE), but must be reported afterwards.
- The implementation of alternative processes should be consistent with the protocol to the extent possible, and sponsors and clinical investigators should document how restrictions related to COVID-19 led to the changes in study conduct, the duration of those changes, and which and how study subjects were affected.
- Changes in study visit schedules, missed visits, or patient discontinuations may lead to missing information. Case report forms should include specific information to explain the basis of the missing data.
- If scheduled visits at clinical sites will be significantly impacted, certain investigational products may be amenable to alternative secure delivery methods (e.g., distributed for self-administration). For other products that are normally administered in a health care setting, sponsors should consult the FDA review division on plans for alternative administration (e.g., home nursing or alternative sites by trained, but non-study personnel). In all cases, regulatory requirements for maintaining investigational product accountability remain and should be documented.
- Sponsors should consult FDA review divisions regarding protocol modifications for the assessment of efficacy endpoints (e.g., virtual assessments, delays in assessments, alternative collection of specimens). If efficacy endpoints cannot be collected, the reason should be documented.
- If changes in the protocol will lead to amending data management and/or statistical analysis plans, the sponsor should consult with the FDA review division. Before locking the trial database, sponsors should address in the statistical analysis plan how protocol deviations related to COVID-19 will be handled for the pre-specified analyses.
- If planned on-site monitoring visits are no longer possible, sponsors should consider use of central and remote monitoring programs.
In general, and if policies and procedures are not already in place for applicable trials, sponsors, clinical investigators, and IRBs/IECs should implement policies and procedures to describe approaches to be used to protect trial participants and manage study conduct during possible disruptions caused by COVID-19 control measures at study sites. Depending on the nature of the change, a protocol amendment may be required by the applicable regulations.
For all trials impacted by the COVID-19 pandemic, sponsors should describe in appropriate sections of the clinical study report (ICH E3 guidance) or in a separate study-specific document:
- Contingency measures implemented to manage study conduct as a result of COVID-19 control measures.
- A listing of all subjects affected by the study disruption by unique subject number identifier and by investigational site, and a description of how the individual’s participation was altered.
- Analyses that address the impact of contingency measures on the safety and efficacy results reported for the study.
Key take-away messages include:
- Ensuring the safety of study subjects
- Consultation by sponsors with clinical investigators, IRBs/IECs, and FDA review divisions
- The need for documentation of changes made and the reason for those changes
- The importance of minimizing impacts on trial and data integrity
Footnotes for this alert are available in the formatted PDF accessible below.