Earlier this month the FDA issued guidance listing general factors for study sponsors to take into consideration to assure the safety of clinical trial participants, maintain a good clinical practice, and minimize risks to trial integrity for clinical trials impacted by the COVID-19 pandemic. Other regulators – including in the UK, EU, and South Africa – have announced similar guidance documents.
On March 27 the FDA updated this guidance to include an appendix with particularly helpful Q&A discussions covering specific considerations for clinical trial sponsors, as well as relaxed reporting requirements for changes necessitated by COVID-19. The Q&A covers the following topics:
Key factors for sponsors to consider when deciding whether to suspend or continue an ongoing study or to initiate a new study during the COVID-19 pandemic.
The FDA emphasized that trial participant safety is paramount in deciding whether to suspend or continue a study and will depend on the nature of the investigational product, the ability to conduct appropriate safety monitoring, the investigational product supply chain, and the nature of the disease under study. The Q&A provides a list of specific factors sponsors should consider, including whether the limitations on protocol implementation imposed by the pandemic create new risks for participants; the availability of investigators, staff, supplies, and IT systems; and whether a data monitoring committee (DMC) will remain in operation if one has been established. For studies that have a DMC, the DMC’s assessment of the impact of modifying or suspending a study should also be considered.
Key factors for sponsors to consider when deciding whether to continue administering or using an investigational product that appears to be providing a benefit to the trial participant during the COVID-19 pandemic.
In deciding whether to continue the use of an investigational product, sponsors should consider whether a trial participant appears to be benefitting from the treatment, whether there are reasonable alternative treatments, the seriousness of the disease or condition being treated, and the risks involved in switching to an alternative. If participation is discontinued, there should be appropriate management after discontinuation.
Managing protocol deviations and amendments to ongoing trials due to COVID-19.
The FDA recognizes that the COVID-19 pandemic may necessitate protocol deviations. Sponsors should document specific protocol deviations and the reasons for the deviations. Protocol amendments necessary to prevent imminent hazards to trial participants can generally be implemented immediately with subsequent IRB approval and FDA notification by filing an amendment. For studies under an IND, pausing enrollment in a trial to decrease potential COVID-19 exposure would not generally be expected to trigger a requirement to submit a protocol amendment under 21 CFR Part 312. The FDA also clarified that where a protocol amendment is not required to prevent an imminent safety risk, several protocol modifications made over a rapidly evolving period can be consolidated as part of a single amendment if done expeditiously.
For studies under an IDE, FDA approval is generally required before implementing changes to the investigational plan, but changes may be made without prior approval if such changes do not affect the validity of the study results; the patient risk to benefit relationship; the scientific soundness of the investigational plan, or the rights, safety, and welfare of the subjects. Usually, such changes must be reported to the FDA within five days of implementation, but, due to the COVID-19 pandemic, the FDA is simply requiring notice and an updated IDE as soon as possible.
Submitting a change in protocol due to COVID-19.
The Q&A recommends specific cover letter subject lines and submission formats for changes to protocols under both INDs and IDEs.
FDA notification of virtual clinical visits for patient monitoring.
The FDA considers protocol changes to allow for telephone or video contact visits to be necessary to eliminate an apparent immediate hazard or to protect the life and well-being of subjects, so these changes can be immediately implemented with subsequent review by the IRB and notification to FDA. Such deviations from the protocol should be documented, and sponsors should evaluate how the lack of on-site visits might impact patient safety.
Capturing data related to changes in clinical trial conduct due to COVID-19.
Sponsors should develop a means to capture specific information for each participant that explains the basis for missing protocol-specified information and its connection to COVID-19 and this information should be included in the clinical study report.
Switching investigational product dispensing to home delivery.
If dispensing an investigational product through a pharmacy or at a clinical site would raise concern regarding COVID-19 exposure, home delivery of an investigational product may be implemented. All requirements for maintaining product storage conditions remain in place and should be documented. Sponsors should document how these conditions are being addressed and the protocol should be amended to permit home delivery.
Home infusion of an investigational product.
Sponsors should consider the safety risk to a trial participant who would miss an investigational product infusion due to the patient’s inability to come to the clinical site for infusion. The appropriate FDA review division should be consulted when considering home infusion or alternative sites for infusion by non-study personnel, especially for complex investigational products where altered storage or handling can have adverse effects on product stability. All requirements for maintaining product storage conditions remain in place. Sponsors should document how these conditions are being addressed, and the protocol should be amended to permit alternative site infusions.
FDA expectations related to on-site monitoring of clinical trials and expected delays due to the pandemic.
FDA recognizes that monitors will be unable to access trial sites for on-site visits in a timely manner, which may result in delayed identification of non-compliance. Sponsors should document any delay or inability to access a clinical site, as well as any protocol deviations or discovery of non-compliance. Documentation should include whether any delay in identification was due to a delay in monitoring. Sponsors should also find alternative approaches to ensure trial participant safety and maintain the integrity and quality of trial data, such as enhanced central monitoring; telephone contact with sites to review procedures, participant status, and study progress; or remote monitoring of individual participants.
Obtaining informed consent from patients in isolation and the restrictions of COVID-19 infection control policies.
FDA regulations require a participant’s informed consent be documented in writing through the use of an IRB-approved consent form. However, COVID-19 infection control policies would prevent the removal of the signed consent form from the isolated patient’s hospital room. If the technology is available, the sponsor should obtain informed consent electronically. If the technology is not available, the FDA has proposed an alternative acceptable means of obtaining consent via telephone or video conference. If the signed form cannot be collected and included in the study records for infection control reasons, the FDA will accept attestations from a witness and the investigator or a photograph of the signed document accompanied by an attestation.
If you have any questions about the latest FDA guidance, please contact the authors.