On Friday, March 27, 2020, FDA issued an update to previous guidance titled, “FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Pandemic” (the “Guidance”), adding an Appendix with ten questions and answers for specific topics based on feedback received on the initial March 18th Guidance. To supplement our prior blog post, we identify some key takeaways from the updated Guidance below:
Prioritize Safety of Clinical Trial Participants
- Ongoing Clinical Trials. Sponsors, investigators, and IRBs should work together to assess whether the participants’ safety is better served by continuing the study as is, discontinuing administration or use of the product, or by ending participation in the trial. The Guidance provides a number of key factors for consideration. FDA also recognizes that there may be an investigational product that is providing benefit to a trial participant, and the sponsor must decide whether to continue administration during the COVID-19 pandemic. This is a context-dependent choice, and sponsors should consider whether there are any reasonable alternative treatments available, the seriousness of the disease or condition, the risks involved in switching treatment, supply chain disruptions, and whether discontinuing administration would pose a substantial risk to the participant.
- New Clinical Trials. With respect to initiating a new clinical trial, other than one to investigate treatments or vaccines related to COVID-19 infection, FDA advises sponsors to consider the ability to effectively mitigate the risks of a trial in order to preserve safety of the participants and trial integrity. Any new trial must also be designed in a way to comply with the Federal and State public health measures implemented in response to COVID-19.
- Documentation. With respect to documentation of protocol deviations and amendments necessitated by the COVID-19 pandemic, FDA states that sponsors may use either existing standard processes or alternative documentation approaches as appropriate (e.g., documentation of all alternative study visits during the pandemic that are deviations from the protocol). FDA emphasizes that it is important to collect specific information regarding individual participants explaining any missing protocol-specified information due to COVID-19 (e.g., missed study visits).
- IND Changes. Study-wide changes in an IND protocol meant to prevent imminent hazards to participants can be implemented immediately, so long as there is subsequent submission and formal approval by the IRB and notice to FDA through a filing of a protocol amendment. One example would be initiation of virtual clinical trial visits to assure patient safety. FDA notes that pausing enrollment in a trial to decrease potential exposure to COVID-19 would not trigger the requirement to submit a protocol amendment.
Other IND protocol changes that are not required to prevent imminent hazards to participants must still be submitted to FDA and receive IRB approval prior to implementation, but sponsors may consolidate several protocol modifications into a single amendment for filing. Any modifications to protocol-specified procedures that occur prior to such approval must be recorded as protocol deviations by the investigator.
Amendments to protocols should be submitted using a formal amendment format, with the subject line identifying the change as “PROTOCOL AMENDMENT – COVID-19” before the title of the protocol. FDA requests that the submission include a tracked changes version of the amendment to expedite review.
- IDE Changes. Study-wide changes in an IDE protocol meant to prevent imminent hazards to participants can be implemented immediately, so long as there is subsequent submission and formal approval by the IRB and notice to FDA through a filing of a protocol amendment. Additionally, FDA notes that sponsors must still adhere to the 5-day Notice requirement for changes that are determined to have no impact on the validity of the study, the patient risk-to-benefit relationship, the scientific soundness of the investigational plan, or the rights, safety or welfare of the subjects. However, due to the impact of COVID-19, sponsors may submit consolidated implemented changes and should subsequently update the IDE as soon as possible. Any supplements must be submitted to FDA with “CHANGE IN PROTOCOL SUPPLEMENT – COVID-19” or “NOTICE OF IDE CHANGE – COVID-19”, and also contain a tracked changes version of the amendment.
- On-Site Monitoring Delays. Sponsors should document situations where monitors were unable to access or were delayed in accessing the clinical site. The Agency recommends finding alternative approaches to maintaining safety and data quality and integrity (e.g., enhanced central monitoring, phone contact with sites to review procedures, participants status, etc.), and recognizes that it will have to consider the unique COVID-19 circumstances upon review of inspectional observations after the pandemic.
- Home-Delivery of Self-Administered Investigational Products. So long as switching to home-delivery of an investigational product is due to concern of COVID-19 exposure and does not raise new safety risks, it is permissible with a protocol amendment (which can be part of a consolidated protocol amendment submitted by the sponsor). Continued adherence to storage requirements and accountability of the product must also be documented.
- Using Home Infusion as an Alternative to the Clinical Trial Site. FDA recommends consulting the appropriate Agency review divisions when considering alternative sites of administration, especially for more complex products such as cell or gene therapy products. Again, FDA encourages documentation of either continued compliance with storage requirements and accountability of the product or the circumstances causing any discontinuation of treatment if suitable alternatives cannot be made.
- Informed Consent. FDA outlines a modified informed consent procedure for use in light of COVID-19 infection control measures. Electronic methods of obtaining informed consent are acceptable if the technology is available.
If electronic informed consent is not possible, the Agency recommends the sponsor (1) arrange the provision of an unsigned consent form to the patient by a health care worker in the room; (2) facilitate a 3-way call or video conference with the patient, an impartial witness, and the investigator; and (3) establish a standard process to ensure that those on the call are identified, review the informed consent with the patient and respond to any questions, confirm with the witness that the questions have been answered and the patient is willing to participate, and verbal confirmation from the patient that s/he is willing to participate and that s/he has signed the consent in his/her possession. If the consent form cannot be collected, FDA will accept an attestation from the witness, or a photograph of the signed informed consent and an accompanying attestation to its validity. The reason for the alternative method of informed consent should be documented in the participant’s file.