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.” In issuing this guidance, FDA recognized that the COVID-19 pandemic may affect the conduct of clinical trials of drugs, medical devices, and biological products (e.g., protocol modifications and deviations). For example, challenges may arise from quarantines, clinical study site closures, travel limitations, interruptions to the supply chain for investigational products, or other considerations if site personnel or trial subjects become infected with the virus that causes COVID-19.
On March 27, FDA issued an updated version of the guidance, adding an “Appendix: Questions and Answers,” that responds to 10 questions the agency has received on this subject. The additional guidance in the appendix is effective immediately, and FDA plans to update this appendix as new questions arise.
We will summarize the key points from the Questions and Answers in this Bulletin.
Key Factors that Sponsors Should Consider When Deciding Whether to Suspend or Continue an Ongoing Study or to Initiate a New Study During the COVID-19 Pandemic
Sponsors, in consultation with clinical investigators and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), should assess whether 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. Sponsors should consider the following aspects of clinical trial conduct when deciding how or whether to proceed with a clinical trial:
- Whether the limitations imposed by the COVID-19 pandemic on protocol implementation pose new safety risks to trial participants, and whether it is feasible to mitigate these risks by amending study processes and/or procedures.
- The availability of the clinical investigators/sub-investigators to provide oversight of the trial, and properly assess and manage safety issues.
- Whether there will be sufficient trained clinical trial support staff, and adequate equipment and materials for their use.
- Whether clinical sites will remain open for required in-person assessments, or whether such assessments can be provided at acceptable alternate locations or conducted virtually.
- The availability of clinical trial supplies and continued operations of vendors, including the supply and product stability (shelf life) of the investigational product.
- The availability of, and support for, information technology systems and other necessary technological tools.
- The continued operations of, and adequate communications with, the IRB, IEC, and Data Monitoring Committee (DMC) staff.
- Whether it is feasible to conduct the trial in light of COVID-19 public health measures implemented by federal and state authorities.
Key Factors that Sponsors Should Consider When Deciding Whether to Continue Administering or Using an Investigational Product that Appears to be Providing Benefit to the Trial Participant
- Whether a trial participant appears to be benefitting from treatment with the investigational product
- Are there reasonable alternative treatments
- The seriousness of the disease or condition being treated, and
- The risks in switching to an alternative treatment if necessary
- If there are participants for whom discontinuing the investigational product might present a substantial risk (e.g., product appears to be providing a clinical benefit to participants), the sponsor should consider amending the protocol, after discussion with the FDA review division, to limit product use to those patients with apparent benefit and discontinue use to other participants. There should be appropriate management of trial participants discontinued from an investigational therapy.
How Should Sponsors Manage Protocol Deviations and Amendments to Ongoing Trials?
- For protocol deviations, sponsors should document the specific deviation and the reason for the deviation using its standard processes or alternative documentation approaches.
- For study-wide protocol changes, protocol amendments that are necessary to prevent imminent hazards to trial participants can generally be immediately implemented with subsequent submission and formal approval by the IRB and notification to FDA by filing a protocol amendment to the IND or IDE.
- For studies under an Investigational New Drug Application (IND), 21 C.F. R. 312.30(b) specifies that sponsors must submit a protocol amendment describing any change in a phase 1 protocol that significantly affects the safety of subjects, or any change in a phase 2 and 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study. Submitting a protocol amendment would generally not be required when pausing enrollment in a trial to decrease potential exposure to COVID-19. Protocol amendments that are not required to prevent imminent safety risks to patients can be implemented once they are submitted to FDA and IRB approval has occurred. Clinical investigators must document as protocol deviations any modifications to protocol-specified procedures that occur prior to IRB approval and FDA submission of the protocol amendment implementing the modification.
- For studies under an Investigational Device Exemption (IDE), 21 C.F.R. 812.35(a) generally requires prior FDA approval before implementing changes to the investigational plan. However, under 21 C.F.R. 812.35(a)(3), protocol changes that the sponsor determines, based on credible information, do not affect the validity of the study results, the likely patient risk to benefit relationship, the scientific soundness of the investigational plan, or the rights, safety or welfare of the subjects may be made without prior FDA approval, if the sponsor reports the modifications to FDA within 5 days, or as soon as possible, of implementing the changes.
How Should Sponsors Submit a Change in Protocol Related to the COVID-19 Pandemic?
For studies under an IND, sponsors should submit a formal amendment to the IND, with the following information added to the cover letter in the subject line:
PROTOCOL AMENDMENT – COVID-19
TITLE OF PROTOCOL
Sponsors should summarize major changes to the protocol in the cover letter and should include a tracked changes version of the protocol. Sponsors seeking FDA input prior to implementation should indicate that in the cover letter.
For studies under an IDE, sponsors should submit a supplement to its existing IDE, with the following information added to the cover letter in the subject line:
CHANGE IN PROTOCOL SUPPLEMENT – COVID-19 or
NOTICE OF IDE CHANGE – COVID-19, as applicable
TITLE OF PROTOCOL
The submission should include a tracked changes version of the protocol.
Can a Sponsor Initiate Virtual Clinical Trial Visits for Monitoring Patients Without Contacting FDA if the Sponsor and Investigator Determine that These Visits are Necessary for the Safety of the Trial Participant and It Will Not Impact Data Integrity?
Yes, if the change is intended to eliminate an apparent immediate hazard or to protect the life and well-being of subjects. Such changes can be immediately implemented with subsequent review by the IRB and notification to FDA. Documentation of the required deviations, as described above, would generally be acceptable. Because the change to telephone or video contact would likely result in some protocol-required procedures not being conducted (e.g., vital signs, blood samples), sponsors must evaluate the potential impact on patient safety, and consider how to mitigate risks to patients, including the need to discontinue the investigational product.
For IDE studies, sponsors must report deviations to address imminent safety risks to FDA within 5 days, or as soon as possible.
With the Rapid Changes in Clinical Trial Conduct that May Occur Due to the COVID-19 Pandemic, What is the Best Way for Sponsors and Investigators to Capture These Data?
As mentioned in the body of the guidance, it is important to capture specific information for individual patients that explains the basis for missing protocol-specified information (e.g., missed study visits or study discontinuations due to COVID-19). If it is not possible to capture this information in the case report forms, sponsors may develop processes to capture these data in a manner that enables the appropriate analysis when the data are submitted to FDA.
If Patients are Currently Dispensed Investigational Product through a Pharmacy for Self-Administration at Home, Can a Sponsor Switch to Home Delivery Without Amending the Protocol?
Home delivery of the investigational product that would not raise any new safety risks may be implemented. However, if the protocol indicates pharmacy dispensing for self-administration at home, and this is changed to direct-to-patient shipments, then a protocol amendment would be required to permit home delivery. Home delivery could be for the entire patient population or limited to certain participants. Sponsors must continue to address and document FDA regulations for maintaining investigational product storage conditions and product accountability.
If Patients are Currently Receiving an Investigational Product Infusion at the Clinical Trial Site, Can a Sponsor Switch to Home Infusion?
In general, sponsors should consult the FDA review division regarding plans for alternative sites for administration (e.g., home nursing or alternative sites with trained, but non-study personnel). In all cases, applicable requirements for maintaining investigational product storage conditions, reconstitution specifications, and product accountability must be addressed and documented.
If There are Delays to On-Site Monitoring, What are FDA’s Expectations?
Sponsors should consider alternative approaches, such as enhanced central monitoring; telephone contact with sites to review study procedures, trial participant status, and study progress, or remote monitoring of trial participants, where appropriate and feasible. Sponsors should carefully document situations where monitors were unable to access, or had to delay, monitoring of a clinical site.
How to Obtain a Signed Informed Consent Form From a Patient in Isolation and the COVID-19 Control Measures Prevent the Investigator from Removing a Document Signed by the Patient from Their Hospital Room?
- Electronic methods of obtaining informed consent are acceptable
- If electronic methods are not available, sponsors should consider the following:
- An unsigned consent form is provided to the patient by a health care worker who has entered the room
- If direct communication with the patient is not feasible or safe, the investigator (or their designee) arranges a telephone call or video conference with the patient, an impartial witness, and additional participants requested by the patient (e.g., next of kin).
- A standard process should be used to:
- Identify who is on the call
- Review of the informed consent with the patient by the investigator (or their designee) and response to any questions by the patient
- Confirmation by the witness that the patient’s questions have been answered
- Confirmation by the investigator that the patient is willing to participate in the trial and signed the informed consent form while the witness is listening on the phone
- Verbal confirmation by the patient that they would like to participate in the trial, and that they have signed and dated the informed consent form
- If the informed consent document cannot be collected from the patient and included in the study records, FDA provides two acceptable options:
- Attestations by the witness who was on the call and by the investigator that the patient confirmed that they agreed to participate in the study and signed the informed consent, OR
- A photograph of the informed consent document with attestation by the person entering the photograph into the study record stating how the photograph was obtained, and that it is a photograph of the informed consent signed by the patient.
- A copy of the informed consent document signed by the investigator and witness should be placed in the patient’s trial source documents, with a notation by the investigator of how the consent was obtained (e.g., telephone). The trial record at the site should document how it was confirmed that the patient signed the consent form (attestation by the witness and investigator or the photograph of the signed consent). The note should explain why the informed consent document signed by the patient was not retained (e.g., due to contamination of the document by infectious material).
- If the patient is unable to provide informed consent and there is a legally authorized representative, investigators must obtain consent from the participant’s legally authorized representative in accordance with 21 C.F.R. 50.27(a).
- Central to any decision on modifying clinical trial conduct should be ensuring that the safety of clinical trial participants can be maintained.
- Involvement of a study’s DMC, if one has been established, can provide support for the determination whether to suspend or continue an ongoing study or to initiate a new study during the pandemic.
- It is important to document, with specificity, any changes made and the reasons for those changes.
- FDA’s recommendations for alternative approaches to meeting regulatory requirements show flexibility. However, sponsors should keep in mind that the regulatory requirements remain in place. FDA offers alternative approaches to meeting the regulations, not enforcement discretion.
- When in doubt about clinical trial issues, we recommend that sponsors contact the FDA review division. While FDA is very busy and working remotely, the agency seems amenable to helping industry during the COVID-19 pandemic.