By Ed Miseta, Chief Editor, Clinical Leader
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The FDA has released guidance for industry, investigators, and IRBs on the conduct of clinical trials during the COVID-19 pandemic. The agency issued the guidance to provide general considerations to assist sponsor companies with protecting the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing the risks to trial integrity during the pandemic.
Because of the public health emergency sweeping the U.S., the FDA implemented the guidance without prior public comment, deeming those actions neither feasible nor appropriate. Although the guidance is being implemented immediately, it will remain subject to comment. As with other FDA guidance documents, the actions noted are recommendations.
COVID-19 has resulted in the Department of Health and Human Services (HHS) declaring a public health emergency and President Trump declaring a national emergency in the U.S. The FDA recognizes these actions may impact the conduct of clinical trials. Challenges may arise from quarantines, site closures, travel limitations, and disruptions to the supply chain of investigational products. Site personnel and trial participants may also become infected with COVID-19. Any of those challenges could lead to difficulties in meeting protocol-specified procedures. In the guidance, the FDA has recognized that protocol deviations may be required and, in some cases, be unavoidable. The following general considerations are intended to assist sponsors in protecting study participants and minimizing the risk to trial integrity.
If policies and procedures are not already in place for a trial, FDA states sponsors, investigators, and IRBs should consider establishing and implementing policies and procedures that describe approaches to be used to protect trial participants and manage the study during possible disruptions due to COVID-19. If policies and procedures already exist, they should be modified. Those changes could address, but not be limited to, the impact on the informed consent process, study visits and procedures, data collection, study monitoring, adverse event reporting, and changes in investigators, monitors, and staff due to travel restrictions and quarantine measures.
For trials that are already ongoing, FDA recommends the following 12 measures:
1. Ensuring the safety of study participants is paramount. Sponsors should consider each circumstance, focus on the potential impact on the safety of participants, and act accordingly. Study decisions could include continuing recruitment, the continued use of investigational products on patients, and the need to change patient monitoring. Study participants should be kept informed of any changes that could impact them.
2. Sponsors may consult with investigators and IRBs in determining if a participant’s safety, welfare, and rights might be best served by continuing in the study per the protocol or by discontinuing use of the investigational product or even participation in the trial. This decision will depend on specific circumstances such as nature of the product, the ability to conduct safety monitoring, potential impact on the supply chain, and nature of the disease being investigated.
3. To assist participants who may not be able to visit a clinic, sponsors should evaluate alternative methods for safety assessments. Those methods may include phone calls, virtual visits, and alternative locations for assessments, such as labs or imaging centers. Additionally, sponsors should determine if in-person visits are necessary and feasible and can ensure the safety of study participants.
4. In some cases where trial participants no longer have access to the investigational product or site, sponsors should consider withdrawal from the active treatment.
5. The need to put new processes in place or modify existing processes will vary by the protocol and local situation. Assessments could include consideration of whether it is appropriate to delay some assessments or if the study cannot be properly conducted under the existing protocol. Consideration should also be given to whether to stop ongoing recruitment or even withdraw trial participants.
6. If COVID-19 screening procedures are mandated by a health care system in which a trial is being conducted, those procedures do not need to be reported as an amendment to the protocol, even if done during clinical study visits.
7. Sponsors and investigators are encouraged to engage with IRBs and independent ethics committees (IECs) as early as possible when urgent or emergent changes to the protocol or informed consent are anticipated due to COVID-19. Changes to minimize or eliminate hazards or to protect the life and well-being of trial participants can be implemented without IRB approval or before filing an amendment but are required to be reported afterwards.
8. The implementation of alternative processes should be consistent with the protocol to the extent possible. Sponsors and investigators should document the reason for any contingency measures implemented, and how restrictions related to COVID-19 led to the changes in study conduct. The duration of the changes and the impact on participants should also be documented.
9. Missed visits and changes in study visits will result in missing information. Specific information in the case report form should explain the basis of the missing information, including the relationship to COVID-19.
10. If scheduled visits to a clinic will be significantly impacted, investigational products that can be self-administered may be amenable to alternative secure delivery methods.
11. Sponsors should consult the appropriate review division regarding protocol modifications related to the collection of efficacy endpoints, such as virtual assessments, delays in assessments, and alternative collection of research-specific specimens. If efficacy endpoints are not collected due to COVID-19, the reasons for failing to obtain the efficacy assessment should be documented. If changes in the protocol will lead to amending data management and/or statistical analysis plans, sponsors should consider doing so in consultation with the applicable FDA review division.
12. Finally, if planned on-site monitoring visits are no longer possible, sponsors should consider optimizing the use of central and remote monitoring programs to maintain oversight of clinical sites.
- For all trials impacted by COVID-19, certain actions should be described in appropriate sections of the clinical study report. That includes the following:
- Contingency measures implemented to manage study conduct during disruptions resulting from COVID-19.
- A listing of participants affected by the COVID-19 virus study disruption. Participants should be noted by unique subject number identifier, by investigational site, and a description of how their participation was altered.
- Analyses and corresponding discussions that address the impact of implemented contingency measures on the safety and efficacy results reported for the study. Those contingency results could include participant discontinuation from a product or study and alternative procedures used to collect safety and/or efficacy data.
The FDA expects robust efforts by sponsors, clinical sites, and IRBs/IECs to maintain the safety of trial participants and data integrity. Those efforts should be documented. Although protocol modifications may be required due to COVID-19, it is important for sponsors to document the reasons for the deviations.
Click here for more information on the FDA guidance.