FDA Updates Guidance for Clinical Trials During COVID-19 Pandemic
In March 2020, as governments around the world were issuing large-scale lockdowns, health facilities shifted their efforts to addressing critical needs of patients while trying to maintain the safety of staff. Clinical trials ended or were paused, and researchers allocated their attention and resources to understanding and managing the novel coronavirus.
To assist researchers, IRBs, and sponsors, the FDA issued guidance last year on the conduct of clinical trials during the COVID-19 pandemic. The guidance aimed to help institutions protect clinical trial participants, maintain compliance with Good Clinical Practice, and ensure data integrity of the research. Among the many challenges brought on by COVID-19, some of the most vexing logistical challenges came from quarantines, site closures, travel limitations, and interruptions of the supply chain for investigational or other products. In addition, institutional leaders have had to address considerations if site personnel or trial participants became infected with COVID-19.
The FDA recently updated this guidance, in August 2021. This is a high-level review of some of the issues addressed in the guidance.
Protocol Deviations
Deviations from a protocol may be necessitated by changes to public health recommendations both at the national and local levels. Also, deviations can occur in the case of exposure, a positive test, or diagnosis of a trial participant.
Deviations can include a change in how patients are monitored — from in-person to remote visits, for example. COVID-19 has increased the acceptance of these alternative methods of monitoring, reducing unnecessary travel and risk of exposure for participants. For the safety of participants, sponsors may consider options such as phone calls, virtual visits, or even remote monitoring devices.
Some changes to the protocol or investigational plan are intended to minimize or eliminate immediate hazards or to protect the life and well-being of research participants. In these urgent cases, deviations may be implemented without IRB approval or before filing an amendment to the investigational new drug (IND) or investigational device exemption (IDE) However, they are required to be reported afterwards.
Investigators should work closely with IRBs to ensure policies and regulatory requirements for reporting deviations are followed and, when needed, develop plans or procedures to prioritize reporting of deviations that may impact the safety of trial participants.
Additional Screening Procedures
Institutions may require COVID-19 screening of clinical trial participants. In these cases, the screening does not need to be reported as an amendment to the protocol, even if done during clinical study visits.
On the other hand, if the sponsor is incorporating the data collected as part of a new research objective, it should be reported as a change to the protocol. This additional protocol-driven screening should also be considered in the clinical trial budgeting process.
The Importance of Documentation
Sponsors and clinical investigators should document how restrictions related to COVID-19 led to the changes in study conduct and duration of those changes. They should indicate which trial participants were impacted, and how those trial participants were impacted.
Some changes, such as an adjustment in a study visit schedule, may lead to missing information. In those cases, it is important to capture in the case report what specific data is missing and the reason for its absence.
Other items that sponsors should document:
- Contingency measures implemented to manage disruptions due to COVID-19
- A list of all participants who were impacted by COVID-19-related study disruptions, and how they were impacted
- Analysis of how contingency measures may have impacted safety and efficacy results
Protecting Data Integrity
Sponsors that anticipate that changes to the protocol will impact data management procedures or statistical analysis plans should coordinate with their respective FDA review division. This includes situations in which the efficacy endpoints may be impacted. For example, assessments may be conducted virtually instead of in-person. Any modifications to the data management or statistical analysis plan but also receive IRB review and approval.
Questions and Answers
The guidance also contains an appendix with 28 questions along with detailed answers for each question. Some of the topics covered include:
- re-monitoring after pandemic related restrictions are lifted
- exclusion criteria for “investigational medical products”
- collecting electronic signatures and Part 11 compliance
- reviewing IND safety reports
Twenty months after the first COVID-19 case was confirmed in the United States, researchers are still trying to understand the long-term impact on non-COVID clinical trials. Researchers and clinical trial professionals have had to demonstrate resilience, flexibility, and adaptation in the face of uncertainty and a changing epidemiological landscape.
The primary guiding principle throughout the guidance is to ensure the safety of clinical trial participants.
