FDA Moves Beyond COVID-19, But Impacts on COVID-19 Era Clinical Trials Remain

On September 18, 2023, FDA published an updated, final iteration of guidance for immediate implementation entitled, “Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions Due to Disasters and Public Health Emergencies.”  This final guidance replaces and supersedes the March 2020 guidance entitled, “Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency.”  The new guidance is meant to expand the earlier’s scope to emergencies outside of the COVID-19 pandemic including but not limited to disasters and public health emergencies such as hurricanes, earthquakes, military conflicts, infectious disease outbreaks, or bioterrorist attacks.

In general, both of these guidances provide recommendations for sponsors to consider and analyze when a disaster (e.g., hurricane) or public health emergency (e.g., pandemic) strikes, causing a major disruption to the conduct of a clinical trial.  For example, a disaster or public health emergency may lead to clinical trial disruptions via population quarantines, travel restrictions, various interruptions to the supply chain, and other logistical issues.  The recommendations provided by the final guidance, and largely included in its previous iteration, center around ensuring the safety of the clinical trial subjects, maintaining adherence with good clinical practice, and limiting the risk to the integrity of the clinical trial (i.e., protecting the clinical trial’s goal of continuing to produce valid data to support eventual regulatory decision-making).

The final guidance largely subsumes the COVID-19-specific guidance with a handful of updates.  First, as previously discussed, FDA broadened the ambit of the final guidance to apply to disasters and public health emergencies generally.  The other major changes come in the appendix which provides a series of questions and answers, including the removal or update of outdated questions (i.e., those specifically related to the COVID-19 public health emergency).  In addition, the final guidance clarifies and expounds upon its previous recommendations, including several potential logistical concerns (e.g., shipment of and charging for investigational product) and a risk-based evaluation for monitoring clinical trial sites and subjects.

While it makes sense for FDA to apply its learnings and considerations to other public health emergencies beyond COVID-19, the shift in focus comes at a time when many medical product programs are still reeling from the effects of the pandemic on their previous or even still-ongoing clinical trials.  Trials that were adapting (or not) in real time due to the emergent nature of the pandemic experienced real, lasting COVID-19 disruptions affecting everything from adherence to study protocols, impacts confounding safety and efficacy evaluation to different degrees at different periods, and less-than-ideal fixes to ongoing protocols and statistical analysis plans in an attempt to protect participants and study personnel.  In our experience, these programs are the ones that seem to be left behind, as FDA has been uncertain of how to handle the results from these COVID-19 era studies.

In the case of trials for orphan drugs, this is particularly concerning because there is often already difficulty in interpreting clinical trial results to establish effectiveness due to the common challenges inherent in rare disease drug development.  Layering on COVID-19 impacts, and the added uncertainty they impart, many of those trials were deemed uninterpretable or negative conclusions of effectiveness were drawn.  This can be the death knell for some rare diseases, as over 95% do not have even a single FDA-approved therapy, so a failure of one program can result in a departure of investment interest by other companies.  While individual sponsors continue to discuss these COVID-19 impacts on orphan drugs in development with FDA, we hope that the Agency will consider the specific impacts on rare disease drug development in future public health emergencies.  There are already enough unique challenges these rare disease drug development programs face, and every patient that participates in clinical trials is precious, so we owe it to them to find a more holistic approach to salvaging clinical trials that are impacted by public health emergencies.