As the world continues to navigate the impacts of the novel coronavirus (COVID-19), the clinical research industry has seen an increase in new trials for the development of COVID-related treatments and products. However, some trials not related to COVID-19 have experienced operational interruptions, compromising the ability to collect meaningful, reliable, and accurate data, and – in some cases – jeopardizing overall trial integrity.

These incidents have presented the need for protocol modifications to adjust for COVID-19 control measures and COVID-19 illness. The U.S. Food and Drug Administration (FDA) recently developed the “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency” to offer advice on managing protocol amendments and deviations, as well as for documenting changes to the trial. This article will discuss a few of the common challenges in conducting non-COVID-related research and the current recommendations offered in the FDA guidance.

Subject Discontinuations and Assuring the Safety of Trial Participants
The uncertainty of the evolving pandemic brings with it a variety of potential roadblocks to current trials, including a decrease in willing participants, travel restrictions, and staff reductions at study sites. Understandably, study participants are expressing a reluctance to visit healthcare settings out of concern of contracting COVID-19. As a result, some trials are experiencing an increase in missed visits or dropouts, and some studies have limited new enrollment and are focusing on subjects already in the trial.

FDA recognizes that protocol modifications may help mitigate the limitations imposed by the COVID-19 emergency, which will depend on many factors, including the disease under study, trial design, and specific difficulties that have been encountered in conducting the study. FDA underscores that sponsors must foremost continue to assure the safety of trial participants, as well as to maintain compliance with good clinical practice (GCP) and minimize risks to trial integrity.

Depending on the specific circumstances of the trial, FDA states that sponsors – along with clinical investigators and institutional review boards (IRBs) – may determine that the protection of a study participant’s safety, welfare, and rights, while maintaining study integrity, is best served by any of the following:
•    Continuing to participate in the trial as per protocol
•    Discontinuing the administration or use of an investigation product
•    Discontinuing participation in the trial
•    Implementation of alternative processes or procedures that do not conflict with the requirements and limitations of the existing protocol
•    Modifying study protocols and documenting the modifications in protocol amendments, keeping in mind that modifications should not be implemented prior to the necessary approvals, unless required to eliminate or reduce an immediate safety risk for a subject  

Modifying Assessment Methods
The decrease in on-site visits makes it difficult to collect data from important assessments, including efficacy outcome measures and those required for patient safety, like visual examinations, vital signs, and procedures such as ECG or MRI. To help mitigate these challenges, FDA recommends that sponsors evaluate whether alternative methods to gather this information are possible. Examples include phone contact, virtual visits, in-home visits by a qualified professional, and use of local labs or diagnostic centers. These alternative methods are only suitable, however, in cases where the data can be objectively and adequately obtained and where subjects incur no increase in risk due to assessment delays or limitations.

Potential Impacts on Clinical Study Results
FDA emphasizes the need for sponsors to clearly document all changes to study conduct, the reasons behind them, and how COVID-19 influenced these changes. Many of these impacts, such as missed visits, may be captured as protocol deviations, while others may be documented as changes to the monitoring plan, findings in site visit monitoring reports, or data within the electronic data capture system. Because changes in study requirements, allowances, and visit schedules, as well as missed visits or patient discontinuations may fundamentally affect the ability of the study to yield valid and interpretable results, full documentation of all of these details in the clinical study reports is of utmost importance, as it allows both FDA and sponsors to look back to determine the extent to which the pandemic and associated modifications might have affected the overall outcome of the trial.

Conclusion
Sponsors must understand the practical limitations that exist due to COVID-19 and seriously consider what modifications might be necessary to assure patient safety, compliance with good clinical practice (GCP), and the integrity of ongoing trials. Today’s technology has provided new ways of working around these challenges, with perhaps the most notable being the rise of video conferencing and telemedicine. By considering these recommendations and complying with current regulations, sponsors can mitigate the risks on study conduct and integrity imposed by COVID-19 and continue working toward discovering new therapies for unmet medical needs.

Additional information on COVID-19 related challenges in drug development can be found here.