Comment from National Center for Health Research

Public Comment of National Center for Health Research Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices (Docket No. FDA-2023-D-50) Thank you for the opportunity to comment on the draft guidance entitled Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices (Docket No. FDA-2023-D-5016). The National Center for Health Research is a nonprofit public health think tank that focuses on the safety and effectiveness of medical and consumer products. Our staff has attended and participated in hundreds of FDA Advisory Committee meetings over the last 25 years, and in that capacity we have often heard FDA scientific staff describe their concerns about protocol deviations and violations that have undermined the integrity of the research results that companies present in support of FDA approval. For that reason, we greatly appreciate the FDA's efforts to clarify the agency's recommendations and expectations in this draft guidance. We are sympathetic to the researchers who want a less time-consuming way to deal with protocol deviations and violations but based on our experience at hundreds of FDA Advisory Committee meetings, we conclude that more specific and more objective FDA instructions and examples are essential for ensuring that study results are persuasive. Too often, the health professionals who work directly with patients to ensure protocol compliance are not as cognizant as they should be of the impact that deviations and violations can have on biasing the results. For a variety of reasons, many health professionals tend to minimize the importance of these intentional or unintentional deviations or violations, thinking that is the best way to protect the clinical trial (and their role in it). Unfortunately, even apparently small deviations can substantially undermine the credibility of study results. For example, in a JAMA Network article published in January 2025, entitled "Reanalysis of Urothelial Cancer Chemoimmunotherapy Trials With Differential Censoring," the authors found that differences in censoring resulted in some studies showing the treatment was effective while others showed it was ineffective. This was not a protocol deviation on the part of the authors; it was just due to variations in the study protocol that researchers selected without necessarily assuming it would have an important impact on the results. We therefore urge the FDA to be very specific about the agency's expectations because while additional documentation may require more effort, ensuring rigor in study protocols ultimately strengthens scientific credibility and regulatory success. The draft guidance is a step in the right direction, but it should be even more specific, rather than loosened as some commenters have requested. In addition, we urge the FDA to also provide guidance regarding protocol deviations and violations regarding study design, implementation, and data analyses, especially those that undermine blinding, randomization, and the unbiased interpretation of the data.