We evaluate the impact of nonbinding guidance documents issued by the FDA on clinical trial design and the selection of outcome measures.
- The selection of outcome measures, called primary endpoints, governs the nature of evidence produced in clinical trials.
- They also serve as an important input for the review of the drugs by regulatory authorities.
- We use Alzheimer’s Disease as a case study to evaluate the impact of FDA-issued nonbinding guidance documents on endpoint selection.
- We find guidance documents are broadly followed by AD trialists.
- The FDA and policymakers should be aware of the impact of the guidance documents on trial design and the implications of this.
The U.S. Food and Drug Administration (FDA)’s issues guidance documents which serve as a means of informal policymaking. These nonbinding documents provide advice and insight on a range of trial elements including recruitment, trial monitoring and trial design – including the development of measures of efficacy that address the main outcome of the trial (aka the primary endpoint selection). Guidance documents are becoming increasingly common in the FDA because they can be changed relatively quickly, but their impact on trial design has not been studied extensively.
Our paper serves as the first empirical study of FDA guidance documents, using clinical trial design in Alzheimer’s Disease (AD) as a case study. There are two major guidance documents within AD that have implications for trial design. The first guidance in 2013 encouraged the use of cognitive/functional endpoints, while the second in 2018 modified this recommendation.
We evaluated primary endpoint selection used in a total of 314 trials conducted from 1997 to 2020.
Although guidance documents do not set new legal standards or impose binding requirements, our findings indicate they are broadly followed by AD trialists. We find that among trials for disease modifying therapies for AD, use of cognitive/functional endpoints increased by almost 13% after the 2013 guidance. Furthermore, use of these endpoints decreased by almost 20% after the 2018 guidance that modified the recommendations.
Given the increasing role of FDA guidances in making substantive policy change, and the presence of guidances that are not revised or finalized, this work provides important information for policymakers and stakeholders. This is especially important to consider given that the guidance may not reflect the most up-to-date science—a concern raised in Congress.
The full study can be accessed at Alzheimer’s & Dementia.
Yu, J. C., Hlávka, J. P., Joe, E., Richmond, F. J., & Lakdawalla, D. N. (2022). Impact of non‐binding FDA guidances on primary endpoint selection in Alzheimer’s disease trials. Alzheimer’s & Dementia, 8(1), e12280.