Impact of non-binding FDA guidances on primary endpoint selection in Alzheimer's disease trials.

Introduction: The U.S. Food and Drug Administration (FDA)'s guidances help describe the agency's current thinking on regulatory issues and serve as a means of informal policymaking that is non-binding. This study examines the impact of two guidance documents for Alzheimer's disease (AD) trials. The first guidance in 2013 encouraged the use of cognitive/functional endpoints, while the second in 2018 modified such recommendation.

Methods: Using pivotal trial data, we applied a regression discontinuity in time (RDiT) framework to examine trialist response to these guidance documents. Results were stratified by disease-modifying therapy (DMT) status, and controlled for disease staging, FDA registration status, and trial phase.

Results: Among AD DMT trials, annual use of cognitive/functional composite endpoints significantly increased after the 2013 guidance (+12.9%,  < .001), and significantly decreased after the 2018 guidance (-19.9%,  = .022).

Discussion: Although guidance documents do not set new legal standards or impose binding requirements, our findings indicate they are broadly followed by AD trialists.