Multiple Co-primary Endpoints: Medical and Statistical Solutions: A Report from the Multiple Endpoints Expert Team of the Pharmaceutical Research and Manufacturers of America

Abstract

There are quite a few disorders for which regulatory agencies have required a treatment to demonstrate a statistically significant effect on multiple endpoints, each at the one-sided 2.5% level, before accepting the treatment’s efficacy for the disorders. Depending on the correlation among the endpoints, this requirement could lead to a substantial reduction in the study’s power to conclude the efficacy of a treatment. To investigate the prevalence of this requirement and propose possible solutions, a multiple-disciplinary Multiple Endpoints Expert Team sponsored by Pharmaceutical Research and Manufacturers of America was formed in November 2003. The team recognized early that many researchers were not fully aware of the implications of requiring multiple co-primary endpoints. The team proposes possible solutions from both the medical and the statistical perspectives. The optimal solution is to reduce the number of multiple co-primary endpoints. If after careful considerations, multiple co-primary endpoints remain a scientific requirement, the team proposes statistical solutions and encourages that regulatory agencies be receptive to approaches that adopt modest upward adjustments of the nominal significance levels for testing individual endpoints. Finally, the team hopes that this report will draw more attention to the problem of multiple co-primary endpoints and stimulate further research.