Changes are still needed on multiple co-primary endpoints.

Abstract

The Food and Drug Administration in the United States issued a much-awaited draft guidance on 'Multiple Endpoints in Clinical Trials' in January 2017. The draft guidance is well written and contains consistent message on the technical implementation of the principles laid out in the guidance. In this commentary, we raise a question on applying the principles to studies designed from a safety perspective. We then direct our attention to issues related to multiple co-primary endpoints. In a paper published in the Drug Information Journal in 2007, Offen et al. give examples of disorders where multiple co-primary endpoints are required by regulators. The standard test for multiple co-primary endpoints is the min test which tests each endpoint individually, at the one-sided 2.5% level, for a confirmatory trial. This approach leads to a substantial loss of power when the number of co-primary endpoints exceeds 2, a fact acknowledged in the draft guidance. We review approaches that have been proposed to tackle the problem of power loss and propose a new one. Using recommendations by Chen et al. for the assessment of drugs for vulvar and vaginal atrophy published in the Drug Information Journal in 2010, we argue the need for more changes and urge a path forward that uses different levels of claims to reflect the effectiveness of a product on multiple endpoints that are equally important and mostly unrelated. Copyright © 2017 John Wiley & Sons, Ltd.