title: Secondary endpoints cannot be validly analyzed if the primary endpoint does not demonstrate clear statistical significance.
abstract: There is lack of consensus surrounding the interpretation of observed treatment effects for secondary clinical endpoints when the primary endpoint for which the clinical trial was initially designed does not meet the objective of a demonstrated effect. We provide some arguments to support caution in making inferences for secondary endpoints in this situation. We examine the definitions of primary and secondary endpoints within the context of a hypothesis-testing framework for multiple endpoints, and we address the relationship of the correlation structure of these endpoints and the statistical adjustments needed to preserve experiment-wise type I error for a valid inference. We also address the hypothesis-testing framework and the estimation framework for valid inference, focusing on the interpretation of p-values associated with differentially powered hypothesis tests for each endpoint to detect an important clinical effect. We point out the limitations on the strength of evidence (and quantification of uncertainty) for a secondary endpoint effect that can be derived from only one study and introduce the likelihood of replication of the finding in another study of identical size and design as a useful concept to guide this interpretation.
authors.affiliation: Office of Epidemiology and Biostatistics, Center for Drug Evaluation and Research/FDA, Rockville, Maryland 20857, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: O'Neill
mesh_terms: D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D006801:Humans; D009026:Mortality; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data*; D015203:Reproducibility of Results; D018401:Sample Size