A flexible fixed-sequence testing method for hierarchically ordered correlated multiple endpoints in clinical trials

Statistical approaches for addressing multiplicity in clinical trials range from the very conservative (the Bonferroni method) to the least conservative the fixed sequence approach. Recently, several authors proposed methods that combine merits of the two extreme approaches. Wiens [2003. A fixed sequence Bonferroni procedure for testing multiple endpoints. Pharmaceutical Statist. 2003, 2, 211–215], for example, considered an extension of the Bonferroni approach where the type I error rate (α)(α) is allocated among the endpoints, however, testing proceeds in a pre-determined order allowing the type I error rate to be saved for later use as long as the null hypotheses are rejected. This leads to a higher power of the test in testing later null hypotheses. In this paper, we consider an extension of Wiens’ approach by taking into account correlations among endpoints for achieving higher flexibility in testing. We show strong control of the family-wise type I error rate for this extension and provide critical values and significance levels for testing up to three endpoints with equal correlations and show how to calculate them for other correlation structures. We also present results of a simulation experiment for comparing the power of the proposed method with those of Wiens’ and others. The results of this experiment show that the magnitude of the gain in power of the proposed method depends on the prospective ordering of testing of the endpoints, the magnitude of the treatment effects of the endpoints and the magnitude of correlation between endpoints. Finally, we consider applications of the proposed method for clinical trials with multiple time points and multiple doses, where correlations among endpoints frequently arise.