Bayesian design and analysis of composite endpoints in clinical trials with multiple dependent binary outcomes

Abstract

The author considers studies with multiple dependent primary endpoints. Testing hypotheses with multiple primary endpoints may require unmanageably large populations. Composite endpoints consisting of several binary events may be used to reduce a trial to a manageable size. The primary difficulties with composite endpoints are that different endpoints may have different clinical importance and that higher-frequency variables may overwhelm effects of smaller, but equally important, primary outcomes. To compensate for these inconsistencies, we weight each type of event, and the total number of weighted events is counted. To reflect the mutual dependency of primary endpoints and to make the weighting method effective in small clinical trials, we use the Bayesian approach. We assume a multinomial distribution of multiple endpoints with Dirichlet priors and apply the Bayesian test of noninferiority to the calculation of weighting parameters. We use composite endpoints to test hypotheses of superiority in single-arm and two-arm clinical trials. The composite endpoints have a beta distribution. We illustrate this technique with an example. The results provide a statistical procedure for creating composite endpoints.

Keywords: Bayesian analysis; Dirichlet distribution; composite endpoints; hypotheses testing; noninferiority.