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This paper discusses multiple testing procedures in dose-response clinical trials with primary and secondary endpoints. A general gatekeeping framework for constructing multiple tests is proposed, which extends the Dunnett test Journal of the American Statistical Association 1955; 50: 1096-1121 and Bonferroni-based gatekeeping tests developed by Dmitrienko et al. Statistics in Medicine 2003; 22:2387-2400. The proposed procedure accounts for the hierarchical structure of the testing problem; for example, it restricts testing of secondary endpoints to the doses for which the primary endpoint is significant. The multiple testing approach is illustrated using a dose-response clinical trial in patients with diabetes. Monte-Carlo simulations demonstrate that the proposed procedure provides a power advantage over the Bonferroni gatekeeping procedure. The power gain generally increases with increasing correlation among the endpoints, especially when all primary dose-control comparisons are significant.
Dmitrienko et al. (Sun,) studied this question.