Gatekeeping procedures in dose-response clinical trials based on the Dunnett test.
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
Alex
A
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. dmitrienko_alex@lilly.com
Offen
Walt
W
Wang
Ouhong
O
Xiao
Dan
D
D002986:Clinical Trials as Topic / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D006801:Humans