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