Closed MCP-Mod for Pairwise Comparisons of Several Doses With a Control

Abstract

The MCP-Mod approach by Bretz et al. is commonly applied for dose-response testing and estimation in clinical trials. The MCP part of MCP-Mod was originally developed to detect a dose-response signal using a multiple contrast test, but it is not appropriate to make a specific claim that the drug has a positive effect at an individual dose. In this paper, we extend the MCP-Mod approach to obtain confirmatory p-values for detecting a dose-response signal as well as for the pairwise comparisons of the individual doses against placebo. We apply the closed test principle from Marcus et al. to the optimal contrast tests based on a candidate set of plausible dose-response shapes available at the planning stage of a clinical trial. We show that the contrast coefficients have to be optimized under suitable constraints to guarantee strong Type 1 error rate control at a pre-specified significance level. Motivated by a recent clinical trial, we evaluate the operating characteristics of the proposed methods in a comprehensive simulation study.

Keywords: contrast tests; dose finding; dose–response; many‐to‐one comparisons; modeling.