Multiple comparisons and multiple contrasts in randomized dose-response trials--confidence interval oriented approaches.

Abstract

According to the ICH E9 recommendation, the evaluation of randomized dose-finding trials focuses on the graphical presentation of different kinds of simultaneous confidence intervals: i) superiority of at least one dose vs. placebo with and without the assumption of order restriction, ii) noninferiority of at least one dose vs. active control, iii) identification of the minimum effective dose, iv) identification of the peak dose, v) identification of the maximum safe dose for a safety endpoint, and vi) estimation of simultaneous confidence intervals for "many-to-one-by-condition interaction contrasts." Moreover, global tests for a monotone trend or a trend with a possible downturn effect are discussed. The basic approach involved obtaining multiple contrasts for different problem-related contrast definitions. For all approaches, definitions of relevance margins for superiority or noninferiority are needed. Because consensus on margins only exists for selected therapeutic areas and the definition of absolute thresholds may be difficult, simultaneous confidence intervals for ratio to placebo were also used. All approaches are demonstrated in an example-based manner using the R-packages multcomp (difference), for hypotheses based on difference, and mratios (ratio), for hypotheses based on ratios.