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In learning-phase clinical trials in drug development, adaptive designs canbe efficient and highly informative when used appropriately. In this article,we extend the multiple comparison procedures with modeling techniques (MCP-Mod)procedure with generalized multiple contrast tests (GMCTs) to two-stageadaptive designs for establishing proof-of-concept. The results of an interimanalysis of first-stage data are used to adapt the candidate dose-responsemodels and the dosages studied in the second stage. GMCTs are used in bothstages to obtain stage-wise p-values, which are then combined to determine anoverall p-value. An alternative approach is also considered that combines thet-statistics across stages, employing the conditional rejection probability(CRP) principle to preserve the Type I error probability. Simulation studiesdemonstrate that the adaptive designs are advantageous compared to thecorresponding tests in a non-adaptive design if the selection of the candidateset of dose-response models is not well informed by evidence from preclinicaland early-phase studies.

Adaptive dose-response studies to establish proof-of-concept in learning-phase clinical trials