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

In learning-phase clinical trials in drug development, adaptive designs can be 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-stage adaptive designs for establishing proof-of-concept. The results of an interim analysis of first-stage data are used to adapt the candidate dose-response models and the dosages studied in the second stage. GMCTs are used in both stages to obtain stage-wise p-values, which are then combined to determine an overall p-value. An alternative approach is also considered that combines the t-statistics across stages, employing the conditional rejection probability principle to preserve the Type I error probability. Simulation studies demonstrate that the adaptive designs are advantageous compared to the corresponding tests in a nonadaptive design if the selection of the candidate set of dose-response models is not well informed by evidence from preclinical and early-phase studies.

Automated summary

Adaptive designs in learning-phase clinical trials can be efficient and highly informative. This article extends the MCP-Mod procedure with GMCTs for two-stage adaptive designs for proof-of-concept. The results of an interim analysis guide adaptations to candidate dose-response models and dosages studied in the second stage, with GMCTs used in both stages to obtain and combine stage-wise p-values for an overall p-value. Simulation studies show advantages of adaptive designs over nonadaptive designs when candidate dose-response models are not well-informed by preclinical and early-phase evidence.