Bayesian multiregional clinical trials using model averaging.

Abstract

Multiregional clinical trials (MRCTs) provide the benefit of more rapidly introducing drugs to the global market; however, small regional sample sizes can lead to poor estimation quality of region-specific effects when using current statistical methods. With the publication of the International Conference for Harmonisation E17 guideline in 2017, the MRCT design is recognized as a viable strategy that can be accepted by regional regulatory authorities, necessitating new statistical methods that improve the quality of region-specific inference. In this article, we develop a novel methodology for estimating region-specific and global treatment effects for MRCTs using Bayesian model averaging. This approach can be used for trials that compare two treatment groups with respect to a continuous outcome, and it allows for the incorporation of patient characteristics through the inclusion of covariates. We propose an approach that uses posterior model probabilities to quantify evidence in favor of consistency of treatment effects across all regions, and this metric can be used by regulatory authorities for drug approval. We show through simulations that the proposed modeling approach results in lower MSE than a fixed-effects linear regression model and better control of type I error rates than a Bayesian hierarchical model.