Flexible Bayesian subgroup analysis in early and confirmatory trials.

Subgroup analysis is one of the most important issues in clinical trials. In confirmatory trials, it is critical to investigate consistency of the treatment effect across subgroups, which could potentially result in incorrect scientific conclusion or regulatory decision. There are many challenges and methodological complications of interpreting subgroup results beyond the regulatory setting. For the early phase or proof of concept trials, particularly in basket trials, it is also important to have reliable estimation of subgroup treatment effect in order to guide the next phase go/no-go decision making when large biases can be introduced due to small sample size or random variability. In this paper, we review several recent methods that have been proposed for subgroup analysis in the Bayesian framework to correct for bias. We present simulation results from applying various novel Bayesian hierarchical models for subgroup analysis to a phase II basket trial. For different scenarios considered, we compare the average total sample size, and frequentist-like operating characteristics of power and familywise type I error rate. We compare the precision of the model estimates of the treatment effect by assessing average relative bias and the width of the 95% credible interval for the bias. We also demonstrate flexible Bayesian hierarchical models in a case study of a phase III oncology trial for subgroup treatment effect estimation to help with regulatory decision making. Finally, we conclude our findings in the discussion section and give recommendations on how these methods could be implemented in confirmatory and early phase clinical trials.