Leveraging machine learning: Covariate-adjusted Bayesian adaptive randomization and subgroup discovery in multi-arm survival trials

Abstract

Clinical trials evaluate the safety and efficacy of treatments for specific diseases. Ensuring these studies are well-powered is crucial for identifying superior treatments. With the rise of personalized medicine, treatment efficacy may vary based on biomarker profiles. However, researchers often lack prior knowledge about which biomarkers are linked to varied treatment effects. Fixed or response-adaptive designs may not sufficiently account for heterogeneous patient characteristics, such as genetic diversity, potentially reducing the chance of selecting the optimal treatment for individuals. Recent advances in Bayesian nonparametric modeling pave the way for innovative trial designs that not only maintain robust power but also offer the flexibility to identify subgroups deriving greater benefits from specific treatments. Building on this inspiration, we introduce a Bayesian adaptive design for multi-arm trials focusing on time-to-event endpoints. We introduce a covariate-adjusted response adaptive randomization, updating treatment allocation probabilities grounded on causal effect estimates using a random intercept accelerated failure time BART model. After the trial concludes, we suggest employing a multi-response decision tree to pinpoint subgroups with varying treatment impacts. The performance of our design is then assessed via comprehensive simulations.

Keywords: Adaptive randomization; Bayesian inference; Multi-arm multi-stage trials; Personalized medicine; Subgroup finding.