Selective Information Borrowing for Region-Specific Treatment Effect Inference under Covariate Mismatch in Multi-Regional Clinical Trials

Abstract: Multi-regional clinical trials (MRCTs) are central to global drug development, enabling evaluation of treatment effects across diverse populations. A key challenge is valid and efficient inference for a region-specific estimand when the target region is small and differs from auxiliary regions in baseline covariates or unmeasured factors. We adopt an estimand-based framework and focus on the region-specific average treatment effect (RSATE) in a prespecified target region, which is directly relevant to local regulatory decision-making. Cross-region differences can induce covariate shift, covariate mismatch, and outcome drift, potentially biasing information borrowing and invalidating RSATE inference. To address these issues, we develop a unified causal inference framework with selective information borrowing. First, we introduce an inverse-variance weighting estimator that combines a "small-sample, rich-covariate" target-only estimator with a "large-sample, limited-covariate" full-borrowing doubly robust estimator, maximizing efficiency under no outcome drift. Second, to accommodate outcome drift, we apply conformal prediction to assess patient-level comparability and adaptively select auxiliary-region patients for borrowing. Third, to ensure rigorous finite-sample inference, we employ a conditional randomization test with exact, model-free, selection-aware type I error control. Simulation studies show the proposed estimator improves efficiency, yielding 10-50% reductions in mean squared error and higher power relative to no-borrowing and full-borrowing approaches, while maintaining valid inference across diverse scenarios. An application to the POWER trial further demonstrates improved precision for RSATE estimation.