Inference of treatment effect and its regional modifiers using restricted mean survival time in multi-regional clinical trials

Abstract: Multi-regional clinical trials (MRCTs) play an increasingly crucial role in global pharmaceutical development by expediting data gathering and regulatory approval across diverse patient populations. However, differences in recruitment practices and regional demographics often lead to variations in study participant characteristics, potentially biasing treatment effect estimates and undermining treatment effect consistency assessment across regions. To address this challenge, we propose novel estimators and inference methods utilizing inverse probability of sampling and calibration weighting. Our approaches aim to eliminate exogenous regional imbalance while preserving intrinsic differences across regions, such as race and genetic variants. Moreover, time-to-event outcomes in MRCT studies receive limited attention, with existing methodologies primarily focusing on hazard ratios. In this paper, we adopt restricted mean survival time to characterize the treatment effect, offering more straightforward interpretations of treatment effects with fewer assumptions than hazard ratios. Theoretical results are established for the proposed estimators, supported by extensive simulation studies. We illustrate the effectiveness of our methods through a real MRCT case study on acute coronary syndromes.