Consistency Assessment and Regional Sample Size Calculation for MRCT Under Random Effects Model

Multi-regional clinical trials (MRCTs) have become common practice for drug development and global registration. Once overall significance is established, demonstrating regional consistency is critical for local health authorities. Methods for evaluating such consistency and calculating regional sample sizes have been proposed based on the fixed effects model using various criteria. To better account for the heterogeneity of treatment effects across regions, the random effects model naturally arises as a more effective alternative for both design and inference. In this paper, we present the design of the overall sample size along with regional sample fractions. We also provide the theoretical properties for assessing consistency probability using Method 1 of Ministry of Health, Labour and Welfare of Japan (MHLW), based on the empirical shrinkage estimator. The latter is then used to determine the regional sample size of interest. We elaborate on the applications to normal, binary, and survival endpoints in detail. Simulation studies show that the proposed method retains the consistency probability at the desired level. We illustrate the application using a real cardiovascular outcome trial in diabetes. An R package is provided for implementation.