Regional consistency evaluation and sample size calculation under two MRCTs

Abstract: Multi-regional clinical trial (MRCT) has been common practice for drug development and global registration. The FDA guidance "Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products Guidance for Industry" (FDA, 2019) requires that substantial evidence of effectiveness of a drug/biologic product to be demonstrated for market approval. In the situations where two pivotal MRCTs are needed to establish effectiveness of a specific indication for a drug or biological product, a systematic approach of consistency evaluation for regional effect is crucial. In this paper, we first present some existing regional consistency evaluations in a unified way that facilitates regional sample size calculation under the simple fixed effect model. Second, we extend the two commonly used consistency assessment criteria of MHLW (2007) in the context of two MRCTs and provide their evaluation and regional sample size calculation. Numerical studies demonstrate the proposed regional sample size attains the desired probability of showing regional consistency. A hypothetical example is provided for illustration of application. We provide an R package for implementation.