Regional consistency evaluation and sample size calculation under two MRCTs

TL;DR

This paper develops a systematic approach for evaluating regional consistency and calculating sample sizes in two MRCTs, aiding drug approval processes and ensuring regional effectiveness evidence.

Contribution

It unifies existing regional consistency evaluation methods, extends criteria for two MRCTs, and provides practical tools including an R package for implementation.

Findings

Proposed regional sample size achieves desired consistency probability

Extended evaluation criteria for two MRCTs are effective

Numerical studies validate the approach

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 effects 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 presented to illustrate the application. We provide an R package for implementation.