Sample Size Estimation of Multiregional Clinical Trials with Heterogeneous Variability Across Regions

Abstract

In recent years, global collaboration has become a conventional strategy for new drug development. To accelerate the development process and shorten approval time, the design of multiregional clinical trials (MRCTs) incorporates subjects from many countries around the world under the same protocol. After showing the overall efficacy of a drug in all global regions, one can also simultaneously evaluate the possibility of applying the overall trial results to all regions and subsequently support drug registration in each of them. Several statistical methods have been proposed for the design and evaluation of MRCTs. Most of these approaches, however, assume a common variability of the primary endpoint across regions. In practice, this assumption may not be true, due to differences across regions (e.g., differences in ethnic factors and/or medical culture/practice). In this article, we use a random-effect model for modeling heterogeneous variability across regions for the design and evaluation of MRCTs. We also address consideration on the determination of the number of subjects in a specific region to establish the consistency of treatment effects between the specific region and the entire group.

Key Words:

• Bridging study
• Consistent trend
• Multiregional clinical trial

ACKNOWLEDGMENTS

We thank the two referees for their detailed, constructive, and thoughtful comments and suggestions, which we believe led to a significant improvement to this article.