Design and Analysis Issues of Multiregional Clinical Trials with Different Regional Primary Endpoints

Abstract

One of the challenges of multiregional drug development program is to design and analyze a multiple regional clinical trial with the objective being to satisfy different regional requirements on primary endpoints. Considered in this article is a multiregional clinical trial (MRCT) designed to test for two primary endpoints. Data of a regular fixed-size well-controlled parallel arm trial are used to test for two null hypotheses in terms of two distinct yet correlated endpoints. The two hypotheses may be tested sequentially or simultaneously. Depending on the structure of the hypotheses to be tested and the understanding of type I error rate control, various scenarios of type I error rate adjustments may be applied. Furthermore, for the objective of getting approval from regional authorities for different primary endpoints, various sample size and power determinations may be applied. In this article, comparisons of different approaches are discussed systematically.

Clinical Development and Initial Approval of Novel Immune Checkpoint Inhibitors in Oncology: Insights From a Global Regulatory Perspective

“…They are conducted to facilitate parallel regulatory submissions and approvals; however, their design, choice of endpoints, and analysis is challenging. [10][11][12][13] In the case of ICI, certain MRCTs served as pivotal clinical trials across the three regions ( Figure 2); for some approvals, different "pivotal" trials were reviewed by the three regulatory agencies. Reasons for the difference in review patterns will be discussed later in this article.…”

“…In today's era of global drug development, pivotal studies are usually planned as multiregional clinical trials (MRCTs). They are conducted to facilitate parallel regulatory submissions and approvals; however, their design, choice of endpoints, and analysis is challenging . In the case of ICI, certain MRCTs served as pivotal clinical trials across the three regions ( Figure ); for some approvals, different “pivotal” trials were reviewed by the three regulatory agencies.…”

Multi-regional clinical trials and global drug development

“…Tsou et al . [ 10 ] have described issues related to design and analysis of the study with the objective to satisfy different regional requirements on primary endpoints.…”

Strategic inclusion of regions in multiregional clinical trials

“…2–6 These include apportioning sample size, with some participating regions even requiring a predefined number or fraction of patients, and using endpoints as well as other trial characteristics that satisfy all participating regulators’ requirements. 7–10 In order to provide guidance in addressing such issues and to increase acceptability of MRCTs in global regulatory submissions, the E17 International Conference on Harmonisation (ICH) guideline on MRCT, “General principles for planning and design of Multi-Regional Clinical Trials” was developed. This was finalized in November 2017.…”