Regional consistency assessment in multiregional clinical trials

Abstract

ABSTRACT Multiregional clinical trials (MRCTs) have become a favored strategy for new drug development. The accurate evaluation of treatment effects across different regions is crucial for interpreting the results of MRCTs. Consistency between regional and overall results ensures the extrapolability of the overall conclusions to individual regions. While numerous statistical methods have been proposed for consistency assessment, a notable proportion necessitate a substantial escalation in sample size, particularly in scenarios involving more than four regions within MRCTs. This, paradoxically, undermines the fundamental intent of MRCTs. In addition, standardized statistical criteria for concluding consistency are yet to be established. In this paper, we develop further consistency assessment approaches in the framework of two multivariate likelihood ratio test-based methods, namely mLRTa and mLRTb, wherein consistency is cast as the alternative and null hypotheses. Notably, our exploration unveils that qualitative methods such as the funnel approach and PMDA methods are special instances of mLRTa. Furthermore, our work underscores that these three qualitative methodologies roughly share the same level of assurance probability (AP). Intriguingly, when the number of regions in an MRCT surpasses five, even when the overall sample size guarantees a power of 90% or more and the true treatment effects remain uniform across regions, the AP remains below the 70% mark. Drawing from our meticulous examination of operational attributes, we recommend mLRTa with positive treatment effects in all regions in the alternative hypothesis with significance level 0.5 or mLRTb with all regional treatment effects being equal in the null and significance level of 0.2.