title: Assessment of regional treatment effect in a multiregional clinical trial.
abstract: The 11th question-and-answer document (Q&A) for ICH E5 (1998) was published in 2006. This Q&A describes points to consider for evaluating the possibility of bridging among regions by a multiregional trial. The primary objective of a multiregional bridging trial is to show the overall efficacy of a drug in all participating regions while also evaluating the possibility of applying the overall trial results to each region. To apply the overall results to a specific region, it suggested that the results in that region should be consistent with the overall results. The Japanese Ministry of Health, Labor, and Welfare (MHLW) published the "Basic Principles on Global Clinical Trials" guidance document (2007) and proposed two methods to support the bridging claims. Due to the limited sample sizes allocated to the region, the regular interaction test for treatment by region is not practical. On the other hand, the sample size requirement for the Japanese region as described in Uyama et al. (2005) and Uesaka (2009) is to satisfy an 80% or greater power for the Japanese region, conditioning on the effect of the overall global trial. Quan et al. (2010) further extended the results to trials with various endpoints. Ko, Tsou, Liu and Hsiao (2010) focused on a specific region and established statistical criteria for consistency between the region of interest and overall results. The proposed method was based on the assumption that true effect size is uniform across regions. In this article, we propose to analyze a completed multiregional trial for any specific regional effect by controlling the type I error rate adjusted for the regional sample size and the planned power of the global trial. Accordingly, in order to attain the approval for a specific region, we propose to determine the sample size requirement for the specific regions using the overall power planned and a regional acceptable type I error rate.
authors.affiliation: Office of Biostatistics, CDER , U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tsong
authors.forename: Wan-Jung
authors.initials: WJ
authors.lastname: Chang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Dong
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Tsou
mesh_terms: D000465:Algorithms; D003627:Data Interpretation, Statistical; D005843:Geography; D006801:Humans; D007564:Japan; D015337:Multicenter Studies as Topic / Q000379:methods* / Q000706:statistics & numerical data; D017063:Outcome Assessment, Health Care; D015203:Reproducibility of Results; D012107:Research Design / Q000706:statistics & numerical data*; D018401:Sample Size; D016896:Treatment Outcome