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.

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

“…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.…”

Statistical implications of extrapolating the overall result to the target region in multi-regional clinical trials

“…The second is, after the overall effect is shown, to evaluate the possibility of applying the overall trial results to each region by checking the consistency of the treatment effect across regions. Hence, an assessment of the consistency of the treatment effect across regions is a key issue in relation to MRCTs (Chen et al, 2010;Liu et al, 2013;Quan et al, 2010aQuan et al, , 2013Tsou et al, 2012;ICH, 2017). Furthermore, it is important to assign a sufficient number of patients to each region in order to evaluate the consistency of the treatment effect across regions (Kawai et al, 2008;Ko et al, 2010;Ikeda and Bretz, 2010;Quan et al, 2010b;Uesaka, 2009;ICH, 2017).…”

“…The challenge is how to utilize the entire dataset to assess individual region effects, and how to leverage the data from outside the local region in a MRCT to make approval decisions in the local region. Therefore, it is very important to analyze MRCTs data from the viewpoint of regional regulatory agencies (Chen et al, 2012a;Tsong et al, 2012;Tsou et al, 2010).…”

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

“…To shorten the time for drug development and regulatory approval, it will be desirable to conduct a trial for simultaneous drug development, submission, and approval in different regulatory regions. Girman et al (2011) and Tsong et al (2012) pointed out the complications of designing a multiregional clinical trial (MRCT) and analyzing data collected in such MRCTs. The regulatory authorities in the two regions may 1052 TSOU ET AL.…”