Multi-regional clinical trials (MRCTs) enable efficient global drug development by assessing treatment effects across regions within a single protocol. While powered for overall efficacy, MRCTs are typically not designed to provide confirmatory evidence on regional differences, making an assessment of observed regional heterogeneity largely exploratory and susceptible to sampling variability. Despite this challenge, understanding regional heterogeneity remains important for interpretation and regulatory decision-making. This paper proposes a structured, question-driven framework to guide exploratory assessments of regional heterogeneity in MRCTs. We formulate four key questions to clarify the objectives of such analyses and propose a set of statistical methods to address them. Simulation studies evaluate performance under scenarios with no heterogeneity and heterogeneity driven by observed or unobserved treatment effect modifiers, illustrating how a structured approach can support transparent and cautious interpretation.

翻译：多区域临床试验(MRCTs)通过在单一方案内评估各区域的治疗效应，实现了高效的全球药物开发。虽然MRCTs对整体疗效具有统计功效，但通常并非旨在为区域差异提供确证性证据，这使得对观察到的区域异质性进行的评估在很大程度上属于探索性分析，且易受抽样变异影响。尽管存在这一挑战，理解区域异质性对于结果解读和监管决策仍然至关重要。本文提出一个结构化的、问题驱动的框架，用于指导MRCTs中区域异质性的探索性评估。我们明确了四项关键问题以厘清此类分析的目标，并提出一组统计方法予以应对。模拟研究评估了在无异质性以及异质性由观测到或未观测到的治疗效应修饰因子驱动等场景下的方法表现，阐明了结构化方法如何支持透明且审慎的解读。