A Workflow for Evaluating Regional Treatment Effect Heterogeneity in Multi-Regional Clinical Trials

TL;DR

This paper introduces a structured framework with statistical methods for exploring regional treatment effect heterogeneity in multi-regional clinical trials, aiding interpretation and regulatory decisions.

Contribution

It proposes a question-driven approach and statistical tools to assess regional heterogeneity, addressing a gap in current MRCT analysis practices.

Findings

Simulation studies demonstrate the framework's effectiveness in various heterogeneity scenarios.

The approach supports transparent and cautious interpretation of regional differences.

Framework clarifies objectives and guides exploratory analyses in MRCTs.

Abstract

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.