ABSTRACT
Accurately assessing treatment effects across regions is a fundamental principle when conducting and interpreting the results of multiregional clinical trials (MRCTs). The ICH E17 guideline [ICH, 2017 (International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use)] defines consistency among regions as “a lack of clinically relevant differences.” Most MRCTs are designed in a conventional manner, powered to detect a treatment effect of importance in the full trial population, so it seems somewhat implicit that at the design stage effects were not expected to differ meaningfully across regions. If there were sound reasons to expect a region to show substantially different effects than others, e.g., due to factors relating to genetics, culture, or local medical practice, then it would often make sense to investigate such a region in a separate trial, or at the very least in an expanded trial, sized to allow stand-alone investigation of regions of particular focus. Trials should be conducted in a manner that will minimize the chance of regional heterogeneity; to the extent possible there should be a uniform implementation of inclusion-exclusion criteria, objectively defined and centrally assessed endpoints, identical background therapy, etc.
