Consistency of Treatment Effect Across Regions in Multiregional Clinical Trials, Part 1: Design Considerations.

Assessment of consistency of treatment effect across regions is often a key issue in a multiregional clinical trial (MRCT) because of differences in intrinsic and extrinsic factors. Careful consideration of consistency assessment of treatment effect across regions is necessary at the design stage. This article is part 1 of a cross-industry PhRMA team's effort to provide perspective and recommendations on the issue of regional consistency, with primary focus on design considerations. We argue that given the premise of an MRCT that there is no or limited regional variation, choices of appropriate consistency criteria for assessing regional consistency need to reflect this a priori belief and should not add an additional burden of proving regional consistency in addition to meeting the primary study objectives. The total sample size of the MRCT should be mainly driven by the primary objectives and hypotheses. Appropriate sample size partitioning and distribution across regions may be considered to achieve a target "assurance probability" based upon predefined consistency criteria such as modified PMDA (Pharmaceutical and Medical Devices Agency) methods. Prespecification and documentation of the plan for regional assessment in the protocol are important for interpreting the results. We also encourage communication with health authorities, and acknowledge negotiation may be necessary to reach an agreement, especially when there are region or country-specific interests. [ABSTRACT FROM AUTHOR]