ICH E17 Guideline of treatment effects across regions is evaluated, and if clinically relevant differences are observed, there should be further exploration to determine if these differences can be at- tributed to differences in intrinsic or extrinsic factors (see Section 2.2.7). These consid- erations should be reflected in the overall design of the MRCT and will influence the sample size planning and allocation to regions. Overall Sample Size The primary objective of an MRCT generally corresponds to an evaluation (estimation and testing) of the treatment effect averaged across all subjects in all regions of the MRCT.
The overall sample-size is determined to ensure that this objective can be met. Examples of commonly defined treatment effects also used in MRCTs, are hazard ratios for morbidity or mortality, differences between treatment groups in average blood pres- sure levels (adjusted for baseline) and relative risks of either favourable or adverse events. The same general principles provided in ICH E9 for determining sample sizes of clinical trials apply to MRCTs.
Two additional factors are particularly important in the MRCT setting; (i) the size of the treatment effect that is considered clinically relevant to all re- gions in the trial, and (ii) the expected variability of the primary outcome variables based on combining data across regions. These factors may result in a sample size increase for an MRCT compared to a single trial in one region. The extent of this increase will depend on the specific disease and the mechanism of action of the drug, as well as the intrinsic and extrinsic factors and their potential impact on drug response in each region.
Data from early exploratory trials with the investigational drug in relevant populations may inform sample size determination. Sample Size Allocation to Regions The MRCT should be planned to include an evaluation of the consistency of treatment effects among regions, where consistency is defined as a lack of clinically relevant dif- ferences. If clinically relevant differences among regions are observed, then the MRCT provides a unique opportunity for additional learning about the factors that may explain these differences.
Regional allocation should have a scientific basis (rather than arbitrary targets), should support the evaluation of consistency and should provide the information needed to support regulatory decisions. 14