ICH E17 Guideline regional treatment effects is also not practical, as this strategy may inflate the sample size beyond feasibility and brings into question the concept of conducting an MRCT. Allo- cating a fixed minimum sample size for regions is not recommended, if there is no scien- tific justification for selecting the minimum. In practice, sample size allocation deliberations will reflect both scientific and logistical considerations. For example, an initial allocation may be determined that targets the pop- ulation affected by the disease, taking disease prevalence and regional size into account. This initial allocation should ensure that the overall sample size can be achieved.
The allocation would then be modified to reduce any large imbalances in regional sample sizes and to support an evaluation of consistency of treatment effects across regions. This modification could entail pooling some regions (as described below) to provide flexibility in sample size allocation. Minimum regional sample size targets that are scientifically justified could also be taken into consideration at this step. One example would be to specify a minimum sample size to provide meaningful descriptive summaries (e.g., forest plots) with sufficient accuracy and precision.
Alternatively, an equal allocation to regions could be planned as the first step, with mod- ification to better reflect regional sample sizes, disease prevalence and trial logistics at the second step. With either strategy, care should be taken to ensure that no single region or regions dominates enrolment, thereby dominating the trial outcome. Note that the five approaches discussed above are not exhaustive. New approaches for sample size allocation in MRCTs may be developed in the future, and innovation in this area is encouraged.
Pooled Regions and Pooled Subpopulations Pre-specified pooling of regions or subpopulations may help provide flexibility in sample size allocation to regions, facilitate the assessment of consistency in treatment effects across regions, and support regulatory decision-making. For definitions of pooled regions and pooled subpopulations, see 3. Glossary. The pooling strategy should be justified based on the distribution of the intrinsic and extrinsic factors known to affect the treat- ment response, and the disease under investigation and similarity of those factors across 16