ICH E17 Guideline Sample size allocation to regions should take into consideration patterns of disease prev- alence across regions, the size and expected accrual rate of each region, the intrinsic and extrinsic factors understood (or hypothesized) to influence treatment effects, the preva- lence of those factors in each region and other logistical considerations thought to impact accrual. A regional allocation strategy that balances these considerations will help to ensure that enrolment can be completed in a timely fashion and that the MRCT objectives are met. There is no uniformly acceptable or optimal approach to sample size allocation in an MRCT. Some approaches currently in use include:
1. Proportional Allocation: Allocation of subjects to regions in proportion to size of region and disease prevalence. 2. Equal Allocation: Allocation of equal numbers of subjects to each region. 3. Preservation of Effect: Allocation of subjects to one or more regions based on preserving some specified proportion of the overall treatment effect. 4. Local Significance: Allocation of a sufficient number of subjects to be able to achieve significant results within each region. 5. Fixed Minimum Number: Allocation of a fixed minimum number of subjects to a region.
Proportional allocation facilitates recruitment by allocating subjects to the regions with the greatest disease burden, and absent other impediments, will generally minimize the time needed to complete enrolment. The disadvantage is that some regions may end up with too few or no subjects, while other regions may dominate the outcome of the trial. Equal allocation has the advantage of optimizing the power available to detect differences in treatment effects between regions for a given overall sample size target.
The disad- vantage is that recruitment may be slowed to a possibly unacceptable level, particularly if disease prevalence or ease of recruitment varies substantially among the regions in the MRCT. A balance between proportional and equal allocation is recommended, to ensure that recruitment is feasible and able to be completed in a timely fashion, but also to pro- vide sufficient information to evaluate the drug in its regional context. Allocation to preserve a proportion of the overall effect is not practical if many regions in the trial have this requirement. Allocation based on achieving local significance of 15