ICH E17 Guideline only for a particular local stakeholder (e.g., regulatory authority), should be described in the protocol. It is in the interest of the sponsor to describe the specific advantages of the investigational drug, in terms of secondary endpoints as precisely as possible during the planning stage of MRCTs, to reduce the need for (and impact of) multiplicity adjustments for multiple endpoints, thereby improving the chance for successfully demonstrating the intended effect. Other Considerations Although endpoints may not require formal validation, some endpoints may be subject to subtle differences in understanding, when used in different cultural settings.
For example, certain types of adverse events may be more sensitively reported (e.g., more or less fre- quently) in some regions than others, resulting in differences in reporting patterns due to cultural variation, rather than true differences in incidence. Use of these variables as endpoints in MRCTs will require careful planning. Approaches to minimise the impact of this variation in data collection and interpretation of the trial results should be described and justified in the study protocol. Endpoints that are only of interest to one or a few regions could be considered for a re- gional sub-trial of the MRCT.
However, care should be taken to ensure that ascertainment of regional sub-trial endpoints do not hamper the conduct of the main trial. In particular, consideration should be given to the impact of additional burden to study subjects and study personnel, and the potential to induce reporting bias with respect to other endpoints, in determining whether regional sub-trials can be conducted or whether a separate trial is needed.
2.2.5 Sample Size Planning General Considerations The key consideration for sample size planning, is ensuring sufficient sample size to be able to evaluate the overall treatment effect, under the assumption that the treatment effect applies to the entire target population, particularly to the regions included in the trial. MRCT offers a unique opportunity to evaluate the extent to which this assumption holds. MRCTs are usually stratified by region for both randomization and analysis. Consistency 13