ICH E17 Guideline investigation is dependent on appropriate stratification and sample size allocation to re- gions (see Section 2.2.5). Figure 2 . Illustration: primary endpoint modulated by intrinsic and extrinsic factors across regions; (2a) by severity of disease, (2b) by ethnic group. 2.2.2 Subject Selection In MRCTs, subject selection should be carefully considered to better understand and pos- sibly mitigate potential sources of regional variability and their impact on trial results. Clear and specific inclusion and exclusion criteria, that are acceptable and can be applied across regions, should be included in the protocol.
To harmonise subject selection, uniform classification and criteria for diagnosis of the disease or definition of the at-risk population should be implemented, such as the use of relevant guidelines for disease definitions. When diagnostic tools (e.g., biochemical test- ing, genetic testing) are needed for the selection of subjects, these should be clearly spec- ified including the degree to which local validated tools and qualified laboratories may be used.
In particular, when subject selection is based on subjective criteria (e.g., use of symptom scales in rheumatoid arthritis), the same methods (e.g., validated symptom scales and/or scores in the appropriate language) should be used uniformly across regions. Even so, reporting of symptoms may vary by region and may lead to differences in the types of subjects included in the studies. This aspect should be considered in the planning stage, in order to implement training requirements and other strategies for potential miti- gation of the impact. 9