ICH E17 Guideline 2.2 Clinical Trial Design and Protocol-related Issues 2.2.1 Pre-consideration of Regional Variability and its Potential Impact on Efficacy and Safety At the planning stage, regional variability, the extent to which it can be explained by intrinsic and extrinsic factors, and its potential to influence the study results, should be carefully considered in determining the role MRCTs can play in the drug development strategy. To facilitate taking into consideration differences among regions in intrinsic and extrinsic factors, it is recommended that investigators and experts representing par- ticipating regions are consulted in the planning and design of MRCTs.
The most current and relevant data should be used to understand the potential sources of regional variability (e.g., early trials, previous experience of the drug class). If historical data are used, it should be considered whether these data are still relevant in terms of scientific and methodological validity and in the current treatment context. The magni- tude of such variability could be examined in exploratory studies before the planning and design of confirmatory MRCTs.
The intrinsic and extrinsic factors important to the drug development programme, should be identified during the planning stage of an MRCT, and information about them should be collected during the confirmatory trial for later evaluation of their impact on treatment effects. The ICH E5 guideline describes intrinsic and extrinsic factors, which may affect the treatment effect. In the MRCT setting, the following factors are particularly important and should be considered to identify regions that are suspected to show differences in treatment effects compared to the overall trial results. 1.
Disease definitions, methods of diagnosis and the understanding of certain end- points may vary between regions. These differences could be mitigated by pre- cisely defining inclusion and exclusion criteria as well as study procedures. 2. There may be differences in medical practices and treatments across regions. Such differences may have an impact on the trial results and/or their interpretation. Standardised protocol and training for investigators and study personnel in each region before initiating the trial in that region may reduce some of the impact of 7