ICH E17 Guideline it may not be necessary to obtain PK-PD or dose-response data from subjects in all regions planned to be included in confirmatory MRCTs, if important regional differences in PK and/or PD and dose-response are not anticipated (e.g., response to the drug is unlikely to be sensitive to intrinsic and extrinsic factors) (see ICH E5, appendix D). The acceptability of dose-selection strategies should be discussed in advance with the relevant regulatory authorities. If substantial differences are anticipated (e.g., the drug response is sensitive to intrinsic and/or extrinsic factors), further investigations may be needed.
These could include a PK-PD or dose-response study conducted in a particular ethnic population or studies conducted for a broader population, that would allow further evaluation of the impact of intrinsic and extrinsic factors on dose-response. The dose regimens in confirmatory MRCTs (based on data from studies mentioned above) should in principle be the same in all participating ethnic population.
However, if earlier trial data show a clear difference in dose-response and/or exposure-response relationships for an ethnic population, it may be appropriate to use a different dosing regimen, provided that the regimen is expected to produce similar therapeutic effects with an acceptable safety margin, and provided it is scientifically justified in the study proto- col. Prospective careful planning of assessment strategies where different doses are used should be tailored to each case and described in the analysis plans. 2.2.4 Choice of Endpoints The general principles for endpoint selection and definitions that are provided in ICH E9 apply.
The aspects of particular importance to MRCTs are described here. Primary Endpoint The primary endpoint should be relevant to the target population. In MRCTs, this rele- vance needs to be considered for all regions in the trial and with respect to the various drug, disease and population characteristics represented in those regions (see Section 2.2.1). An ideal clinical trial endpoint is one that is clinically relevant, accepted in med- ical practice (e.g., by regulatory guidance or professional society guidelines) and suffi- ciently sensitive and specific to detect the anticipated effect of the treatment.
For MRCTs, the primary endpoint, whether efficacy or safety, should satisfy these criteria as well as being acceptable to all concerned regulatory authorities, to ensure that interpretation of 11