ICH E17 Guideline Recommended tools, such as validated imaging instruments and measurements of bi- omarkers, should be available, or made available, in all regions when these tools are uti- lised for subject selection. Imaging methods, as well as methods for specimen collection, handling and storage should be clearly defined and standardised across regions to the degree required. 2.2.3 Selection of Doses for Use in Confirmatory MRCTs It is important to execute well-planned early development programmes that include PK and/or PK-PD studies of applicable parameters, in order to identify regional differences which may impact dose selection.
To understand the impact of ethnicity on PK and/or PK-PD, data may be obtained from single-region trials in multiple regions, or a trial with multiple ethnicities conducted in one region. Alternatively, early phase MRCTs may be considered, if they aid in efficiently gathering such data and improve the understanding of regional differences in PK-PD. PK studies should be undertaken in the major ethnic groups most relevant to the regions to be included in MRCTs, if differences are expected that are not yet adequately under- stood (see ICH E5).
Adequate PK comparisons between subpopulations known to be associated with differences in PK will allow for decisions with respect to the need for pharmacodynamic studies and dose-response studies in different regions and/or subpop- ulations. It is encouraged to collect genetic data (e.g., genotypes of drug metabolising enzymes) from subjects enrolled in the early studies to examine the effects of genetic factors on PK and PD. Such early data may provide useful information when determining dosing regi- men(s) for future studies, where subjects with specific genotypes may be considered a subpopulation.
A strategy for dose-selection involving population PK approaches and/or model-based approaches (e.g., exposure-response models) may be useful to identify important factors affecting drug responses in different populations, and to set an appropriate dose range for further dose-response studies. Dose-response studies should cover a broad range of doses and generally include the populations to be enrolled in confirmatory MRCTs. However, 10