ICH E17 Guideline this variability. 3. Diet, environmental factors, cultural or socio-economic factors (e.g., contracep- tive use, preferences for a particular route of administration) and access to healthcare may impact trial results. They may also impact recruitment, compli- ance, and study subject retention, and may inform relevant mitigation strategies. 4. Subjects’ responses to different drugs may be more or less sensitive to intrinsic factors, leading to regional variability.
For example, genetic polymorphisms in drug metabolism or receptor sensitivity (described in ICH E5 Appendix D) or body weight and age may impact PK-pharmacodynamics (PD), as well as efficacy and safety of the drug. This applies not only to the investigational drug, but also to comparators and concomitant medications and should be taken into account during planning of MRCTs. Some sensitivity of the treatment effect to intrinsic and/or extrinsic factors may be ex- pected in different regions, but should not preclude consideration of MRCTs. Often, the degree of variability based on the factors mentioned above can be mitigated by proper design and execution of MRCTs.
Providing additional support as needed (e.g., logistical, infrastructure, laboratory) to specific regions or other mitigation strategies should be con- sidered and implemented to reduce variability. However, it is important to consider whether the degree of mitigation may impact the generalizability of the study results. Even with the mitigation strategies described above, regional differences may still exist, and these differences are usually due to underlying intrinsic and extrinsic factors. In this sense, region is an indicator for other, often unknown (or unanticipated) factors causing regional differences in treatment effects.
For this reason, MRCTs are usually stratified by region (see Section 2.2.5). Figure 2 illustrates the way in which intrinsic and/or extrinsic factors such as disease severity (Figure 2a) or ethnicity (Figure 2b) may manifest as re- gional differences in treatment response. However, these factors may explain such ap- parent differences across regions. In Figure 2a, response to treatment increases with dis- ease severity, and disease severity differs by region. This scenario is manifested by ob- served regional differences in response to treatment that are explained by differences in the distribution of the underlying factor (disease severity) among regions.
The same phe- nomenon is illustrated in Figure 2b, where regional differences in response to treatment can be explained by differences in the ethnic distribution of the regions. This type of 8