Safety or Efficacy

Many participants expressed that there is more willingness to stratify on the basis of pharmacogenetics and pharmacogenomics for safety than for efficacy. For example, it was felt that for a CYP2D6 substrate (confirmed by in vitro and Phase I data), a stratified design in Phase II, with CYP2D6 poor metabolizers (PMs) being randomized to a standard or low dose, was appropriate. The seriousness and consequences of nonresponse or an adverse event and the ethical implications of these outcomes need to be considered. Using pharmacogenetics and pharmacogenomics was suggested as being analogous to the study of patients with reduced renal function. In the case of low creatinine clearance, patients may be excluded from Phase II/3 studies until a small study in the renally impaired population is conducted. Then the Phase II/3 studies may be amended to include such patients, or these patients may continue to be excluded, depending on results of the small study.

11.6.3.2.1 Magnitude of Effect Relative to the Therapeutic Index

If a drug has a narrow therapeutic index, it may be appropriate to stratify on the basis of pharmacogenetics and pharmacogenomics. If the therapeutic index is wide, some large effects may not be important enough to warrant stratification.

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