clinical trials which involve a therapeutic intervention. Furthermore, let me further exclude the issue of fetal toxicity, as this has been well covered in other presentations. My focus, then, is whether exclusion or underrepresentation underrepresentation of women in clinical studies involving therapeutic interventions may lead to negative health consequences for the potential female population to be administered this therapeutic intervention. Although not all therapeutic interventions will be drugs or chemicals, I will focus my remarks in that area since that is my field.
Basically, the question can be rephrased as, "Will differences in drug disposition or drug response due to gender be clinically significant?" My answer is, "Rarely, if ever."
The basis for my negative response concerning the potential for health consequences in women relates to the intersubject and intrasubject variability which patients exhibit in both the pharmacokinetics and pharmacodynamics of drugs. Most drugs on the market today exhibit a wide therapeutic index. That is, major differences exist between the dose, blood concentration, or receptor concentration necessary to achieve a positive therapeutic response versus those measurements which elicit a toxic response. However, there are a number of drugs critical to our therapeutic armamentarium which exhibit a narrow therapeutic index. That is, small changes in dose or concentration can shift a patient from an efficacious state to a toxic condition or to a state where no efficacy is exhibited (corresponding respectively to increases and decreases in dose or concentration from the therapeutic dosage regimen). It is not well recognized that although many drugs exhibit substantial intrasubject, variability as well as marked intersubject variability, all narrow therapeutic index drugs, by definition, must exhibit low intrasubject variability. If this were not true, a patient maintained on a particular dose would experience cycles of efficacy, lack of efficacy, and toxicity during a constant dosage regimen. In fact, if a narrow therapeutic index drug does exhibit high intrasubject variability, such drugs never get past Phase II testing during the drug development Process, since it is not possible to show efficacy for a particular dose (or steady state concentration).
Narrow therapeutic index drugs, however, may and often do exhibit marked interpatient variability and thus these drugs are titrated in the patient by the clinician to the appropriate dose or concentration, which, once achieved, will be maintained owing to the low intrasubject variability of the drug. It is my hypothesis, that the health consequences of exclusion or underrepresentation of women in clinical studies for narrow therapeutic index drugs will be minimal, since it is immaterial whether women differ significantly from men in their pharmacokinetics and/or pharmacodynamics of the drug, since in each case the drug will be titrated by the clinician to the appropriate dose or concentration.
Similarly, there should be few health consequences to large gender differences for wide therapeutic index or range drugs, since the variability inherent in the male population most likely already encompasses the difference