Community advocates routinely remind clinical trial sponsors how important it is to insure that drugs are studied in women. Trial sponsors routinely say they agree and want to do better as they recite the percentages of women in their studies. The advocates then point out that it is not sufficient to merely increase the representation of women in a study to reflect their proportion of the epidemic. To obtain statistically significant results, there should be enough women enrolled to allow an independent analysis. That's when the meeting peters out.

The representation of women in clinical trials should be increased. Sponsors can start by conducting more trials at sites that treat large numbers of women. If studies continue to run primarily at centers that serve mostly men, then little will change. This may require investment in training and capacity to develop new research sites, but it's a small price to pay if we can better generalize the results. Our commitment to community-based research also needs to be reaffirmed -- even as our expectations for its performance are increased.

But simply (or not so simply) increasing the proportion of women enrolled in trials does not address the call for statistically significant results. The sample sizes of drug efficacy trials are chosen to yield convincing results with the contribution of data from every participant. Unless the study drug is a blockbuster, conclusions that rely on only a subset of the data can never be as sure as those from a full analysis. The only way to have equal confidence in the results for both men and women is to enroll equal numbers of each.

That's not likely to happen. Clinical trials for efficacy are expensive and slow going. Doubling the sample size of a trial will double its cost and probably double the time to get results -- something neither sponsors nor the community want. Still, we need to get better information about the effects of drugs on women. Body weight, hormonal variation, and menstruation are understudied variables. The nature, frequency and severity of toxicities seem to be different for women. Women may typically have lower viral loads than men. Add to these genetic factors and differences in immunological response -- which we understand even less -- and our ignorance seems appalling.

But there are some immediate steps that sponsors can take to start producing improved woman-specific data in two critical areas: pharmacokinetics and safety. Pharmacokinetics (PK) is the study of how a drug is absorbed and distributed as it moves through a body. If women process and eliminate drugs at different rates than men -- and there is evidence that they may -- then women risk inadequate viral suppression (if drug levels are too low) or increased toxicity (if drug levels are too high). Safety studies rely on time and numbers of patients to uncover a drug's side effects. The number of women receiving a new drug and the length of time they are studied need to be increased if we hope to understand a drug's safety profile before it goes to market. Specifically:

• Continue intensive, longer-term PK studies in women after the initial Phase I studies are complete. We need to know about possible dose adjustments before large efficacy trials begin.

• Start expanded access programs early and promote enrollment from sites that treat women in significant numbers. If slots are limited, preferentially enroll women -- expanded access programs are safety studies, too.

• Increase basic science research on all factors affecting drug metabolism in women. Centers of PK studies such as the University of Liverpool, UK should be doing much more.

Efficacy data from HIV drug trials in the U.S. are unlikely to ever provide statistically significant results when stratified for female gender. Industry should take proactive steps to develop supplementary data on two key areas where woman-specific information is lacking: pharmacokinetics and safety. Patients and doctors will have more confidence extrapolating efficacy data to women if there are studies to reassure them that a drug is biologically available and that it is safe.

Back to the GMHC Treatment Issues April 2001 contents page.