Tibotec's clinical development program for the protease inhibitor darunavir (Prezista, TMC114) delivered the drug to market several months ahead of schedule. But even as it began shipping to pharmacies around the country one nagging uncertainty remained: Would darunavir be safe and effective for women? Few women had enrolled in Tibotec's series of large Phase 3 studies (POWER 1, 2, and 3) that the FDA relied upon to make its approval determination, so consequently there was little information about how well the drug suppressed HIV in women, whether women had any characteristic side effects, and whether the drug was absorbed into the bloodstream the same as in men.

Tibotec was by no means unique in gaining approval for a new drug with only limited data on women. Few drug companies are keen to enroll women in the Phase II studies that precede the large Phase III trials because the risks of toxicity are not yet well established. Women can become pregnant, and because no one wants to expose a developing fetus to unknown risk, women are not often enrolled in drug trials before Phase III. Even then there are many barriers to the full participation of women in drug research. Because Tibotec's POWER studies actually began as a Phase II trial that rolled over into a Phase III trial, it is not surprising that so few women participated in the studies.

There may be many reasons why so few women enter clinical trials. For salvage trials like TORO and POWER, it may be that there are fewer women than men with extensive drug resistance. It's also likely that women with HIV -- who tend to be poor and live in large cities -- have less access to the academic medical centers where so much drug research takes place. It's also likely that women are much more cautious about putting their bodies into the hands of researchers they don't necessarily trust, and that many women's experience with medical professionals has left them wary.

Nevertheless, 35% of the HIV-infected population in the U.S., Canada, Europe, Brazil, and Argentina (all places where darunavir was studied), are women. In many places women make up the majority of people with HIV, yet even in the most successful cases, it is rare for the enrollment of women in an HIV drug trial to exceed 25%

Industry-sponsored HIV drug trials designed and conducted expressly for women have been extremely rare. Recently, however, as one of its post marketing commitments to the FDA, Tibotec launched a new study called GRACE that will by design enroll a majority of women.

The FDA negotiated with Tibotec to "Conduct a study of darunavir/r in treatment-experienced female patients to elucidate any potential gender differences in efficacy and safety" post-approval. GRACE was designed to collect "comprehensive and meaningful" data on the use of darunavir in a racially diverse group of 320 women and 100 men.

Melanie Thompson, founder and principal investigator of the AIDS Research Consortium of Atlanta, is an investigator in GRACE. She thinks that if drug companies want full approval for a new drug, they had better study it in women.

"Specific data on pharmacokinetics, toxicity, and efficacy according to gender should be required by FDA for full licensing of all antiretroviral drugs. A well-managed conditional approval program would assure that studies begin in earlier phases of development for most drugs, and that women are included in higher numbers or in specific women-centered trials earlier. This should be required as part of a phase IIB package for all drugs."

Heidi Nass is a community advocate who works at the University of Wisconsin HIV Clinic and consulted with Tibotec during the design of GRACE: "This trial is poised to show that women can be enrolled and retained in clinical trials when the trials are relevant to their lives and they are given an opportunity to participate. For too long, women in research have been treated like a different species whose needs and wants are so foreign as to be impossible to address. It's about time someone challenged that in a meaningful way."