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By Rob Camp

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.

Few Women Enrolled in Recent Clinical Trials

Trial (Drug) Total Enrollment Number of Women Enrolled Number of Women Who Received Test Drug
995 99 (10%) 66 (6.6%)
1159 141 (12.2%) 80 (6.9%)
458 53 (11.6%) 53 (11.6%)
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.”

What Is GRACE?

GRACE is a non-randomized, open-label, multi-center, Phase III trial designed to evaluate efficacy, safety, and tolerability of darunavir/r in a 48-week treatment period. The study will be conducted in the U.S., Puerto Rico, Mexico and Canada, and will enroll 420 persons from 55 sites. The protocol states that 320/420 (70%) subjects enrolled will be women and each GRACE study site will be required to recruit and maintain at least 70% female enrollment. A male subject will not be allowed to enroll unless his addition will not compromise the 70% quota. There will also be race-based quotas, with a 30% cap on the number of white men able to enroll (10% overall), so meaningful comparisons can be made by race as well as sex.

What Will GRACE Tell Us?

The primary objective of the trial is to evaluate sex differences in treatment response — defined as viral load <50 copies/mL — to darunavir/r plus an optimized background regimen (OBT) over a 48-week treatment period. Secondary objectives will determine the change in viral load and in CD4 count; determine the percentage of participants who discontinue due to lack of virologic response or due to an adverse event; evaluate changes in lipid profiles, metabolic parameters and any change in cardiac risk score; and evaluate safety, tolerability, and quality of life. All of these endpoints will be analyzed by sex, as well as by race.

Can I Join?

GRACE requires only that participants have experienced minimal virologic failure (or intolerance) with a prior regimen (either PI- or NNRTI-based). This is not the advanced population for which darunavir/r is currently approved. It is an earlier “second-line” group, and future approval for this indication in this population is dependent on results from GRACE.

Excluded Populations

Women who are pregnant or breast-feeding are excluded from GRACE. Dr. Thompson said, “Although no teratogenicity issues were identified in animal studies, no data have been obtained in pregnant women. The sponsor is considering a PK substudy for women who become pregnant during the trial, but that has yet to be developed.”

What Now?

Details on the GRACE study can be found at The study is currently enrolling, and should report some preliminary data within a year.



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