FDA expected to OK N-9 for STD protection
FDA expected to OK N-9 for STD protection
(Editor’s note: Developing an unobtrusive, female-controlled barrier to HIV has become a top priority in AIDS research. In last month’s issue of AIDS Alert, we provided an overview of existing microbicide research. This month’s issue focuses on upcoming labeling changes proposed for spermicides.)
A joint meeting of U.S. Food and Drug Administration advisory committees has recommended that the agency approve nonoxynol-9 (N-9) as prophylaxis for gonorrhea and chlamydia.
The new indication could boost use of N-9 for protection against HIV as well, but researchers won’t know for another month how effective the spermicide is against the virus.
"There was near-unanimity that the data clearly showed that N-9 provided a small but measurable impact on gonorrhea and chlamydia," says Willard Cates, MD, MPH, vice president of biomedical affairs at Family Health International in Durham, NC, and an FDA consultant on spermicides.
The recommendation resulted from a three-day joint meeting of the FDA’s nonprescription drugs, reproductive health drugs, anti-infective drugs, and antiviral drugs advisory committees. The meeting, which was held in late November in Gaithersburg, MD, brought together experts to make research evaluations on spermicides for STD prevention as well as their development as potential topical microbicides to prevent HIV transmission.
N-9 products, which have been sold over the counter for several decades, never have been evaluated for clinical efficacy, either as a contraceptive or a prophylaxis for STDs. N-9 products make no claims against STDs, and as late as last year, the Centers for Disease Control and Prevention was reluctant to recommend N-9 for prophylaxis against chlamydia and gonorrhea. Presented with the most recent data on N-9 studies, including estimates that the product reduces the two STDs by 20% to 40% in the absence of condoms, the committees agreed that the effectiveness was great enough to change the labeling if manufacturers of N-9 ask for that indication.
The committees showed less unanimity over the safety of N-9, due specifically to concerns that high doses and/or high-frequency use of the spermicide have been shown to cause vaginal irritation. Nonetheless, with 40 years of clinical history to weigh in its favor, the committees voted 11 to 8 that safety should not be a major issue in the product labeling, Cates says.
Another issue the committees wrestled with was how to word the labeling in such a way that the new indication would not lead consumers to substitute N-9 for the use of male condoms.
"There was concern about a substitution effect for a less effective method," Cates says, adding that the availability and use of the product would have to be monitored to determine how to best word that message.
The second day of the meeting focused on how much research information would be needed to evaluate the protective effect of spermicides against HIV. The committees agreed that more research was needed before spermicides could be indicated for HIV protection, and cautioned that the recommendation was for gonorrhea and chlamydia only.
"We need to be extremely careful that it [our recommendation] was not made for HIV," says Debra Birnkrant, MD, medical officer for the FDA’s division of antiviral drug products. "We can’t extrapolate from other STDs because transmission is probably different."
In some ways, researchers evaluating spermicide efficacy against HIV face some of the difficulties experienced in early AZT research, she adds.
Two large studies designed to answer the efficacy question were conducted in the late 1980s and came up with conflicting conclusions. The weaknesses of the studies, as well as philosophical differences about how to ethically evaluate spermicides for HIV in clinical trials, caused further delays in evaluating a female-controlled product.
"We have been trying to answer this question for so many years," says Paul Feldblum, PhD, deputy director of the contraceptive use and epidemiology division at Family Health International. "It is unfortunate that the first two human epidemiological studies suffered from weaknesses, and that probably cost us a couple of years."
One of the studies in question, involving sex workers in Kenya, showed higher HIV rates and excessive lesions in women who used N-9 compared to those who did not use it. However, the study had several flaws and its results were questioned. The second study involved women in Cameroon who were given condoms and N-9 suppositories and urged to use both. The study found a strong inverse association between consistency of N-9 use and HIV risk, Feldblum says. The study, conducted by Family Health International, may have suffered from selection bias in that women at higher risk could have reported their use of N-9 or condoms less accurately.
"These are two studies with diametrically opposed results, each of which had its problems," says Feldblum. "They have lead to a condition of what could be called clinical equipoise, which means nobody really knows what is going on."
That situation should change soon with the results of the first randomized controlled trial involving N-9, expected early next year. The study enrolled more than 1,300 sex workers in Cameroon who have been followed for several years. The study group was given a spermicide and male condoms, while the control group was given a placebo and male condoms. The spermicide was a film formulation containing about 70 mg of N-9 per dose.
The study will compare HIV infection rates between the two groups. The women also were given pelvic exams to determine whether N-9 causes irritation of the vagina. "It is possible that it [irritation] could increase the risk of HIV infection, but no one has demonstrated that yet," Feldblum says.
After the study closes at the end of the year, the results will be analyzed and possibly presented at a conference in Washington, DC, in early spring, rather than waiting six months for publication.
"These results have been eagerly awaited," he says. "It has a strong design, it’s extremely large in size, and it has the best counseling, interviewing, and recordkeeping we can do."
Nonetheless, there was discussion at the joint meeting over whether the trial was large enough, considering that the women were urged to use condoms with N-9 and its statistical power depends on the subset of women who failed to use condoms.
While some research experts say a spermicide HIV efficacy trial would need as many as 6,000 women, they acknowledge that finding the funds and resources to conduct such a large trial would be difficult.
50% decrease would justify N-9 labeling
Regardless of its power, the Cameroon trial could set the stage for HIV labeling for N-9. While no one expects that N-9 offers 100% protection against HIV, a significant decrease would warrant labeling changes, Feldblum says. If the Cameroon study shows that N-9 results in a 50% decrease in HIV transmission, it would be hard for the FDA not to recommend N-9 for protection against HIV.
The committees didn’t discuss what protection rates would be acceptable for spermicides to have HIV labeling, but "if it’s truly a 50% reduction, I’m sure that would be acceptable," Birnkrant says.
Whatever their effectiveness, spermicides still would be labeled for use in conjunction with condoms. "This would be in concert with recommendations for using condoms, but we also are seeing how this product might be used as a backup, something that can be used jointly or, if condoms can’t be used, then alone," Feldblum adds.
While the Cameroon study winds down, a similar trial of another N-9 product, Advantage 24, is under way in Africa and Asia. The spermicide, manufactured by Roberts Pharmaceuticals in Toronto, is being tested by the United Nations AIDS program and the National Institutes of Health in Bethesda, MD. Unlike the N-9 product in the Cameroon study, Advantage 24 is formulated with a bioadhesive gel. Results from that study should be known in another year, but researchers are hoping to see at least a 50% decrease in HIV infection, Birnkrant says.
The study is important in light of new findings that different cultures prefer different types of spermicide formulations gels, films, or suppositories. In a study presented at the XI International Confer ence on AIDS in Vancouver, British Columbia, last summer, researchers at the Population Council in New York City reported that women varied by geography and culture in their preference for specific products based on their drying effect, messiness, storage requirements, and pleasure.1
In another spermicide preference study, women ranked films as the most preferred formulation, followed by gels and suppositories. Although most women felt positive about spermicides as a possible microbicide, about 5% reported itching and burning sensations during intercourse.2
"One of the messages coming out of the meeting is that studies on acceptability have shown that the wider the array of methods available for STD/HIV prevention, the more likely that one or more of those methods will be used," Cates says.
Because of the differences in the populations used for the spermicide studies (i.e., sex workers) and the general consumer in the United States, the FDA has concerns about how applicable the results will be. Consequently, it has proposed that research answer that question. Traditionally, the FDA has asked manufacturers to conduct a second efficacy trial to confirm the results of the first one. One possibility discussed at the meeting was allowing only one large efficacy trial, but requiring a second trial on how to introduce the product to a new population.
"We would like some study to link the use to the United States with the results of a clinical trial in a higher-risk population," Birnkrant says.
References
1. Elias C, Coggins C, Atisook R, et al. Women’s preferences regarding the formulation of over-the-counter vaginal spermicides. Presented at the XI International Conference on AIDS. Vancouver; July 1996. Abstract No. Th.C.322.
2. Thongkrajai E, Anusorntheerakul S, Kuchaisit C, et al. A study of the formulation preferences of existing over-the-counter vaginal preparations. Presented at the XI International Conference on AIDS. Vancouver; July 1996. Abstract No. Th.C.4499.
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