Docket Management
Docket: 80N-0280 - Over-the-Counter Vaginal Contraceptive Drug Products Containing Nonoxynol 9; Required Labeling
Comment Number: EC -143

Accepted - Volume 14

Comment Record
Commentor Dr. Willard Cates, Jr. Date/Time 2003-04-16 16:15:57
Organization Family Health International
Category Company

Comments for FDA General
Questions
1. General Comments I am writing to express scientific concerns about the proposed re-labeling change for nonoxynol-9 products. Because of subtleties in wording, the label change as indicated may do more to confuse than illuminate. The wording implies that the data support nonoxynol-9’s causing harm. We are concerned about the effect that such a labeling change would have on the majority of couples at low risk who rely on nonoxynol-9 as a vaginal spermicide for its contraceptive effect, either as a primary method alone or as a supplement to female barrier methods. The proposed re-label wording by the FDA was primarily based on a statement from the World Health Organization about nonoxynol-9 use. We participated in the workshop which prepared the WHO statement and concur that the overwhelming preponderance of data show that nonoxynol-9 (N-9) is NOT effective in preventing acquisition of sexually transmitted infections, including the human immunodeficiency virus. However, evidence of no effect is not evidence of harm. This conclusion about harm has been largely based on a study sponsored by UNAIDS, and reported in the Lancet in the fall 2002 (1). The UNAIDS team found that sex workers using a gel containing N-9 had a higher risk of acquiring HIV than those using the placebo vaginal moisturizer. Using subgroup analysis, the relative risk of HIV acquisition increased with self-reported adherence to the use of either product, thus supporting a causal inference. However, as we have seen with recent VaxGen HIV vaccine reports, subgroup analysis of randomized controlled trials can be misleading, and thus are exploratory at best. A previous FHI study of N-9 film in Cameroon found exactly the opposite in its subgroup analysis, namely those women who reported more frequent use of nonoxynol-9 film had lower rates of HIV (2). However, the main problem is the UNAIDS study’s generalizability. The sex workers averaged 3.6 coital acts a day, with a mean of 70 sexual episodes a month. This is highly atypical sexual activity for the vast majority of women worldwide, and severely limits generalizing the conclusions outside the study. In the US, most women using N-9 products for contraception have characteristics associated with much lower levels of coital activity (3). When the UNAIDS study is viewed in the context of prior data examining N-9 and HIV transmission, no clear evidence of harm emerges. Three previous trials of this chemical, all of which were also conducted in sex workers, have shown conflicting results (4-6). While the four randomized studies of N-9 all had different strengths and weaknesses, taken together they provide a “consistently inconsistent” picture, indicating neither a harmful nor a protective effect. We strongly agree with the proposed message that N-9 does not prevent infection. However, if the proposed re-labeling about potential harm is approved, we believe some clinicians will advise low-risk clients not to use N-9 as an adjunct to diaphragm use. Quite possibly, more unintended pregnancies may result. Until we have further data on the safety of N-9 in low-risk settings, we feel women currently using N-9-containing spermicides for contraceptive purposes should continue to do so. A label change that could be misconstrued is premature at this time. References: 1. Van Damme L, Ramjee G, Alary M et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet 2002; 360(9338):971-7. 2. Feldblum PJ, Weir S, Cates W Jr. The protective effect of condoms and nonoxynol-9 against HIV infection (Letter). Am J Public Health 1999;89:108-109. 3. Piccinino LJ, Mosher WD. Trends in contraceptive use in the United States: 1982-1995. Fam Plann Perspect 1998;30:4-10 + 16. 4. Kreiss J, Ingugi E, Holmes KK, et al. Efficacy of nonoxynol-9 contraceptive sponge use in preventing heterosexual acquisition of HIV in Nairobi prostitutes. JAMA 1992;268:477-482. 5. Roddy RE, Zekeng L, Lyon KA, Tamoufe U, Weir SS, Wong EL. A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases. N Engl J Med 1998;339:504-510. 6. Richardson BA, Lavreys L, Martin HL Jr et al. Evaluation of a low-dose nonoxynol-9 gel for the prevention of sexually transmitted diseases: a randomized clinical trial. Sex Transm Dis 2001; 28(7):394-400.




EC -143