HHS: Efforts to Research and Inform the Public about Nonoxynol-9 and HIV
Published: 2005-03-31T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: Preventing the transmission of HIV, the virus that causes AIDS, is an important public health challenge. Researchers have sought to develop a microbicide--a substance to help users protect themselves against HIV. In the mid-1980s, researchers found that Nonoxynol-9 (N-9), a spermicide found in various contraceptive products, showed potential as a microbicide. However, more recent studies raised concerns that N-9 may increase certain users' risk of contracting HIV. GAO was asked to describe federal agencies' and contraceptive product manufacturers' actions related to N-9 and HIV. In this report, GAO reviewed (1) the efforts by federal agencies and manufacturers of contraceptive products to assess the safety of N-9 and its effectiveness as a microbicide for preventing HIV transmission and (2) the information provided to the public about the safety of N-9 and its effectiveness as a microbicide. GAO reviewed journal articles, Federal Register notices, product packaging, educational materials, and other documents. GAO also interviewed officials from the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and selected manufacturers of N-9 contraceptive products.
section_title: What GAO Found
paragraphs: Federal agencies have undertaken a variety of efforts to research N-9 as a potential microbicide--including conducting, funding, or reviewing studies on the safety and effectiveness of N-9. In the 1990s, CDC and NIH conducted and funded research on the effectiveness and safety of N-9 as a microbicide to prevent HIV infection. For example, in 1996 CDC and others began a 4-year study on the effectiveness of an N-9 vaginal contraceptive product in preventing the transmission of sexually transmitted diseases, including HIV. The results of the research by the agencies during this period were inconsistent--some research indicated that N-9 reduced the incidence of HIV while other research suggested that frequent use of N-9 may increase the risk of contracting the virus. Then in 2000, the preliminary results of a major clinical study suggested more strongly that N-9 vaginal contraceptive products did not prevent HIV infection and may increase the risk of infection among frequent users. As a result of the study, CDC and NIH stopped conducting and funding research on N-9 as a microbicide out of concern for participants' safety. FDA continued to review available research on the safety of N-9 as part of its regulation of vaginal contraceptive products and, in 2003, proposed new warning labels for N-9 vaginal contraceptive products. As of March 2005, FDA was also in the process of developing a proposal for new warning labels for N-9 condoms. As of that date, FDA had not finalized the new warning labels for N-9 vaginal contraceptive products and had not proposed new warning labels for N-9 condoms. Representatives from two manufacturers of N-9 contraceptive products have reviewed research on N-9's safety for the purpose of commenting on FDA's proposed warning labels. The information CDC and FDA have provided to the public about the use of N-9 as a microbicide has been, at times, inconsistent. In the early 1990s, CDC cautioned that there was insufficient information to conclude that N-9 may prevent HIV transmission. By 1998, in response to new research, the agency informed the public that N-9 vaginal contraceptive products did not prevent HIV. During the same period, FDA also cautioned that N-9 had not been proven to prevent HIV transmission, but in 1999, a brochure posted on its Web site stated that N-9, along with a condom, may be used to prevent HIV transmission. By 2000, CDC had responded to new research findings and had revised its educational publications to state that N-9 may actually increase the risk of contracting HIV when used frequently. In contrast, FDA did not revise the brochure on its Web site that stated that some experts believe N-9 may prevent HIV and suggested using N-9 along with a condom. FDA left this information on its Web site until these statements were deleted in September 2003 when FDA officials realized the information was inconsistent with proposed warning labels. In commenting on a draft of this report, the Department of Health and Human Services (HHS) provided clarification that GAO incorporated where appropriate.

section_title: Letter
paragraphs: Preventing the transmission of HIV, the virus that causes AIDS, is an  important public health challenge.  The Centers for Disease Control and  Prevention (CDC) has reported that an estimated 850,000–950,000 HIV  positive people live in this country, including 180,000–280,000 who do not  know they are infected.
Researchers have sought to develop a microbicide that could be used to  prevent HIV transmission.  If developed, a microbicide could be a topically  applied substance to help users protect themselves against HIV or other  sexually transmitted diseases (STD).  One of the advantages of a  microbicide over other methods of preventing HIV—such as condoms or  mutual monogamy—would be that an individual could use the microbicide  without the cooperation of a sexual partner.
In the mid-1980s researchers found that Nonoxynol-9 (N-9), a widely  available spermicide found in various over-the-counter contraceptive  productsincluding some condoms and certain vaginal contraceptive  products such as foams and gelsshowed promise as a potential  microbicide for STDs, including HIV.  In 1988, the Surgeon General, in  collaboration with CDC, distributed brochures to 107 million U.S.  households that stated that based on laboratory tests, condoms with N-9  may provide additional protection against HIV.  Around this time, it was  also widely reported in newspapers and journals that it was advisable to  use contraceptive products with N-9 because it might help prevent HIV.   However, more recent studies have raised concerns that N-9 vaginal  contraceptive products may not be effective against HIV and may in fact  increase certain users’ risk of contracting the virus.  Public health  organizations have also expressed concerns that consumers may use  condoms lubricated with N-9 (N-9 condoms) for anal intercourse in order  to protect themselves against HIV without knowing the degree to which the  use of such condoms may put them at risk.  Because of the potential risks  involved, the use of N-9 is an important public health issue—one that  involves CDC, the Food and Drug Administration (FDA), and the National  Institutes of Health (NIH) and their research, regulatory actions, or efforts  to educate the public about N-9 and HIV.
You asked us to describe federal agencies’ and contraceptive product  manufacturers’ actions related to N-9 and HIV. This report describes  (1) efforts by federal agencies and manufacturers of contraceptive  products to assess the safety of N-9 and its effectiveness as a microbicide  for preventing HIV transmission, (2) the information federal agencies and  manufacturers of contraceptive products have provided to the public about  the safety of N-9 and its effectiveness as a microbicide, and (3) decisions by  manufacturers and public health organizations that may have affected the  availability of N-9 condoms.
To describe the efforts of federal agencies and manufacturers of  contraceptive products to assess the safety of N-9 and its effectiveness as a  microbicide for preventing HIV transmission, we reviewed reports, journal  articles, Federal Register notices, agency Web sites, and other documents  related to N-9 and HIV.  We interviewed officials from CDC, FDA, and NIH.   We also interviewed officials from the three largest condom manufacturers  in the United States—Armkel, LLC; SSL International; and Ansell Limited— which account for an estimated 98 percent of U.S. condom retail sales; as  well as officials from two manufacturers of other N-9 contraceptive  products—Apothecus Pharmaceutical Corporation and Johnson & Johnson  Consumer Companies, Incorporated. To describe the information federal  agencies and manufacturers of contraceptive products have provided to  the public about the safety of N-9 and its effectiveness as a microbicide, we  reviewed articles, pamphlets, agency and manufacturer Web sites,  manufacturer product packaging, and other educational materials related  to N-9 and HIV.  We also interviewed officials from CDC, FDA, and the  manufacturers of contraceptive products.  Because concerns about the  safety of N-9 in preventing HIV first began to surface around 1990, we  focused our review on efforts to research and provide public information  on N-9 and HIV from 1990 to the present. To describe decisions by  manufacturers and public health organizations that may have affected the  availability of N-9 condoms, we interviewed officials from CDC; FDA; NIH;  three national reproductive health organizations—Planned Parenthood  Federation of America (PPFA), Family Health International, and the Global  Campaign for Microbicides; and the three largest condom manufacturers in  the United States. We also interviewed a researcher who conducted a key  clinical study on N-9 and HIV.  We performed our work from October 2003  through March 2004 and August 2004 through March 2005 in accordance  with generally accepted government auditing standards.
subsections: section_title: Background
paragraphs: N-9 was developed as a contraceptive and is the only spermicide available  in the United States.  It is found in a variety of over-the-counter vaginal  contraceptive products—including creams, foams, gels, and  suppositories—and on N-9 condoms.  Vaginal contraceptive products that  contain N-9 have been sold over-the-counter in the United States for almost  50 years.  N-9 condoms have been available over-the-counter in the United  States since the early 1980s.
subsections: section_title: Federal Agency Responsibilities
paragraphs: Three federal agencies within HHS—CDC, NIH, and FDA—have  responsibilities that affect the public’s use of N-9 contraceptive products.
CDC is responsible for conducting and reviewing research related to public  health issues and disseminating this information to state public health  agencies, medical professionals, and the public.  CDC shares information,  for example, on diseases such as HIV and uses a variety of means to do this,  including publications such as the Morbidity and Mortality Weekly Report  (MMWR) and treatment guidelines.  It also provides information through  its Web site and in letters issued directly to state health departments and  other public health professionals.
NIH, which comprises 27 separate institutes and centers, conducts  research in its own laboratories and funds research in universities, medical  schools, hospitals, and other research institutions.  Some of this research  investigates drugs used to prevent and treat various diseases, including  HIV. In order to provide information to the public on various health issues,  NIH may post the results of its research on its Web site and sometimes  publishes summary reports on various research topics.
FDA is responsible, among other things, for regulating the manufacture and  sale of drugs and medical devices sold in the United States.  FDA also  regulates the labeling information provided by manufacturers of drugs and  medical devices.  FDA also seeks to educate the public about the products  it regulates and uses a variety of means, including pamphlets, Web site  information, and the FDA Consumer magazine to do this.  Within FDA,  two centers are involved in the review of N-9 contraceptive products—the   Center for Drug Evaluation and Research (CDER), which oversees vaginal  contraceptive drug products, and the Center for Devices and Radiological  Health (CDRH), which oversees condoms, including N-9 condoms.
FDA reviews the active ingredients in specific categories of drugs that were  sold over-the-counter in the United States prior to 1975 through a process  known as the “monograph process.”  Under the monograph process, FDA  establishes the conditions under which specific categories of drugs, rather  than specific products, are generally recognized as safe and effective and  not misbranded.  Examples of categories of drugs subject to the  monograph process include antacids and certain cold and cough remedies.  When FDA completes the monograph process, it issues a final monograph  that describes labeling indications, warnings, and directions for use, among  other things.  Prior to the issuance of a final monograph, FDA policies  allow over-the-counter drugs to stay on the market.  However, FDA may  pursue regulatory actions against these drugs—such as requiring labeling  changes—if the agency determines that the failure to act poses a potential  health hazard to consumers.
Since N-9 was available over-the-counter prior to 1975, it is the subject of a  monograph review for a category of drugs called vaginal contraceptive  drug products.  As of March 2005, FDA had not issued a final monograph  for this category of drugs.   Although some condoms on the market are  lubricated with N-9, these N-9 condoms are not subject to the monograph  review process for vaginal contraceptive products because FDA regulates  these products as medical devices.
section_title: Federal Agencies Have Researched the Safety and Effectiveness of N-9 as a Microbicide, While Manufacturers Reviewed Its Safety
paragraphs: Federal agencies have undertaken a variety of efforts to research the safety  and effectiveness of N-9 as a microbicide.  This research included funding,  conducting, or reviewing studies on the safety and effectiveness of N-9 as a  microbicide.  It was largely conducted until 2000, when the preliminary  results of a major clinical study prompted CDC and NIH to halt further  research on N-9 as a microbicide because of safety concerns.  FDA—as  part of its regulation of vaginal contraceptive products—continued to  review research on the safety of N-9 and proposed new warning labels for  vaginal contraceptive products in 2003.  Manufacturers reviewed the safety  of N-9 for the purpose of commenting on the proposed warning labels.
subsections: section_title: Federal Agencies Researched the Safety and Effectiveness of N-9 as a Microbicide until 2000
paragraphs: During the 1990s, three federal agencies—CDC, NIH, and FDA—funded,  conducted, or reviewed medical research to determine whether N-9 was  safe and effective as a microbicide.  CDC, as part of its public health efforts  to prevent the spread of HIV, conducted and funded research involving N-9.   For example, in 1996, CDC and others began a major 4-year study on the  effectiveness of N-9 vaginal contraceptive products in preventing the  transmission of STDs, including HIV, among female sex workers located in  four countries.  In addition, CDC compiled a bibliography of research on  potential microbicides conducted through September 1996.  Containing  abstracts of over 55 safety and effectiveness studies and other reviews of  N-9 vaginal contraceptive products and N-9 condoms, the bibliography was  intended as a resource for clinicians, researchers, and public health  specialists interested in microbicide research.
Like CDC, NIH conducted and funded research during the 1990s on N-9’s  safety and effectiveness as a microbicide.  Within NIH, two institutes were  primarily responsible for most of its N-9 research—the National Institute of  Allergy and Infectious Diseases and the National Institute of Child Health  and Human Development. NIH’s research ranged from laboratory studies of N-9’s effect on animal tissue to randomized clinical trials that measured the  effect of various N-9 vaginal contraceptive products in preventing HIV  transmission among women.
Although the FDA did not conduct or fund research on N-9, the agency  reviewed research on N-9 vaginal contraceptive products as part of its  monograph process.  The agency convened an advisory committee meeting  in 1996 to review available research on the safety and effectiveness of N-9  as both a contraceptive and a microbicide.  This meeting included  presentations on a wide variety of published and unpublished research,  including laboratory studies of N-9 and clinical studies on N-9 vaginal  contraceptive products.  The meeting also included discussion about the  implications of this research and identified guidelines for the design of  future studies to address concerns about dosage and formulation  differences in the research available at the time, among other things.
The results of the research on N-9 that federal agencies conducted, funded,  and reviewed during the 1990s were inconsistent.  For example, among the  studies compiled in CDC’s bibliography on microbicide research, some  found that the use of N-9 vaginal contraceptives reduced the incidence of  HIV as well as other STDs, while other studies indicated that frequent use  of N-9 vaginal contraceptives may have irritated subjects’ vaginal tissue,  which may result in subjects being more susceptible to HIV infection.   Throughout the 1990s, various reviews in clinical journals also  characterized the results of research on N-9 as inconsistent.  For example,  a 1995 review in the journal AIDS noted the existence of “substantially different opinions” about the safety and effectiveness of N-9 when used for  HIV prevention.  Similarly, a 1999 commentary in the American Journal  of Public Health noted that epidemiologic studies on N-9 were conflicting.
During the 1990s, reviewers of studies involving N-9 observed that several  factors may have accounted for the inconsistency of the research results.   For example, studies varied in terms of the dosage of N-9 and the chemical  formulation of the contraceptive product used.  Additionally, the  different populations studied may have affected the outcomes of the  research.  For example, some studies were based on the experience of sex  workers, who used N-9 vaginal contraceptive products with relatively  higher frequency than the populations in other studies.  Studies were also  not always comparable to the extent that they varied in their sample sizes.
In 2000, after the preliminary results of a major clinical study—known as  the COL-1492 study—were reported, CDC and NIH stopped conducting and  funding research on N-9 as a microbicide out of concern for participants’  safety.  Compared to the results of earlier studies, the preliminary results  of the COL-1492 study suggested more strongly that N-9 did not prevent  HIV infection and, in addition, that N-9 may increase the risk of infection  among frequent users.  The COL-1492 study compared the use of an N-9  vaginal contraceptive gel called COL-1492 to a vaginal moisturizer without  N-9 among 892 sex workers in Benin, Cote d’Ivoire, South Africa, and  Thailand.  The preliminary results of this study indicated that the incidence  of HIV infection among users of the N-9 vaginal contraceptive gel was 48  percent higher than among users of the moisturizer without N-9.  Moreover,  the study showed there was little effect of N-9 vaginal contraceptive use on  the incidence of certain other STD infections, such as gonorrhea and  chlamydia.  After the preliminary results of the COL-1492 study became  available, officials at CDC and NIH decided to discontinue researching N-9  as a possible microbicide for HIV.
section_title: After 2000, FDA Continued to Review Research on the Safety of N-9 as Part of Its Regulation of N-9 Contraceptive Products
paragraphs: Although federal agencies stopped conducting and funding research on N-9  as a potential microbicide in 2000, FDA continued to review research on  the safety of N-9 as part of the agency’s regulation of vaginal contraceptive  products under the monograph process. During this review, FDA  considered, among other things, the recommendations of two key public  health reports, published in 2002 by CDC and by the World Health  Organization (WHO) in collaboration with the CONRAD Program.  The  reports recommended that N-9 not be used to prevent HIV transmission  and warned that frequent use of N-9 vaginal contraceptive products may  cause genital lesions, which may increase the risk of HIV infection in  persons at high risk for HIV. The reports also recommended that N-9  condoms not be promoted because there was no published scientific  evidence that N-9-lubricated condoms provide any additional protection  against STDs compared with other condoms.  The reports also  recommended that N-9 contraceptive products, including both N-9  condoms and vaginal contraceptive products, should not be used during  anal intercourse.   The WHO/CONRAD report concluded that for women at  low risk for HIV infection, the use of N-9 vaginal contraceptives remained a  viable option.
Based on its review of this and other information, including the published  results of the COL-1492 study, FDA determined that the use of N-9 vaginal  contraceptive products may pose a potential health hazard to consumers  and proposed new warning labels for N-9 vaginal contraceptive products in  January 2003.  Specifically, FDA proposed adding warning labels that  indicate that vaginal contraceptive products with N-9 do not protect against  HIV or other STDs and that frequent use, such as more than once a day, of  N-9 can increase vaginal irritation, which may increase the risk of  contracting HIV from infected partners.  The proposed warnings also  indicate that the labeled products are for vaginal use only.
As of March 2005, FDA was in the process of finalizing the rule for new  warning labels for vaginal contraceptive products containing N-9.   According to FDA officials, a draft of the final rule had been completed,  and the rule had begun the clearance process within HHS.  Officials told us  that they expected the clearance process to be completed by September  2005, after which the final rule would be published.  According to FDA  officials, the rule-making process used to establish new warning labels  typically takes more than 2 years.
As part of the process for establishing new warning labels for N-9 vaginal  contraceptive products, FDA reviewed more than 150 comments submitted  in response to the proposed warning labels.  These comments ranged from  concerns that the proposed language was not strong or specific enough to  comments indicating that FDA had gone too far in its proposed warning.    FDA officials also stated that 10 specific issues brought up in the public  comments on the proposed warning labels required extensive review,  including comments that the labels should specifically warn against using  vaginal contraceptive products for anal intercourse and concerns that the  proposed warning labels might discourage women who are at low risk for  HIV from using N-9 as a contraceptive.
FDA officials told us they also plan to issue guidance and proposed new  warning labels for condoms—including warnings for N-9 condoms.  They  said they expect a draft to be issued for public comment in 2005.  These  officials noted that they considered new warning labels for N-9 condoms in  the context of a larger initiative started in 2001 to review condom labeling  for medical accuracy with respect to the overall effectiveness of condoms  against STDs.  FDA officials told us that officials from CDRH and CDER  collaborated to ensure that the new labeling proposals for N-9 condoms  and N-9 vaginal contraceptive products will be consistent.  As of March  2005, an HHS official told us that HHS had completed its review of the draft  guidance and labels.  After this review, FDA officials told us the draft would  be sent to the Office of Management and Budget for review before being  issued for public comment.  FDA officials said that FDA expects to be able  to issue the draft guidance and condom warning labels by May 2005.
section_title: Manufacturers of N-9 Contraceptive Products Have Researched the Safety of N-9
paragraphs: Two manufacturers of N-9 contraceptive products that we interviewed  have researched the safety of N-9.  Specifically, they reviewed the research  literature on the safety of N-9 in order to prepare comments in response to  the language of FDA’s proposed warning labels for vaginal contraceptive  products.  For example, one manufacturer concluded that FDA’s proposed  labeling—that implied a link between the use of N-9 vaginal contraceptive  products and an increased risk of HIV transmission—was not sufficiently  supported by the scientific literature.  However, no manufacturers we  interviewed have conducted research on N-9’s effectiveness as a  microbicide.  Manufacturers would only be required to conduct such  research if they were to seek approval from FDA to use N-9 vaginal  contraceptives for a new indication—such as HIV prevention.  However,  FDA officials reported that no manufacturers sought approval for a new  indication for N-9.
section_title: The Information Provided to the Public about the Use of N-9 as a Microbicide Has Been, at Times, Inconsistent
paragraphs: The information CDC and FDA provided the public about the use of N-9 as  a microbicide has been, at times, inconsistent.  In the early 1990s, CDC  cautioned that there was insufficient information to conclude that N-9 may  prevent HIV transmission. By 1998, in response to new research, CDC  informed the public that N-9 vaginal contraceptive products did not prevent  HIV.  During the same period, FDA also cautioned that N-9 had not been  proven to prevent HIV transmission, but in 1999, a brochure on its Web site  stated that N-9, along with a condom, may be used to prevent HIV  transmission.  By 2000, CDC stated that N-9 may actually increase the risk  of contracting HIV when used frequently.  FDA, in contrast, did not revise  the brochure on its Web site that stated some experts believe N-9 may  prevent HIV and suggested using N-9 along with a condom.   Some  manufacturers we interviewed have also taken steps to inform the public  about N-9 and HIV, while others have not.  (See app. I for a timeline of  selected events and publications related to N-9’s potential use as a  microbicide.)
subsections: section_title: At Times, CDC and FDA Provided Inconsistent Information about the Use of N-9 to Prevent HIV
paragraphs: In the early 1990s, based on the information that was available at the time,  CDC cautioned that there was insufficient information to conclude that N-9  may prevent HIV transmission.  According to CDC’s 1993 STD treatment  guidelines, “protection of women against HIV infection should not be  assumed from the use of vaginal spermicides, vaginal sponges, or  diaphragms.”  This document also stated, “No data exist to indicate that  condoms lubricated with spermicides are more effective than other  lubricated condoms in protecting against the transmission of HIV  infection….”  This document recommended the use of condoms, with or  without a spermicide in order to protect against STDs, including HIV.   Similarly, an article in a 1993 issue of CDC’s MMWR cautioned that there  was no evidence that N-9 prevents HIV transmission.  According to this  issue of MMWR, “No reports indicate that nonoxynol-9 used alone without  condoms is effective for preventing sexual transmission of HIV.”  This  document also repeated the recommendation to use condoms with or  without a spermicide.
By 1998, in response to new research, CDC informed the public that N-9  should not be used as a microbicide because it does not protect against HIV  and revised its STD treatment guidelines to state that “vaginal spermicides  offer no protection against HIV infection, and spermicides are not  recommended for HIV prevention.”  At this time, CDC did not revise its  recommendation to use condoms with or without spermicide.
FDA’s educational publications during the 1990s also cautioned that N-9  had not been proven to prevent HIV transmission, but in some cases, the  agency suggested that N-9, along with a condom, may be used to prevent  HIV transmission.  For example, a 1990 article published in the magazine  FDA Consumer stated, “Although it has not been scientifically proven, it is  possible that Nonoxynol-9 may reduce the risk of transmission of the AIDS  virus during intercourse as well.  Using a spermicide along with a latex  condom is therefore advisable, and is an added precaution in case the  condom breaks…. Some experts think that even if a condom with  spermicide is used, additional spermicide in the form of a jelly, cream or  foam should be added.”  In 1998, an FDA Consumer article stated that N-9  may reduce the risk of transmitting certain STDs, but cautioned that it has  not been proven to prevent sexual transmission of HIV.  Another 1998  FDA Consumer article stated that spermicides alone do not give adequate  protection against HIV.  However, in 1999, FDA indicated to the public  that N-9 may protect them against HIV transmission.  An FDA brochure  posted to the Web site and titled Condoms and Sexually Transmitted  Diseases…Especially AIDS stated, “Some experts believe nonoxynol-9  may kill the AIDS virus during intercourse, too.  So you might want to use a  spermicide along with a latex condom as an added precaution….”
In response to the preliminary results of the COL-1492 study that were  released at the 2000 International AIDS Conference, CDC revised its earlier  position on N-9.  CDC had previously cautioned that N-9 used alone without  a condom offered no protection against HIV infection and was not  recommended for HIV prevention.  However, by 2000 CDC’s educational  publications had included the statement that N-9 may increase the risk of  transmission when used frequently.  In an August 2000 letter to health care  providers and public health personnel, CDC reported that the preliminary  results of the COL-1492 study demonstrated that N-9 did not protect against  HIV infection and may have caused more transmission.  This letter also  stated that N-9 should not be recommended as an effective means of HIV  prevention and that the use of N-9 for HIV prevention may be harmful to  certain users.  This warning was also published in an August 2000 issue of  MMWR.  Similarly, in 2002 when CDC revised its STD treatment  guidelines, it included information indicating that spermicides containing  N-9 were not effective in preventing HIV infection and that frequent use had  been associated with genital lesions, which may be associated with an  increased risk of HIV transmission.  These revised STD treatment  guidelines further stated that condoms lubricated with spermicides are no  more effective than other lubricated condoms in preventing HIV  transmission, and also stated that “purchase of any additional condoms  lubricated with the spermicide N-9 is not recommended.”  This  information also appeared in an article in a May 2002 issue of MMWR.
While CDC was informing the public that N-9 was not effective in  preventing HIV and that frequent use of N-9 may increase the risk of HIV  transmission, the public would have obtained different information from  FDA.  An FDA official told us that the agency has not disseminated any new  educational materials related to N-9 and HIV transmission since 2000.   However, FDA left its brochurewhich stated that some experts believe  that N-9 may prevent HIV transmissionon its Web site until this  information was deleted in September 2003 when FDA officials realized the  information in the brochure on the Web site was inconsistent with the  proposed warning labels for N-9 vaginal contraceptive products.   According to one FDA official, documents on the agency’s Web site were  updated in an “ad hoc” manner, rather than through an official process.
section_title: Some Manufacturers Have Taken Steps to Inform Consumers about N-9 and HIV
paragraphs: The three largest condom manufacturers have taken steps to inform the  public about N-9 and HIV.  In particular, one condom manufacturer has  taken multiple steps to inform its consumers that N-9 does not prevent HIV  transmission and may increase some users’ risk of contracting HIV.  This  large manufacturer of condoms has added warning labels to N-9 condom  packaging that indicate that N-9 is not effective in protecting against HIV.  This manufacturer has also published pamphlets and used similar language  on its Web site to explain to consumers the risks associated with N-9.  In  addition, two other large manufacturers of condoms added warnings to  their Web sites about the use of N-9.  In contrast, officials from major  manufacturers of vaginal contraceptive products that we interviewed told  us they have not disseminated such information.  One of these  manufacturers reported that its review of research on N-9 suggested that  the link between the use of N-9 and an increased risk of HIV infection was  speculation.
section_title: Some Manufacturers and Public Health Organizations Have Stopped Producing and Distributing N-9 Condoms
paragraphs: In recent years, there have been several changes in the production,  distribution, and promotion of N-9 condoms.  In January 2004, the condom  manufacturer SSL International announced that it was halting production  of its Durex brand condoms that are lubricated with N-9 because of a  decrease in sales to public health agencies and because of an anticipated  decrease in retail sales.  SSL International representatives attributed this  decrease in sales to safety concerns raised by the 2002 release of the  WHO/CONRAD report.  Another large manufacturer of condoms reported  that the percentage of N-9 condoms sold on the retail market declined from  2000 to 2003.
Like SSL International, PPFA and a leading distributor—Mayer  Laboratories—have also stopped manufacturing and distributing N-9  condoms.  A representative from PPFA told us that the organization  stopped manufacturing N-9 condoms in June 2002 because of safety  concerns based on published scientific studies indicating that N-9 does not  protect against HIV and that frequent N-9 use may actually increase HIV  transmission.  In addition, a representative from PPFA stated that its  decision to halt production of N-9 condoms was influenced by the release  of the conclusions of the WHO/CONRAD report and the outcome of a  meeting with public health entities organized by the Global Campaign for  Microbicides.  Another public health organization, the Gay Men’s Health  Clinic in New York, has also begun to recommend that clients not use N-9  condoms.  As of early in 2003, a distributor—Mayer Laboratories—stopped  distributing N-9 condoms.  Information from Mayer Laboratories stated  that this decision was based on a concern about the safety of N-9 condoms.
section_title: Concluding Observations
paragraphs: CDC’s and NIH’s efforts to research N-9’s potential use as a microbicide  ended in 2000, when the preliminary results of a major clinical trial  indicated that N-9 may actually increase the risk of contracting HIV.  CDC  has warned that N-9 may increase the risk of HIV transmission when used  frequently, and some manufacturers of N-9 condoms have taken steps to  either add their own warning labels or remove their N-9 condoms from the  market, while other manufacturers have not taken such steps.  FDA has  proposed requiring new warning labels that indicate that N-9 vaginal  contraceptive products do not protect against HIV or other STDs and that  frequent use, such as more than once a day, may increase the risk of  contracting HIV.  FDA is also developing proposed warning labels for N-9  condoms.  While FDA expects to issue the final rule for the new warning  labels for vaginal contraceptive products by September 2005, it has not yet  issued proposed warning labels for N-9 condoms, and it has not indicated a  target date to issue the final warning labels for N-9 condoms.  Since FDA is  still in the process of completing warning label changes for N-9 vaginal  contraceptive products and condoms, the public may be left in doubt about  the appropriate uses of these products until FDA finalizes these warnings.   Further, the public may be at risk if the products are used inappropriately.
section_title: Agency Comments
paragraphs: HHS provided written comments on a draft of this report. (See app. II).
In its written comments, HHS stated that the final sentence in the draft  report—that said the public may be at risk until FDA finalizes the warning  labels for N-9 vaginal contraceptive products and N-9 condoms—may  unintentionally undermine efforts to inform the public of the protection  provided by condoms.  HHS suggested we modify this to say that  consumers may be left in doubt about the appropriate uses of these  products.  We have revised the conclusion to acknowledge that until FDA  finalizes its warning labels, consumers may be left in doubt about the  appropriate uses of these products.  However, the conclusion also states  that the public may be at risk if the products are used inappropriately.
In its written comments, HHS stated that the draft did not indicate that  FDA had never permitted condom labeling to claim that N-9 provides any  additional protection against HIV or other STDs.  To ensure clarity on this  issue, we have added this statement to the report.  HHS’s written comments  also stated that it is important to make clear that the barrier features of  condoms provide the primary protection against STDs and the primary  contraceptive protection.  While this is an important fact in educating  consumers about methods to protect themselves against STDs, the  objectives of this report were focused on N-9 and its potential as a  microbicide.
HHS’s written comments also stated that FDA’s primary means of public  health communication is through product labeling oversight and that FDA  has, on occasion, provided supplementary information through consumer  outreach efforts.  The draft report noted the role FDA has in labeling  oversight and described FDA’s proposed warning labels for N-9 vaginal  contraceptive products and its efforts to develop proposed warning labels  for N-9 condoms.  The draft report also described the information FDA  provided to the public through a brochure that it posted to its Web site and  through FDA Consumer magazine articles.  HHS’s written comments also  stated that the supplementary statements FDA provided to the public  through consumer outreach efforts always acknowledged the scientific  uncertainty concerning the effectiveness of N-9 as a protection against  STDs.  Examples of FDA’s acknowledgement of scientific uncertainty were  provided in the draft report.
HHS also commented that the timeline in appendix I should begin with the  1988 CDC brochure Understanding AIDS, which advised that N-9, when  used with a condom, might provide additional protection against HIV.  We  mentioned this brochure in the introduction to the draft report when we  stated that in the mid-1980s N-9 showed promise as a potential microbicide  for STDs, including HIV.  However, as we stated in the scope and  methodology section of the draft report, we focused our review on efforts  to research and provide public information on N-9 and HIV from 1990 to the  present because concerns about the safety of N-9 in preventing HIV first  began to surface in about 1990.  Further, HHS commented that the timeline  should make clear that the first indication that N-9 presented added risks  did not emerge until 2000 (the COL-1492 study).  However, this study was  not the first indication that N-9 presented added risks, and the draft report  discussed earlier concerns.
HHS’s written comments also made a number of other suggestions to  clarify the draft report, which we incorporated.  First, HHS suggested that  we clearly indicate in the report when we are discussing vaginal  contraceptive products containing N-9, condoms with N-9, or both.  We  have reviewed the report for clarity and made changes where necessary.   Second, HHS’s comments stated that much of the research discussed in the  report was restricted to vaginal contraceptive products and that these  studies did not involve N-9 condoms.  We have clarified this point in the  report.  Finally, HHS’s comments stated that the 1999 FDA brochure  Condoms and Sexually Transmitted Diseases . . . Especially AIDS was an  Internet posting of a brochure initially issued in 1990. We clarified the text  of our report to note that the Web site posting was of a brochure originally  issued in 1990 and that the document stated the information was current as  of December 2, 1999.  We also added the 1990 brochure to the timeline in  appendix I.
HHS included several other comments.  First, HHS stated that we should be  clear that N-9 condoms are regulated as medical devices not through the  monograph process.  This information was discussed in the background  section of the draft report.  Second, HHS’s written comments stated that  the report should recognize that some manufacturers stopped selling  condoms with N-9 because of economic considerations and not safety  concerns.  This information was included in the draft report and we noted  further that one manufacturer attributed the decrease in sales of N-9  condoms to the safety concerns raised by the 2002 release of the  WHO/CONDRAD report.  Third, HHS raised concerns that the draft report  had not explained the significance of the actions of manufacturers.  This  information was included in the draft report.  Finally, HHS’s comments said  we should note that the report on the COL-1492 study was published in  2002 and the information available prior to that time could be considered  only preliminary.  This information was also reflected in the draft report  and in the timeline in appendix I.
HHS’s comments are reprinted in appendix II.  HHS also provided technical  comments, which we incorporated into the report as appropriate.
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section_title: Timeline of Selected Events and Publications Related to N-9’s Potential Use as a Microbicide, 1990–2004
paragraphs: 1990: An FDA brochure, Condoms and STDs. . .  Especially AIDS, stated that “Some experts  believe nonoxynol-9 may kill the AIDS virus  during intercourse, too. So you might want to use  a spermicide along with a latex condom as an  added precaution. . . .” s 0 9 9 1 1998: An FDA Consumer magazine article, “On  the Teen Scene: Preventing STDs,” stated that   “... spermicides alone ... do not give adequate  protection against HIV and other STDs.”
subsections: section_title: 1990: An FDA Consumer magazine article, “Latex Condoms Lessen the Risk of STDs,” stated that “Although it has not been scientifically proven, it is possible that nonoxynol-9 may reduce the risk of transmission of the AIDS virus during intercourse. . . .”
paragraphs: 1999: An FDA brochure on its Web site and   titled Condoms and STDs... Especially AIDS  continued to include the statement “Some  experts believe nonoxynol-9 may kill the AIDS  virus during intercourse, too. So you might want  to use a spermicide along with a latex condom  as an added precaution....”
2002: CDC’s 2002 STD treatment guidelines  stated that “Recent evidence has indicated that  vaginal spermicides containing nonoxynol-9 (N- 9) are not effective in preventing . . . HIV infection.  Thus, spermicides alone are not recommended  for STD/HIV prevention. Frequent use of sperm- icides containing N-9 . . . may be associated with  an increased risk of HIV transmission . . . .  Purchase of any additional condoms lubricated  with the spermicide N-9 is not recommended. . . .”
1993: “CDC Update: Barrier Protection Against  HIV Infection and Other Sexually Transmitted  Diseases” in MMWR stated that “No reports  indicate that nonoxynol-9 used alone without  condoms is effective for preventing sexual  transmission of HIV.. . . No data exist to indicate  that condoms lubricated with spermicides are  more effective than other lubricated condoms in  protecting against the transmission of HIV  infection.... Therefore, latex condoms with or  without spermicides are recommended.” s 0 0 0 2 2000: Preliminary results of a major clinical study  among high-risk female sex workers were  presented at the International AIDS conference  in Durban, South Africa. The results indicate that  N-9 is not effective as a microbicide against HIV  and may increase certain users’ risk of  contracting the virus.
2002: WHO and CONRAD published the  summary report of their consultation on the  available literature regarding N-9’s safety and  effectiveness as a spermicide and a microbicide. 2002: PPFA halted production and distribution   of N-9 condoms. 2003: Mayer Laboratories halted distribution of  N-9 condoms.
2000: NIH and CDC reported that the agencies  halted all studies actively pursuing N-9’s use as   a microbicide between 2000 and 2001.
1993: CDC’s 1993 STD treatment guidelines  stated that “protection of women against HIV  infection should not be assumed from the use   of vaginal spermicides, vaginal sponges, or  diaphragms.”
2000: A CDC letter issued to health care  providers and public health personnel stated that  because N-9 has been shown to be ineffective  against HIV and may increase HIV risk among  certain user groups, N-9 should not be  recommended for HIV prevention.
2003: FDA proposed warning labels for vaginal  contraceptive drug product packaging. The  proposed warning stated that vaginal contra- ceptive products with N-9 do not protect against  HIV or other STDs and that frequent use of   N-9 can increase vaginal irritation, which may  increase the risk of contracting HIV or other  STDs. The warnings also indicated that the  labeled products were for vaginal use only.
1997: CDC publication What We Know About  Nonoxynol-9 for HIV and STD Prevention stated  that “CDC does not recommend using  spermicide alone to prevent HIV infection.”
2001: WHO, in collaboration with CONRAD,  convened a meeting to review the available  literature regarding N-9’s safety and effect- iveness as a spermicide and a microbicide.
2004: SSL International halted production of its  Durex brand condoms that were lubricated with   N-9 because of a decrease in sales to public  health outlets and a projected decrease in   retail sales.
1998: CDC’s 1998 STD treatment guidelines  stated that “vaginal spermicides offer no  protection against HIV infection, and spermicides  are not recommended for HIV prevention . . . the  consistent use of condoms, with or without  spermicidal lubricant or vaginal application of  spermicide is recommended.”
2002: The final results of the presentation at the  International AIDS conference held in Durban,  South Africa, were published in The Lancet.
1998: An FDA Consumer magazine article,  “Condoms: Barriers to Bad News,” stated that   “The spermicide nonoxynol-9, used in some  condoms, has been shown to be effective as a  contraceptive, and may reduce the risk of  transmitting certain STDs. But the spermicide  has not been proven to prevent sexual  transmission of HIV.”
2002: CDC published a report in MMWR stating,  “Sexually active women should consider their  individual HIV/STD infection risk when choosing  a method of contraception. Providers of family  planning services should inform women at risk  for HIV/STDs that N-9 contraceptives do not  protect against these infections.”
section_title: Comments from the Department of Health and Human Services
section_title: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
section_title: Acknowledgments
paragraphs: In addition to the person named above, Kelly DeMots, Krister Friday, Mary  Giffin, and Mary Reich made key contributions to this report.