HHS: Efforts to Research and Inform the Public about Nonoxynol-9 
and HIV (31-MAR-05, GAO-05-399).				 
                                                                 
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.	 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-05-399 					        
    ACCNO:   A20584						        
  TITLE:     HHS: Efforts to Research and Inform the Public about     
Nonoxynol-9 and HIV						 
     DATE:   03/31/2005 
  SUBJECT:   Contraception					 
	     Health hazards					 
	     Health research programs				 
	     Immunization services				 
	     Pharmacological research				 
	     Public health research				 
	     Sexually transmitted diseases			 
	     Publications					 
	     Consumer education 				 
	     Medical research					 
	     Preventive health care services			 
	     HIV/AIDS						 

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GAO-05-399

                 United States Government Accountability Office

                     GAO Report to Congressional Requesters

March 2005

HHS

      Efforts to Research and Inform the Public about Nonoxynol-9 and HIV

                                       a

GAO-05-399

[IMG]

March 2005

HHS

Efforts to Research and Inform the Public about Nonoxynol-9 and HIV

  What GAO Found

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.

                 United States Government Accountability Office

Contents

  Letter

Results in Brief
Background
Federal Agencies Have Researched the Safety and Effectiveness of

N-9 as a Microbicide, While Manufacturers Reviewed Its Safety The
Information Provided to the Public about the Use of N-9 as a Microbicide
Has Been, at Times, Inconsistent Some Manufacturers and Public Health
Organizations Have Stopped

Producing and Distributing N-9 Condoms Concluding Observations Agency
Comments

1 3 5

8

14

19 19 20

Appendixes

                                       Appendix I: Appendix II: Appendix III:

Timeline of Selected Events and Publications Related to
N-9's Potential Use as a Microbicide, 1990-2004 23

Comments from the Department of Health and Human
Services 24

GAO Contact and Staff Acknowledgments 28
GAO Contact 28
Acknowledgments 28

Contents

Abbreviations

CDC Centers for Disease Control and Prevention
CDER Center for Drug Evaluation and Research
CDRH Center for Devices and Radiological Health
FDA Food and Drug Administration
HHS Department of Health and Human Services
MMWR Morbidity and Mortality Weekly Report
N-9 Nonoxynol-9
NIH National Institutes of Health
PPFA Planned Parenthood Federation of America
STD sexually transmitted disease
WHO World Health Organization

This is a work of the U.S. government and is not subject to copyright
protection in the United States. It may be reproduced and distributed in
its entirety without further permission from GAO. However, because this
work may contain copyrighted images or other material, permission from the
copyright holder may be necessary if you wish to reproduce this material
separately.

A

United States Government Accountability Office Washington, D.C. 20548

March 31, 2005

The Honorable Mark Souder
Chairman
Subcommittee on Criminal Justice, Drug Policy and Human Resources
Committee on Government Reform
House of Representatives

The Honorable Tom Coburn
United States Senate

The Honorable Joseph Pitts
House of Representatives

The Honorable David Weldon
House of Representatives

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.1

Researchers have sought to develop a microbicide2 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.

1 Centers for Disease Control and Prevention, Basic Statistics: HIV
Estimate, http://www.cdc.gov/hiv/stats.htm (downloaded Jan. 31, 2005).

2 A microbicide is any agent that kills microbes such as bacteria, fungi,
and parasites. Some microbes are capable of causing disease.

In the mid-1980s researchers found that Nonoxynol-9 (N-9), a widely
available spermicide3 found in various over-the-counter4 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.5 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.6 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.7
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

3 A spermicide is a chemical compound that inactivates sperm by damaging
their cell membranes.

4 Over-the-counter refers to drug products sold without a prescription.

5 For example, N-9, available over-the-counter for almost 50 years, was
first demonstrated to be effective against HIV in a laboratory study in
1985. D.R. Hicks, L.S. Martin, J.P. Getchell, et al., "Inactivation of
HTLV-III/LAV-Infected Cultures of Normal Human Lymphocytes by Nonoxynol-9
In-vitro," The Lancet (1985).

6 C.E. Koop, Surgeon General, and Centers for Disease Control, Public
Health Service, Understanding AIDS (1988).

7 For example the New York Times reported in 1987 that "Additional
protection is gained by applying spermicides containing nonoxynol-9, which
kills the AIDS virus." See J.E. Brody, "Personal Health," New York Times
(Mar. 4, 1987). That same year, the Journal of the American Medical
Association reported that the Surgeon General recommended that condoms be
lubricated with N-9 "which some evidence shows may inhibit the virus." See
C.E. Koop, "Physician Leadership in Preventing AIDS," Journal of the
American Medical Association, vol. 258 (1987).

(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.

Results in Brief	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, and
manufacturers have reviewed

research on the safety 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 STDs, including HIV. In the 1990s, NIH
funded a range of laboratory and clinical studies of N-9 as a possible
microbicide for HIV. During this time, FDA reviewed research on N-9 as
part of its regulatory process for reviewing the safety and effectiveness
of N-9 as a vaginal contraceptive. The results of the research conducted,
funded, and reviewed 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 in preparing comments 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. For example, CDC's 1993 STD treatment guidelines cautioned
that women should not assume that N-9 vaginal contraceptive products
protect them against HIV, and the updated 1998 guidelines stated that
vaginal contraceptive products offer no protection against HIV infection.
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
suggested 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 this
information was inconsistent with the proposed warning labels for N-9
vaginal contraceptive products. The three largest condom manufacturers
have also taken steps to inform the public about N-9 and HIV. For example,
one condom manufacturer has informed its consumers that N-9 does not
prevent HIV transmission and may increase some users' risk of contracting
HIV. In contrast, other manufacturers of contraceptive products that we
interviewed have not taken such steps.

In recent years, some key manufacturers and public health organizations
have stopped producing, distributing, or promoting N-9 condoms, and the
percentage of these condoms on the market is reported to have decreased.
In January 2004, one of the three largest condom manufacturers stopped
producing N-9 condoms. Similarly, according to representatives from PPFA,
the organization stopped manufacturing N-9 condoms in 2002. A
representative from PPFA explained that this decision was based on a
concern about the safety issues associated with N-9 condoms. Like PPFA,
another key public health organization we interviewed has begun to
recommend against the use of N-9 condoms.

In commenting on a draft of this report, the Department of Health and
Human Services (HHS) provided clarification that GAO incorporated where
appropriate.

Background	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.

Federal Agency Three federal agencies within HHS-CDC, NIH, and FDA-have
Responsibilities responsibilities that affect the public's use of N-9
contraceptive products.

CDC	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) 8 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	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	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 magazine9 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." 10 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

8 CDC's MMWR is a series of articles on public health issues that are
based on reports sent to CDC by state and territorial health departments.

9 FDA Consumer is a publication intended to educate the public as well as
health care providers about products that FDA regulates.

10 FDA also refers to the monograph process as the Over-the-Counter Drug
Review.

not misbranded.11 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.12

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.13 As of March 2005, FDA had not issued a final monograph
for this category of drugs.14 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.15

11 In the first step of the three-step monograph process, an Advisory
Review Panel of nongovernment experts reviews data on active ingredients
and provisionally classifies the ingredients as Category I (safe and
effective), Category II (not safe and effective), or Category III (more
data needed). The panel's report is published as an advance notice of
proposed rule making in the Federal Register. In the second step, FDA
publishes a tentative final monograph or proposed rule for the particular
category of drugs. In the third step, FDA publishes a final monograph or
final rule containing FDA's final conclusions. See 21 C.F.R. S: 330.10.

12 FDA Compliance Guide No. 7132b.15, March 1995.

13 In the rest of this report, we refer to FDA's category of "vaginal
contraceptive drug products" as vaginal contraceptive products.

14 The first step of the monograph process for this category of drugs
occurred in 1980 when FDA published the report of the Advisory Review
Panel on over-the-counter contraceptives and other vaginal drug products,
which provisionally classified N-9 as safe and effective as a
contraceptive. See 45 Fed. Reg. 82014 (Dec. 12, 1980). The second step
occurred in 1995, when FDA issued a proposed rule that required additional
clinical research to determine the contraceptive effectiveness for
different formulations of N-9. See 60 Fed. Reg. 6892 (Feb. 3, 1995).
According to FDA officials, the issuance of the final monograph is pending
its review of a large contraceptive efficacy study that was published in
March 2004. FDA is allowing the continued marketing of vaginal
contraceptive products pending completion of this review.

15 See 21 C.F.R. S: 884.5300 and 21 C.F.R. S: 884.5310.

Federal Agencies Have Researched the Safety and Effectiveness of N-9 as a
Microbicide, While Manufacturers Reviewed Its Safety

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.

Federal Agencies Researched the Safety and Effectiveness of N-9 as a
Microbicide until 2000

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 1996.16 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

16 Centers for Disease Control and Prevention, Guide to Microbicide
Research and Development: HIV Infection, Selected Bibliography through
September 1996.

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.17

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.18 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.19 For
example, a 1995 review in the journal AIDS noted the existence of
"substantially

17 Laboratory testing is conducted to determine whether a drug has an
effect on a disease in animals and whether it is reasonably safe for
initial testing in humans. Randomized clinical trials are studies designed
to determine the safety and effectiveness of a drug in humans by comparing
the outcomes for a group using the drug to the outcomes for a similar
group using a placebo or a standard therapy.

18 The meeting included representatives from the FDA advisory committees
for antiinfective drugs, antiviral drugs, reproductive health drugs, and
nonprescription drugs. FDA advisory committees are composed of
academicians, clinicians, consumer group representatives, industry
representatives, and patients or their caregivers. The committees provide
independent advice to FDA in order to contribute to the quality of the
agency's regulatory decision making.

19 Most of the reviewed research involved N-9 vaginal contraceptives.

different opinions" about the safety and effectiveness of N-9 when used
for HIV prevention.20 Similarly, a 1999 commentary in the American Journal
of Public Health noted that epidemiologic studies on N-9 were
conflicting.21

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.22,23 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.24 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.25 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

20 C. Elias and L.L. Heise, "Nonoxynol-9: The Need for Policy in the Face
of Uncertainty," AIDS, vol. 9, no. 3 (1995).

21 P. Feldblum, S. Weir, and W. Cates, "The Protective Effect of Condoms
and Nonoxynol-9 Against HIV Infection," American Journal of Public Health,
vol. 89, no. 1 (1999).

22 Since the monograph process for over-the-counter drugs evaluates the
active ingredients in categories of drugs rather than specific products,
N-9 vaginal contraceptive products on the market may vary in formulation
and dosage.

23 See, for example, R.L. Cook and M.J. Rosenberg, "Do Spermicides
Containing Nonoxynol9 Prevent Sexually Transmitted Infections? A
Meta-Analysis," Sexually Transmitted Diseases, vol. 25, no. 3 (March
1998).

24 Although NIH stopped conducting and funding research on N-9 as a
microbicide, it continued research on the effectiveness of N-9 as a
contraceptive product.

25 This study was conducted primarily in locations with a high prevalence
of HIV infection and among sex workers, who typically have multiple
partners and were, therefore, considered high risk. The risk of becoming
infected with HIV increases with the number of sexual partners, whether or
not condoms are used, and the local prevalence of infection.

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.

After 2000, FDA Continued to Review Research on the Safety of N-9 as Part
of Its Regulation of N-9 Contraceptive Products

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, 26 published in 2002 by CDC and by the World Health
Organization (WHO) in collaboration with the CONRAD Program.27 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.28 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

26 Centers for Disease Control and Prevention, "Nonoxynol-9 Spermicide
Contraception Use - United States, 1999," Morbidity and Mortality Weekly
Report, vol. 51, no. 18 (May 2002). World Health Organization/CONRAD,
WHO/CONRAD Technical Consultation on Nonoxynol-9: Summary Report (June
2002).

27 The CONRAD Program, which is a nonprofit organization, supports the
development of methods to prevent pregnancy and STDs, including HIV/AIDS.
Funded primarily by the Agency for International Development, the program
offers both financial support as well as technical assistance for the
various stages of product development.

28 CDC did not advise against using previously purchased N-9 condoms.
However, because of their shorter shelf life, higher cost, association
with urinary tract infections in women, and lack of apparent benefit
compared with other lubricated condoms, CDC recommended against purchasing
any additional N-9 condoms.

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,29 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 2003.30 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,

29 While there were some differences between the published study and the
preliminary results reported in 2000, the conclusions of the published
study were consistent with those of the preliminary results. The published
study reported that "nonoxynol-9 increased the risk of HIV infection
compared with the placebo." It also stated that "risk was especially high
in women who used the study drug more than 3.5 times per day." See L. Van
Damme, et al., "Effectiveness of COL-1492, a Nonoxynol-9 Vaginal Gel, On
HIV-1 Transmission in Female Sex Workers: A Randomised Controlled Trial,"
The Lancet, vol. 360 (September 2002).

30 FDA policy states that FDA may pursue regulatory action against
over-the-counter drugs prior to the adoption of a final monograph if the
agency determines that the failure to act would pose a potential health
hazard to consumers. See FDA Compliance Guide No. 7132b.15, March 1995.

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.31

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.32 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.33 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.

31 Among the more than 150 comments, FDA received a range of comments from
15 health and research organizations-such as the American College of
Obstetricians and Gynecologists and Family Health International. The
majority of these organizations supported FDA's labeling proposal, and
half of them recommended that the FDA go even further than saying "for
vaginal use only," either by warning that N-9 vaginal contraceptives
should not be used for anal intercourse or by notifying consumers that
there is an increased risk when used for anal intercourse. Four
organizations stated that the warnings should be more specific in assuring
women at low risk for HIV that N-9 can be safe and effective as a
contraceptive. In addition to comments from health and research
organizations, FDA received comments from two manufacturers of
contraceptive products containing N-9. These manufacturers indicated that
the proposed warning labels went too far in suggesting that N-9 may lead
to increased HIV transmission and might discourage women who are at low
risk for HIV from using N-9 as a contraceptive.

32 The Consolidated Appropriations Act of 2001 required FDA to examine
condom labeling. See Pub. L. No. 106-554, App. A, S: 516(b), 114 Stat.
2763, 2763A-73 (2000).

33 Officials also noted that in the past, FDA had not permitted condom
labeling to claim that N-9 provided any additional protection against HIV
or other STDs.

Manufacturers of N-9 Contraceptive Products Have Researched the Safety of
N-9

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.

The Information Provided to the Public about the Use of N-9 as a
Microbicide Has Been, at Times, Inconsistent

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.)

At Times, CDC and FDA Provided Inconsistent Information about the Use of
N-9 to Prevent HIV

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.34 According to CDC's 1993 STD
treatment guidelines,35 "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.36
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.37

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." 38 At this time, CDC did not revise
its recommendation to use condoms with or without spermicide.

34 Before 1990, CDC published three articles in MMWR stating that based on
information from laboratory studies, additional protection against HIV and
other STDs might be obtained from using spermicides in conjunction with
condoms.

35 CDC's STD treatment guidelines include information for the treatment of
patients who have STDs. The guidelines were developed after consultation
with a group of professionals knowledgeable in the field of STDs. These
guidelines are periodically updated as new information becomes available.

36 Centers for Disease Control and Prevention, "1993 Sexually Transmitted
Diseases Treatment Guidelines," Morbidity and Mortality Weekly Report,
vol. 42, no. RR-14 (September 1993).

37 Centers for Disease Control and Prevention, "Update: Barrier Protection
Against HIV Infection and Other Sexually Transmitted Diseases," Morbidity
and Mortality Weekly Report, vol. 42, no. 30 (August 1993).

38 Centers for Disease Control and Prevention, "1998 Guidelines for
Treatment of Sexually Transmitted Diseases," Morbidity and Mortality
Weekly Report, vol. 47, no. RR-1 (January 1998).

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."39 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.40 Another 1998 FDA
Consumer article stated that spermicides alone do not give adequate
protection against HIV.41 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...."42

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

39 Food and Drug Administration, "Latex Condoms Lessen Risks of STDs," FDA
Consumer (1990).

40 Food and Drug Administration, "Condoms: Barriers to Bad News," FDA
Consumer (1998).

41 Food and Drug Administration, "On the Teen Scene: Preventing STDs," FDA
Consumer (1998).

42 This Web site posting was of a brochure originally issued in 1990. The
document stated that the information was current as of December 2, 1999.
See Food and Drug Administration, Condoms and Sexually Transmitted
Diseases...Especially AIDS (Rockville, Md.: 1990).

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.43 Similarly, in 2002 when CDC revised its STD treatment
guidelines,44 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."45 This information also appeared in an article in a May 2002
issue of MMWR.46

43 Centers for Disease Control and Prevention, "Notice to Readers: CDC
Statement on Study Results of Product Containing Nonoxynol-9," Morbidity
and Mortality Weekly Report, vol. 49, no. 31 (August 2000).

44 Since 1990, CDC has revised it STD treatment guidelines three times-in
1993, 1998, and 2002.

45 Centers for Disease Control and Prevention, "Sexually Transmitted
Diseases Treatment Guidelines 2002," Morbidity and Mortality Weekly
Report, vol. 51, no. RR-6 (May 2002).

46 Centers for Disease Control and Prevention, "Nonoxynol-9 Spermicide
Contraception Use - United States, 1999," Morbidity and Mortality Weekly
Report, vol. 51, no. 18 (May 2002).

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.47
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.48

Some Manufacturers Have Taken Steps to Inform Consumers about N-9 and HIV

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.

47 In January 2003, 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.

48 An official from FDA's Office of Public Affairs stated that the office
is responsible for updating information available on the FDA Web site.

Some Manufacturers and Public Health Organizations Have Stopped Producing
and Distributing N-9 Condoms

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.49 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.

Concluding	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

Observations	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

49 The Global Campaign for Microbicides is an organization that works to
accelerate microbicide development, facilitate widespread access and use,
and protect the needs and interests of users through advocacy, policy
analysis, and social science research.

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.

Agency Comments 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.

As we agreed with your offices, unless you publicly announce the contents
of this report earlier, we plan no further distribution of it until 30
days from its date. We will then send copies to others who are interested
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report will be available at no charge on GAO's Web site at
http://www.gao.gov.

If you or your staff have any questions about this report, please call me
at (202) 512-7114. Another contact and key contributors are listed in
appendix III.

Marjorie Kanof Managing Director, Health Care

Appendix I

Timeline of Selected Events and Publications Related to N-9's Potential
Use as a Microbicide, 1990-2004

Source: GAO.

Appendix II

Comments from the Department of Health and Human Services

Appendix II
Comments from the Department of Health
and Human Services

Appendix II
Comments from the Department of Health
and Human Services

Appendix II
Comments from the Department of Health
and Human Services

Appendix III

                     GAO Contact and Staff Acknowledgments

GAO Contact Kristi A. Peterson, (202) 512-7951

Acknowledgments	In addition to the person named above, Kelly DeMots,
Krister Friday, Mary Giffin, and Mary Reich made key contributions to this
report.

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