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entitled 'HHS: Efforts to Research and Inform the Public about
Nonoxynol-9 and HIV' which was released on April 12, 2005.
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Report to Congressional Requesters:
March 2005:
HHS:
Efforts to Research and Inform the Public about Nonoxynol-9 and HIV:
GAO-05-399:
GAO Highlights:
Highlights of GAO-05-399, a report to congressional requesters:
Why GAO Did This Study:
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.
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.
www.gao.gov/cgi-bin/getrpt?GAO-05-399.
To view the full product, including the scope and methodology, click on
the link above. For more information, contact Marjorie Kanof at (202)
512-7114.
[End of section]
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:
Appendixes:
Appendix I: Timeline of Selected Events and Publications Related to N-
9's Potential Use as a Microbicide, 1990-2004:
Appendix II: Comments from the Department of Health and Human Services:
Appendix III: GAO Contact and Staff Acknowledgments:
GAO Contact:
Acknowledgments:
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:
Letter 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.[Footnote 1]
Researchers have sought to develop a microbicide[Footnote 2] 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[Footnote 3] found in various over-the-
counter[Footnote 4] contraceptive productsæincluding some condoms and
certain vaginal contraceptive products such as foams and gelsæshowed
promise as a potential microbicide for STDs, including HIV.[Footnote 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.[Footnote 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.[Footnote 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
(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 Responsibilities:
Three federal agencies within HHS--CDC, NIH, and FDA--have
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)[Footnote 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 magazine[Footnote
9] 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."[Footnote 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 not misbranded.[Footnote 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.[Footnote
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.[Footnote 13] As of March 2005, FDA had not
issued a final monograph for this category of drugs.[Footnote 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.[Footnote 15]
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.[Footnote 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 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.[Footnote 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.[Footnote 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.[Footnote 19] 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.[Footnote 20] Similarly, a 1999 commentary in the American
Journal of Public Health noted that epidemiologic studies on N-9 were
conflicting.[Footnote 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.[Footnote 22],[Footnote 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.[Footnote 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.[Footnote
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 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,[Footnote 26] published in 2002 by CDC and by the
World Health Organization (WHO) in collaboration with the CONRAD
Program.[Footnote 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.[Footnote 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 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,[Footnote 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.[Footnote 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, 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.[Footnote 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.[Footnote 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.[Footnote 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.
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.[Footnote 34] According to CDC's
1993 STD treatment guidelines,[Footnote 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.[Footnote 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.[Footnote 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."[Footnote 38] 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."[Footnote 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.[Footnote 40] Another 1998 FDA
Consumer article stated that spermicides alone do not give adequate
protection against HIV.[Footnote 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…."[Footnote 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 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.[Footnote
43] Similarly, in 2002 when CDC revised its STD treatment
guidelines,[Footnote 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."[Footnote 45] This information also
appeared in an article in a May 2002 issue of MMWR.[Footnote 46]
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 brochureæwhich stated that some experts
believe that N-9 may prevent HIV transmissionæon 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.[Footnote 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.[Footnote 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.
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.[Footnote 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 Observations:
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.
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 and make copies available to others who request them. In
addition, this 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.
Signed by:
Marjorie Kanof:
Managing Director, Health Care:
[End of section]
Appendixes:
Appendix I: Timeline of Selected Events and Publications Related to N-
9's Potential Use as a Microbicide, 1990-2004:
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. . . ."
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. . . ."
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."
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."
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."
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."
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."
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."
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...."
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.
2000: NIH and CDC reported that the agencies halted all studies
actively pursuing N-9’s use as a microbicide between 2000 and 2001.
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.
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.
2002: The final results of the presentation at the International AIDS
conference held in Durban, South Africa, were published in The Lancet.
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."
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. . . ."
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.
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.
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.
[End of section]
Appendix II: Comments from the Department of Health and Human Services:
DEPARTMENT OF HEALTH & HUMAN SERVICES:
Office of Inspector General:
Washington, D.C. 20201:
MAR 22 2005:
Ms. Marjorie Kanof:
Managing Director, Health Care:
U.S. Government Accountability Office:
Washington, DC 20548:
Dear Ms. Kanof:
Enclosed are the Department's comments on the U.S. Government
Accountability Office's (GAO's) draft report entitled, "HHS-Efforts to
Research and Inform the Public About Nonoxynol-9's Safety and
Effectiveness in Preventing HIV" (GAO-05-399). The comments represent
the tentative position of the Department and are subject to
reevaluation when the final version of this report is received.
The Department provided several technical comments directly to your
staff.
The Department appreciates the opportunity to comment on this draft
report before its publication.
Sincerely,
Daniel R. Levinson:
Acting Inspector General:
Enclosure:
The Office of Inspector General (OIG) is transmitting the Department's
response to this draft report in our capacity as the Department's
designated focal point and coordinator for U.S. Government
Accountability Office reports. OIG has not conducted an independent
assessment of these comments and therefore expresses no opinion on
them.
COMMENTS OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES ON THE U.S.
GOVERNMENT ACCOUNTABILITY OFFICE'S DRAFT REPORT: "HHS-EFFORTS TO
RESEARCH AND INFORM THE PUBLIC ABOUT NONOXYNOL-9'S SAFETY AND
EFFECTTVENESS IN PREVENTING HIV" (GAO-05-399):
The Department of Health and Human Services (HHS) appreciates the
opportunity to comment on the U.S. Government Accountability Office's
(GAO's) draft report.
Key Points:
Condom labeling. GAO's draft does not include any discussion of a key
feature of the HHS, Food and Drug Administration's (FDA) regulation of
condoms with spermicidal lubricant containing Nonoxynol-9 (N-9). FDA
has never permitted condom labeling to claim that N-9 provides any
additional protection against human immunodefciency virus (HIV) or
other sexually transmitted diseases (STDs). The only claims that may be
made in condom labeling concerning N-9 relate to its use as a
spermicide which some believe provides the condom with additional
contraceptive protection. It is also important to make clear that the
barrier features of condoms provide the primary protection against STDs
and the primary contraceptive protection.
Public health message. HHS is concerned that the final sentence of the
draft report (page 26) may unintentionally undermine efforts to inform
the public of the protection provided by condoms. If the choice is to
use a condom with N-9 or to have unprotected sex in a potentially risky
situation, an N-9 condom is by far the better choice. GAO's language
may leave some consumers to believe that the reverse is true, because
"the public may be at risk." We suggest GAO modify the sentence to
read, "Until FDA completes the rules making changes to the labels for N-
9 vaginal contraceptive products and condoms with N-9, consumers may be
left in doubt concerning the appropriate uses of these products." FDA
recognizes the importance of making these labeling changes, and is
committed to completing them as rapidly as possible.
General Comments:
The report would be improved, and would be more accurate, if it clearly
indicated when it is discussing both vaginal contraceptive products
containing N-9 (regulated as drugs) and condoms with N-9 (regulated as
devices), and when it is discussing only vaginal contraceptive products
or only condoms. The report would also be improved if it separately
discussed FDA's role in product labeling and FDA's public
communications concerning N-9 products.
With regard to public communications, FDA's primary means of public
health communication is through product labeling oversight. FDA has on
occasion provided supplementary information through consumer outreach
efforts, and those supplementary statements have always acknowledged
the scientific uncertainty concerning the effectiveness of N-9 as a
protection against STDs. With regard to labeling, as discussed above,
FDA has never permitted condom labeling to claim that N-9 provides any
additional protection against HIV or other STDs, and GAO's report
should make this clear.
How Devices Are Regulated:
FDA previously provided GAO a short discussion of how medical devices,
including condoms with N-9, are regulated; this discussion has been
omitted from the draft report. The report discusses the monograph
process used to approve drugs, but many readers may not understand that
condoms with N-9 are regulated as medical devices and are cleared
through the 510(k) premarket notification process, not the monograph
process. If GAO needs further information about the 510(k) process, or
clarification of the information previously provided, FDA would be glad
to help.
Limits of Reported Research:
GAO needs to make clear that much of the research discussed in the
report was restricted to vaginal contraceptive products, and that these
studies did not involve condoms with N-9. For example, the completed
arm of the COL-1492 study was confined to very narrow circumstances
(sex workers using N-9 vaginal contraceptive products three or more
times a day) and did not involve condoms with N-9.
Actions by Manufacturers:
GAO should recognize that some of the manufacturers' actions discussed
were prompted by economic considerations, not by safety concerns. One
manufacturer informed FDA that it stopped selling condoms with N-9
simply because there was insufficient consumer demand for their condoms
with N-9. Although some manufacturers have decided not to manufacture
condoms with N-9, other manufacturers still see market demand from low-
risk couples who want the additional contraceptive protection an N-9
condom may offer.
Additional information on Durex cessation of marketing of condoms with
N-9. FDA has provided a letter dated January 12, 2004, from Durex to
its customers explaining why it would no longer market condoms with N-
9. Durex did not cite safety concerns as a reason it would no longer
market these products; the reason cited was an anticipated "reduction
in demand for spermicidally-lubricated condoms."
The draft report at times mentions that manufacturers have taken some
action, but does not explain the significance, if any, of that action.
For example, page 6, paragraph 1, last sentence states:
"Representatives from two manufacturers ... reviewed research ... in
preparing comments on FDA's proposed warning labels." What did these
manufacturers conclude, and how did those conclusions affect their
comments? (This language is also on the Highlights page, last sentence
of the paragraph "What GAO found.") In other instances, actions by
manufacturers are discussed, but the discussion does not link clearly
to the immediately preceding or surrounding content. For example, the
last three sentences of the first partial paragraph on page 7 appear to
belong to a separate paragraph. One of the examples given in these last
three sentences also states that the manufacturer has informed its
consumers, and it would be useful to include information on those
actions.
It may be useful for GAO to consolidate its discussion of manufacturer
actions in a separate section of the report, particularly since the
major focus of the report is on actions taken by HHS agencies.
The "1999 Brochure"
A review of the 1990 FDA brochure, Condoms and Sexually Transmitted
Diseases ... especially AIDS, and the 1999 Internet posting with the
same title will show that the two documents are identical. except the
Internet posting omits graphics, corrects two single-letter typos, and
omits a short paragraph about the (hardcopy) booklet ("This Booklet
will answer many of your questions about condoms. . ."). FDA believes
that the "1999 Brochure" is better called the "1999 Internet posting"
throughout the report and that the posting should not be described as
"updated" (for example, as in the Timeline). The "1990 Brochure" and
the "1999 Internet posting" should be shown as separate items in the
Timeline.
Appendix 1, Timeline:
The timeline should begin with the 1988 Centers for Disease Control
brochure, Understanding AIDS, which advised that N-9, when used with a
condom, might provide additional protection against HIV. The brochure
reflected the prevalent scientific view at that time: "Condoms are the
best preventive measure against AIDS besides not having sex and
practicing safe behavior." That statement is as true today as it was in
1988. However, the brochure continues, "A condom with a spermicide may
provide additional protection [against HIV]. Spermicides have been
shown in laboratory tests to kill the virus." Later research slowly
eroded the scientific underpinnings of this belief.
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, that evidence was confined to very narrow circumstances (sex
workers using N-9 vaginal contraceptive products three or more times a
day) and did not involve or implicate condoms with N-9. Also, it would
be appropriate to note that the definitive report on the COL-1492 study
was published in 2002; the information available prior to that time
could be considered only preliminary.
[End of section]
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.
(290314):
FOOTNOTES
[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.
[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).
[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.
[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. § 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. § 884.5300 and 21 C.F.R. § 884.5310.
[16] Centers for Disease Control and Prevention, Guide to Microbicide
Research and Development: HIV Infection, Selected Bibliography through
September 1996.
[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 anti-infective 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.
[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 Nonoxynol-9 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.
[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.
[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.
[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, § 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.
[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).
[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).
[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).
[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.
[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.
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