Women's Health: Women Sufficiently Represented in New Drug	 
Testing, but FDA Oversight Needs Improvement (06-JUL-01,	 
GAO-01-754).							 
								 
This report reviews the Food and Drug Administration's (FDA)	 
inclusion of women in clinical drug trials. GAO found that women 
were a majority of the clinical trial participants in the new	 
drug applications (NDA) it examined and that every NDA included  
enough women in the pivotal studies to be able to statistically  
demonstrate that the drug is effective in women. Although these  
findings are welcome, GAO also found three areas of concern. The 
first is the relatively small proportion of women in early	 
small-scale safety studies. These early studies provide important
information on drugs' toxicity and safe dosing levels for later  
stages of clinical development, and many of the NDAs GAO examined
found significant sex differences in a drug's pharmacokinetics,  
or how it is absorbed, distributed, metabolized, and excreted,	 
and concentrated in the bloodstream. Second, GAO is not confident
that either NDA sponsors or FDA's reviewers took full advantage  
of the available data to learn more about the effects of the drug
in women and to explore potential sex differences in dosing. This
is because NDA summary documents are not required to include	 
analyses of sex differences, and many of them do not. Third, FDA 
lacks appropriate management systems to monitor how many women	 
are in clinical trials, to be certain that NDAs and		 
investigational new drug applications (IND) annual reports comply
with regulations for presenting outcome data by sex and 	 
tabulating the number of women included in ongoing trials, and to
confirm that its medical officers have adequately addressed	 
sex-related issues in their reviews. Although FDA has taken some 
promising initial steps to address these deficiencies, it is	 
important that the agency finalize the pilot programs it has	 
underway and give sustained attention to these management issues.
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-01-754 					        
    ACCNO:   A01149						        
  TITLE:     Women's Health: Women Sufficiently Represented in New    
             Drug Testing, but FDA Oversight Needs Improvement                
     DATE:   07/06/2001 
  SUBJECT:   Health research programs				 
	     Pharmaceutical industry				 
	     Pharmacological research				 
	     Women						 
	     Drugs						 
	     Product safety					 

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GAO-01-754
     
Report to Congressional Requesters

United States General Accounting Office

GAO

July 2001 WOMEN?S HEALTH Women Sufficiently Represented in New Drug Testing,
but FDA Oversight Needs Improvement

GAO- 01- 754

Page i GAO- 01- 754 Women in Clinical Drug Trials Letter 1

Results in Brief 2 Background 5 FDA?s Regulation Not As Specific As Earlier
Guidance 10 NDA and IND Submissions Often Fail to Present Required

Information 12 NDAs Include Appropriate Numbers of Women, but Analyses

Sometimes Missing 13 FDA Oversight Needs Improvement 17 Conclusions 19
Recommendations for Executive Action 20 Agency Comments 20

Appendix I Objectives, Scope and Methodology 22

Appendix II Estimates of the Number of Men and Women in Clinical Drug Trials
27

Appendix III Comments From the Food and Drug Administration 32

Appendix IV GAO Contact and Staff Acknowledgments 35

Related GAO Products 36

Tables

Table 1: NDAs With Evidence of Sex- Related Analyses 15 Table 2: NDAs That
Reported Differences Between Men and

Women. 16 Table 3: NDAs That Reported Differences in Drug Response

Between Women Using the Test Drug and Women in the Comparison Group 16 Table
4: Medical Officer Reviews Not Discussing Sponsor- Reported

Sex- Related Analyses of Differences in Drug Response 18 Contents

Page ii GAO- 01- 754 Women in Clinical Drug Trials

Table 5: Decision Rules for Collection of Data From NDA Critical Summary
Documents. 23 Table 6: Description of the IND Annual Report Sample 24 Table
7: Estimate of Women and Men in Clinical Drug Trials by

Drug Class 28 Table 8: Estimate of Men and Women in Pivotal Drug Trials by

Drug Class 30

Figure

Figure 1: Participants in Clinical Drug Trials by Sex 4

Abbreviations

DES diethylstilbestrol FDA Food and Drug Administration IND investigational
new drug IOM Institute of Medicine NDA new drug application NME new
molecular entity OTC over- the- counter PPA phenylpropanolamine

Page 1 GAO- 01- 754 Women in Clinical Drug Trials

July 6, 2001 The Honorable Tom Harkin The Honorable James Jeffords The
Honorable Barbara A. Mikulski The Honorable Olympia J. Snowe United States
Senate

The Honorable Henry A. Waxman House of Representatives

Men and women sometimes respond differently to the same drug. For example,
we recently reported that four of the ten prescription drugs withdrawn from
the U. S. market in recent years induced potentially fatal cardiac
arrhythmias in women more often than in men. 1 Because of potential sex
differences in the safety and efficacy of new drugs, it is important to
include women and men in all stages of drug development and to analyze the
resulting data for sex differences. In 1992, we reported that the Food and
Drug Administration (FDA) was not adequately ensuring the representation of
women or the study of sex differences in clinical drug trials conducted by
the pharmaceutical industry. 2 Although FDA subsequently has taken some
steps to increase the participation of women in clinical drug trials,
concerns remain that women continue to be underrepresented and that sex
differences in responses to drugs continue to go unexamined during drug
development.

You asked us to investigate FDA?s progress in addressing the inclusion of
women in clinical drug trials since our 1992 report. In response to your
request, our work addressed: (1) what FDA guidance documents and regulations
govern the inclusion of women in clinical drug trials; (2) are the
regulations being followed; (3) are appropriate numbers of women included in
the clinical drug trials to ensure the safety and efficacy of drugs for
women; and (4) how does FDA oversee the collection, presentation, and
analysis of data related to sex differences?

1 Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks
for Women, (GAO- 01- 286R, January 19, 2001). 2 Women?s Health: FDA Needs to
Ensure More Study of Gender Differences in Prescription Drug Testing, (GAO/
HRD- 93- 17, October 29, 1992).

United States General Accounting Office Washington, DC 20548

Page 2 GAO- 01- 754 Women in Clinical Drug Trials

To address these questions, we reviewed new drug applications (NDA) for new
molecular entities (novel drugs subject to FDA review for the first time),
submitted to FDA from August 10, 1998 through December 31, 2000. 3 Out of 82
original NDAs for new molecular entities (NME) submitted during that period,
we reviewed all 36 of the NDAs that met our selection criteria, namely that
FDA had approved them or categorized them as approvable by December 31,
2000, and had labeled them for use in both men and women. 4 We excluded NDAs
for biologic products, such as vaccines, diagnostic drugs used in medical
imaging, drugs for sex- specific conditions, and pediatric drugs. For each
NDA, we analyzed three critical summary documents submitted by the drug?s
sponsor- the Integrated Summary of Safety, the Integrated Summary of
Efficacy, and the Pharmacokinetics and Bioavailability Summary- and the FDA
Medical Officer Review. These documents were chosen because they summarize
clinical trial data and because pertinent regulations direct NDA sponsors to
include relevant information in the safety and efficacy summary documents
submitted to FDA. We also randomly sampled 100 annual reports for
investigational new drugs. These are drugs in development for which drug
manufacturers typically have not yet sought FDA?s approval for marketing. In
addition, we interviewed FDA officials, pharmacology and drug safety
experts, and representatives of the pharmaceutical industry. We also
reviewed relevant literature. (For additional information on our
methodology, see appendix I.) We conducted our work from July 2000 through
May 2001 in accordance with generally accepted government auditing
standards.

Since 1992, FDA has addressed the inclusion of women in clinical drug trials
through the publication of three primary documents, guidance in 1993 and
regulations in 1998 and 2000. While not legally binding, the 1993 guidance
recommends that clinical studies include enough men and

3 We sampled NDAs filed after the effective date for FDA?s 1998 regulation,
which required the presentation of data on women in clinical trials, through
December 31, 2000. Some drug classes that have been cited by experts as
including insufficient numbers of women are not well represented in our
sample because few of the NDAs in these classes submitted to FDA during our
study period met our selection criteria.

4 Approvable NDAs have the potential to receive marketing approval. FDA
judges an NDA approvable if there is substantial evidence that the drug is
safe and effective, but the agency requires the sponsor to either supply
additional information or agree to some limiting conditions before FDA
grants final approval. Results in Brief

Page 3 GAO- 01- 754 Women in Clinical Drug Trials

women to detect clinically significant sex differences in drug efficacy and
safety, and that analyses of sex differences should be reported in new drug
applications. The 1998 regulation has the force of law, but it is less
specific than the guidance. The regulation requires that safety and efficacy
data already collected be presented separately for men and women in new drug
application summary documents. 5 It does not include criteria for
determining the number of women to be included in clinical studies, nor does
it require any analysis of the data presented. The 1998 regulation also
requires the tabulation of the number of study participants by sex in
investigational new drug annual reports. The regulation enacted in 2000
allows FDA to halt research programs for drugs for life- threatening
conditions if otherwise eligible men or women are excluded from
participation in studies based solely on their reproductive potential, but
it does not require inclusion of any particular number of men or women.

We found that new drug application summary documents and investigational new
drug annual reports often failed to meet the data presentation requirements
of the 1998 regulation. About one- third of the time new drug application
summary documents submitted to FDA by drug sponsors did not fulfill the
requirements of the 1998 regulations for the presentation of available
safety and efficacy outcome data by sex. We also found that 39 percent of
the investigational new drug annual reports in our sample did not include
the demographic information required by the 1998 regulation. Although FDA
has the authority under its 2000 regulation to suspend proposed research for
life- threatening conditions if men or women are excluded because of their
reproductive potential, it has not yet done so. We did not evaluate whether
FDA should have invoked this rule.

All of the new drug applications we examined included enough women to
demonstrate statistically that the drug was effective in women. Women were
the majority of clinical drug trial participants for over half of the new
drug applications we reviewed. Overall, women were 52 percent of the study
participants in all of the new drug applications in our sample. However, the
proportion of women included in different stages of drug

5 The differences between data presentation and data analysis are not
explained in the regulation. We regarded data presentation as any inclusion
of outcome measures stated separately for men and women. Safety outcome
measures include the percentage of study participants suffering an adverse
reaction to the drug, for example. Efficacy outcome measures include average
symptom improvements or the percentage of study participants cured of a
particular infection. We defined sex- related data analysis as any
comparison of outcomes between men and women, or between women and a
comparison group of women.

Page 4 GAO- 01- 754 Women in Clinical Drug Trials

development varied greatly (see figure 1). Women were 22 percent of the
participants in the initial, small- scale safety trials used to set the
dosing levels for larger- scale trials but were more than one- half of the
participants in the subsequent larger trials.

Figure 1: Participants in Clinical Drug Trials by Sex

Source: GAO?s review of 36 new drug applications.

FDA has not effectively overseen the presentation and analysis of data
related to sex differences in drug development. There is no management
system in place to record and track the inclusion of women in clinical drug
trials or to monitor compliance with relevant regulations, so FDA is unaware
that many new drug application submissions failed to meet standards. The
agency also does not routinely review the required tabulation of demographic
data by sex in the annual reports for drugs in development. Finally, FDA
management has lacked procedures to determine whether the written reviews of
new drug applications prepared by its medical officers adequately discuss
sex differences. FDA?s medical officers have not been required to discuss
sex differences in their reviews of new drug applications, and we found that
many of them have not done so. Furthermore, even though about one- third of
new drug applications specified that the concentrations of the drug in the
bloodstream were greater in people who weighed less, such as women, FDA
reviewers did not comment in their summaries on the lack of dose adjustments
based on sex. Without this documentation FDA management cannot be sure that

Page 5 GAO- 01- 754 Women in Clinical Drug Trials

sex- related issues have been properly addressed. Recently, FDA has started
to pilot test several initiatives that could help standardize the
application review process, including a special worksheet to be used by its
reviewers to capture information about the sex of clinical trial
participants and a standardized template for the medical officers? reviews
that requires them to discuss sex differences.

We are recommending that FDA implement management tools, such as the
proposed demographic worksheet and the standardized template for the medical
officers? reviews, that will allow it to enforce current regulations about
the presentation of data for women in clinical drug trials and to ensure
that its reviewers consistently and systematically document and discuss sex
differences in their written reviews of new drug applications. In comments
on a draft of this report, FDA generally agreed with our findings and did
not comment on our recommendations.

FDA is responsible for helping to ensure the safety and efficacy of drugs
marketed in the United States. It does this by overseeing the drug
development process, reviewing applications for the marketing of new drugs,
and monitoring the safety and efficacy of drugs once they are marketed. A
growing body of literature has demonstrated that in responses to some drugs
there are medically important sex differences that require the participation
of women in clinical trials for new drugs. In the 1970s, FDA recommended the
exclusion of women of childbearing potential from early clinical drug trials
because of concerns for the health of the women and of their potential
offspring.

FDA, an agency in the Department of Health and Human Services, is charged
with helping to ensure that safe and effective food, drugs, medical devices,
and cosmetics reach the United States market. FDA assists drug manufacturers
in designing clinical drug trials, reviews proposals for conducting clinical
drug trials, and approves drugs for sale in the United States based on its
determination that the clinical benefits of a drug outweigh its potential
health risks. FDA also approves drug labeling, which indicates the medical
conditions and patient populations for which the drug has been tested and
approved as safe and effective. Once a drug reaches the market, FDA
continues to monitor its safety and efficacy. Background

The Role of FDA

Page 6 GAO- 01- 754 Women in Clinical Drug Trials

Before any new drug can be tested on humans, a drug?s sponsor must submit an
investigational new drug (IND) application to FDA that summarizes the
investigations conducted prior to trials in humans, lays out a plan for how
the drug will be tested in humans, and provides assurances that appropriate
measures will be taken to protect study participants. Specifically, the IND
application demonstrates that the drug is reasonably safe for subsequent
testing in humans based on laboratory and animal testing and exhibits enough
potential effectiveness to justify its commercial development. Unless FDA
determines that a proposed study is unsafe, clinical testing may begin 31
days after the IND application is submitted to FDA. The sponsor then
proceeds with the three main stages of clinical drug testing:

 Phase 1 small- scale safety trials generally study small numbers of
healthy volunteers to determine toxicity and safe dosing levels. These
trials also study a drug?s pharmacokinetics, or how it is absorbed,
distributed, metabolized, and excreted, and its concentration in the
bloodstream;

 Phase 2 small- scale efficacy trials generally study patient volunteers
with the disease or condition against a comparison group 6 to assess drug
efficacy and side effects; and

 Phase 3 full- scale safety and efficacy trials study thousands of patient
volunteers against a comparison group to further evaluate efficacy and
monitor adverse responses to the drug. Drugs for life- threatening diseases
for which there is no other effective course of treatment sometimes cannot
be compared against another treatment and will sometimes use historical
information about patient outcomes as a point of comparison.

Drug sponsors are required to submit IND annual reports to FDA during the
typically 2- to 10- year span of the clinical drug trials. When the sponsor
wants to market a new drug, it submits a new drug application (NDA). FDA
regulations on NDA content and format require that the NDA include
integrated summaries of the evidence demonstrating the drug?s safety,
including adverse events suffered by those in the clinical drug trials, and
effectiveness. Evidence is also required to support the dosing section of
the labeling, including the recommended dose and modifications in dose for
specific population subgroups. Each NDA must include at least one

6 A comparison group may include participants who receive a placebo or
nontherapeutic treatment, or participants who receive an alternate therapy.
The Drug Development

and Approval Process

Page 7 GAO- 01- 754 Women in Clinical Drug Trials

pivotal clinical trial, generally an ?adequate and well- controlled? Phase 3
study that demonstrates the drug?s efficacy, or effectiveness. 7

There are many examples in the medical literature of sex differences in the
way men and women absorb, distribute, and metabolize drugs. 8 The effects of
women?s hormones and the variations in body size between men and women are
the likely causes of many sex differences in responses to drugs. Women
metabolize some drugs differently if they are pregnant, lactating, pre- or
postmenopausal, menstruating, or using oral contraceptives or hormone
replacements. Women?s generally smaller body weight compared to men can
result in higher levels of drug concentration in the bloodstream.

These and other established physiological and anatomical differences may
make women differentially more susceptible to some drug- related health
risks and demonstrate the importance of including women in all stages of
drug development. For example, phenylpropanolamine (PPA), a common
ingredient in over- the- counter (OTC) and prescription cough and cold
medications and OTC weight- loss products, was found to increase the risk of
bleeding into the brain or tissue around the brain in women, but not in men.
Certain classes of drugs can in some circumstances prolong the interval
between the heart muscle?s contractions and induce a potentially fatal
cardiac arrhythmia. Women have a higher incremental risk of suffering such
an arrhythmia after taking these drugs than do men, probably because (1) the
interval between heart muscle contractions is naturally longer for women
than for men and (2) male sex hormones moderate the heart muscle?s
sensitivity to these drugs. We recently reported that four of the ten
prescription drugs withdrawn from the U. S. market in the last 3 years posed
a greater health risk to women than to men because they induced arrhythmia.
9 Similarly, there is evidence that not all drugs are effective in both
sexes. For example, one class of

7 Food and Drug Administration Modernization Act of 1997, P. L. 105- 115,
sect.115( a). 8 Many of these were synthesized in the recent Institute of
Medicine report, Exploring the Biological Contributions to Human Health:
Does Sex Matter?, National Academy Press

(Washington, D. C.: 2001). 9 GAO- 01- 286R, January 19, 2001. The Importance
of

Ensuring Women?s Representation in Trials

Page 8 GAO- 01- 754 Women in Clinical Drug Trials

painkillers, kappa opioids, has been found to be twice as effective in women
as in men. 10

Discoveries of birth defects and other problems resulting from fetal
exposure to certain drugs between the 1940s and early 1970s prompted
societal interest in protecting women and their fetuses from the potentially
devastating effects of clinical drug research. For example,
diethylstilbestrol (DES) was taken by women in the 1940s and 1950s to
protect against miscarriages. About 20 years later, many daughters of women
who had taken the drug developed reproductive abnormalities and had an
increased risk of developing vaginal cancer. Similarly, in the 1960s many
women outside of the United States took thalidomide to prevent early
miscarriages, and the drug caused over 10,000 birth defects worldwide. In
1977, partially in response to the thalidomide scare, FDA recommended that
women of childbearing potential be excluded from participating in small-
scale safety and efficacy trials unless the drug was intended to treat a
life- threatening disease. 11 As a result, women were typically excluded
from these clinical drug trials. Through the next decade there were growing
concerns that the 1977 guideline may have restricted the early accumulation
of information about women?s responses to drugs that could be used in
designing later clinical drug trials and that it stifled the production and
analysis of data on the effects of drugs in women.

In 1994, the Institute of Medicine (IOM) reported that the FDA guidance that
discouraged the participation of women of childbearing potential in initial
small- scale trials led to the widespread exclusion of women in later large
scale trials. In addition, analyses of published clinical drug trials for
life- threatening conditions have concluded that many past clinical trials
included few or no women, making it uncertain whether the studies?

10 See ?Equality in Clinical Trials: Drugs and Gender,? FDA Consumer Special
Report, Willis, J. , FDA, 1997, and ?Distinguishing Mars from Venus:
Emergence of Gender Biology in Health and Disease,? Insights on Human
Health, Slavkin, H. C., National Institutes of Health, National Institute of
Dental Research, March 1998.

11 General Considerations for the Clinical Evaluation of Drugs, HEW
Publication No. (FDA) 77- 3040. Women Were Historically

Excluded From Some Clinical Drug Trials

Page 9 GAO- 01- 754 Women in Clinical Drug Trials

results applied to women. These conditions include cardiovascular disease
and HIV. 12

This report is our second to address FDA and women in clinical drug trials.
13 In 1992, we investigated FDA?s policies and the pharmaceutical industry?s
practices regarding research on women in clinical drug trials. We reported
that women were generally underrepresented in clinical drug trials in
comparison to the proportion of women among those persons with the disease
for which the drug was intended and that sex- related analyses were not
routinely conducted. Even so, there were enough women in most clinical drug
trials to detect sex differences in men and women?s response to drugs.

FDA has conducted its own studies on the inclusion of women in clinical drug
trials. Surveys of NDAs in 1983 and 1988 found that, in general, both sexes
were represented in clinical drug trials in proportions that usually
reflected the prevalence of the disease in the total population but were not
necessarily statistically sufficient to prove the safety or efficacy of the
drug for either sex. Despite the participation of women, few analyses of the
data were being conducted to detect possible sex differences in drug safety
or efficacy. FDA has also looked at the tabulation of demographic data in
IND annual reports. FDA recently reported that in IND annual reports filed
with the agency women made up 44 percent of participants in clinical drug
trials in which sex was identified. However, the FDA

12 See Federal Register, Vol. 58, No. 139, p. 39406, July 22, 1993; ?Women?s
Participation in Clinical Research: From Protectionism to Access,? Johnson,
T. et al., Women and Health Research: Ethical and Legal Issues of Including
Women in Clinical Studies, Vol. 2, Institute

of Medicine, National Academy Press, Washington, DC: 1994., pp. 1- 10; and
?Equality in Clinical Trials: Drugs and Gender,? FDA Consumer Special
Report, Willis, J. , FDA, 1997.

13 We have also conducted studies on women in research funded by the
National Institutes of Health. See National Institutes of Health: Problems
in Implementing Policy on Women in Study Populations (GAO/ T- HRD- 90- 50,
July 24, 1990) and Women?s Health: NIH Has Increased Its Efforts to Include
Women in Research (GAO/ HEHS- 00- 96 , May 2, 2000). Previous Studies on the

Participation of Women in Clinical Drug Trials

Page 10 GAO- 01- 754 Women in Clinical Drug Trials

researchers found that sex could not be determined for more than one half of
the participants in the IND annual reports. 14

FDA has addressed women in clinical drug trials through the publication of
guidance in 1993 and regulations in 1998 and 2000. 15 The 1993 guidance for
the pharmaceutical industry recommends that clinical studies include men and
women ?in numbers adequate to allow the detection of clinically significant
gender differences in drug response? and that analyses of sex differences be
included in NDAs. 16 The 1998 regulation is less specific. It does not
include references to how the number of women to be included in clinical
drug trials should be determined. It requires only that safety and efficacy
data already collected be presented separately for men and women in NDAs,
but it does not require any discussion or analysis of these data. The 1998
regulation also requires the tabulation of study participants by sex in IND
annual reports. The regulations issued in 2000 allow FDA to temporarily halt
research programs for drugs for life- threatening conditions if men and
women with reproductive potential are excluded from participation in ongoing
studies.

In response to our 1992 report, FDA issued policy guidance in 1993 regarding
women in clinical drug trials, explicitly reversing its 1977 recommendation
to restrict some women?s participation in drug development. Its 1993
Guideline for the Study and Evaluation of Gender

14 A recent study by FDA on women in clinical trials for biological
products, such as vaccines, serums, and antitoxins, had similar findings. It
found that the enrolled populations in the product applications reflected
the population for which the product was indicated but did not necessarily
include a statistically significant sample of women, that there was no
consistent documentation of demographic data or outcome data by sex, and
that sex- related analyses often were not available. (See ?Participation of
Females in Clinical Trials and Gender Analysis of Data in Biologic Product
Applications,? FDA Scholarship in Women?s Health Program, April 3, 2001.)

15 Regulations have the force and effect of law, while FDA guidance does not
legally bind either FDA or drug sponsors. Guidance is intended to show how
statutory and regulatory requirements may be met, but drug sponsors can
choose alternative methods to fulfill regulatory requirements. Where the
regulations are issued subsequent to guidance, as in this case, FDA applies
the guidance in a manner consistent with the regulations. ( Federal
Register, Vol. 62, No. 39, pp. 8961- 8972, Feb. 27, 1997.)

16 Clinically significant differences are those that are judged to be
medically relevant, i. e., have a medical effect that should be taken into
account, even if they are not statistically different. Conversely,
statistically significant differences may not be considered clinically
significant. FDA?s Regulation Not

As Specific As Earlier Guidance

FDA?s Guidance and Regulations

Page 11 GAO- 01- 754 Women in Clinical Drug Trials

Differences in the Clinical Evaluation of Drugs 17 recommended that clinical
drug trials should, in general, reflect the population that will receive the
drug when it is marketed. This guidance also advised that enough men and
women be included in clinical drug trials to allow for the detection of
clinically significant sex differences in drug response, including those
differences attributable to hormones and body weight variations. 18

On August 10, 1998, FDA implemented regulations amending requirements for
INDs and NDAs to include demographic data. 19 The regulation requires
sponsors to tabulate the sex, age, and race of study participants in IND
annual reports and to present available safety and efficacy data by sex,
age, and race in two NDA documents submitted to FDA: the Integrated Summary
of Safety and the Integrated Summary of Efficacy. 20 The regulation also
requires that evidence be presented to support dose determinations. FDA has
the authority under these regulations to refuse to accept, or ?file,? any
NDA for review that does not include this information. In addition, FDA
promulgated regulations on June 1, 2000, allowing it to halt IND studies
involving drugs that are intended to treat life- threatening diseases or
conditions if men or women of reproductive potential are excluded from
participation solely because of risks to their reproductive potential. This
regulation does not, however, impose requirements to recruit or enroll a
specific number of men or women with reproductive potential, and FDA has not
halted any studies under this authority. We did not evaluate whether FDA
should have invoked this rule.

17 Federal Register, Vol. 58, No. 139, pp. 39406- 39416, July 22, 1993. 18
In addition, FDA issued in 1996 the ICH (International Conference on
Harmonization of Technical Requirements for Registration of Pharmaceuticals
for Human Use) Guideline: E3 Structure and Content of Clinical Study
Reports, which recommends that individual clinical

study reports describe demographic characteristics of participants,
including sex, and present data by demographic category. In 1999 FDA also
published Guidance for Industry: Population Pharmacokinetics, which made
recommendations on the use of population

pharmacokinetics in the drug development process to help identify
pharmacokinetic differences among population subgroups, including sex. In
1995, FDA published another ICH guideline, E1A The Extent of Population
Exposure to Assess Clinical Safety: For Drugs Intended for Long- term
Treatment of Non- Life- Threatening Conditions, which specified

that 1,500 persons should be a minimum number for determination of the
safety of a drug. 19 Federal Register, Vol. 63, No. 28, pp. 6854- 6862, Feb.
11, 1998.

20 While the Federal Food, Drug, and Cosmetic Act (21 U. S. C. sect.355( i)( 1)(
C)) requires some IND reporting by the manufacturer or sponsor of data that
?the Secretary finds will enable him to evaluate the safety and
effectiveness of such drug,? the specific requirement for annual reports was
established by FDA in its regulations (21 C. F. R. 312.33).

Page 12 GAO- 01- 754 Women in Clinical Drug Trials

The language of the 1998 demographic regulation is less specific than the
1993 guidance. The 1998 regulation has the force and effect of law, while
the 1993 guidance does not legally bind either FDA or drug sponsors. The
1993 guidance specifically discusses the need to analyze clinical data by
sex, evaluate potential sex differences in pharmacokinetics, including those
caused by body weight, and conduct specific additional studies in women,
where clinically indicated. The 1998 regulation requires the presentation of
safety and efficacy data already collected in the NDA by sex, but no
analysis of such data is required. The regulation does not include a
standard for the inclusion of women; it requires only

?presentation of data? without clarifying the extent of data or the format
to be used. The regulation does require the identification of any
modifications in dose or dose interval because of sex, age, or race, but not
weight.

We found that the NDA summary documents and IND annual reports submitted to
FDA by drug sponsors frequently did not present information already
collected during drug development separately for men and women, as required
by the 1998 regulation. We found that 33 percent of the NDAs in our sample
did not include presentations of both safety and efficacy outcome data
separately for men and women. Similarly, we found that 39 percent of the IND
annual reports in our sample did not include the required information about
the sex of study participants.

One- third of the NDAs we examined did not include presentations for men and
women of both safety data in the Integrated Summary of Safety and of
efficacy data in the Integrated Summary of Efficacy. We considered the
presentation of outcome data by sex in an NDA for just one of the studies
included in that NDA to meet our criteria for regulatory compliance. Safety
outcome data by sex, either data about toxicity or adverse events or both,
were not included in 17 percent of the NDAs we reviewed. Similarly, 22
percent of the NDAs did not present efficacy outcome data separately for men
and women.

We found that 39 percent of the IND annual reports in our sample did not
include the demographic information required by regulation: 15 percent of
the annual reports were not submitted to FDA and 24 percent did not tabulate
the number of men and women enrolled in clinical drug trial FDA?s 1998
Regulation

Lacks Important Provisions of 1993 Guidance

NDA and IND Submissions Often Fail to Present Required Information

Page 13 GAO- 01- 754 Women in Clinical Drug Trials

studies. 21 Only 37 percent of the annual reports tabulated the enrolled
study populations by sex, as required by the 1998 regulations; 24 percent of
the annual reports stated that there were no ongoing studies.

All of the NDAs we examined included enough women in the pivotal trials to
demonstrate statistically that the drug was effective in women, even if the
sponsors did not report such an analysis or did not include the required
presentation of outcome data in the NDAs. Overall, more women than men
participated in clinical trials for the drugs we examined, although women
were a minority of the participants in the initial, smallscale safety
studies used to set the dosing levels for subsequent trials. We found that
most of the NDAs included analyses to detect differences between men and
women, but fewer of the NDAs explicitly included descriptions of both safety
and efficacy analyses that compared women taking the drug with a comparison
group of women taking a placebo or an alternative treatment. Analyses often
detected sex differences. The sex differences that were detected were
sometimes attributed to differences in body weight between men and women;
none of the sex differences that were detected were judged to be clinically
relevant, even when statistically significant. The NDA sponsors did not
recommend different dosage levels for men and women based on the sex
differences they detected.

All of the NDAs in our sample included enough women in the pivotal trials to
demonstrate statistically that the drug was effective in women; that is, the
numbers of women in the treatment and comparison groups of the pivotal
studies were sufficient to detect a statistically significant difference
between the treatment and comparison groups, given the magnitude of symptom
improvement experienced by the treatment group. However, one drug was
approved for use in men even though the NDA reported that no men
participated in the pivotal studies.

We did not attempt to demonstrate statistically that the drugs in our sample
were safe for women, because there are no absolute standards for the number
of required study participants for assessing drug safety. Generally, the
more patients that are exposed to a drug during its

21 These percentages are based on 75 INDs that were active in November 2000
and that were required to submit an annual report. For the remainder of the
100 IND application, 15 had been withdrawn, annual reports were not required
for nine, and FDA could not find one annual report that had been recorded as
having been filed. (See appendix I). NDAs Include

Appropriate Numbers of Women, but Analyses Sometimes Missing

Sufficient Numbers of Women Included to Determine Efficacy and Safety

Page 14 GAO- 01- 754 Women in Clinical Drug Trials

development, the more likely that significant adverse events will be
detected. Safety determinations are largely based on adverse events reported
for all participants in all studies. Since more women than men were included
in clinical trials for the NDAs we examined, the adverse event data gathered
for women were at least as extensive as the adverse event data gathered for
men.

A larger percentage of participants in clinical drug trials are women than
we found in our 1992 analysis of trials performed between 1988 and 1992.
Adjusting for differences in the classes of drugs included in the studies,
we found that the percentage of women participants in small- scale efficacy
and full- scale safety and efficacy trials increased from 44 percent in our
1992 study to 56 percent in the NDAs we examined. 22 In the current study,
summing across all the clinical trials for all of the NDAs we examined, 52
percent of the study participants were women, 39 percent were men, and 9
percent were not identified by sex. 23 When participants? sex was
identified, women were the majority of participants for 58 percent of the
NDAs.

Women made up more than one- half of all the participants in small- scale
efficacy and full- scale safety and efficacy trials. However, women were 22
percent of the participants in the initial, small- scale safety studies. One
of the NDAs included no women in the early safety trials. These early safety
studies are important because they measure how participants absorb,
metabolize, and excrete a drug, and their findings are used to help set the
dosage amounts for subsequent trials.

NDAs usually contained sex- related analyses of safety and efficacy,
regardless of whether the outcome data were presented in the summary
documents as required by regulation (see table 1). Evidence of these
analyses ranged from one- line summaries stating that there were no sex
differences, to more complete, multi- page tables and descriptions of
statistical methods and results. Specifically, most NDAs included analyses

22 These percentages do not include women in small- scale safety trials or
women in trials for types of drugs not included in both the 1992 and current
studies. (See appendix I.) 23 Our inability to determine the sex of some
study participants is due, in part, to the inclusion in some NDAs of data
from the medical literature and overseas trials that sometimes do not
present the number of clinical drug trial participants by sex. Progress Made
in Including

Women Overall, but Relatively Few Women in Early Studies

Frequency of Sex- Related Analyses Differs by Type and Purpose of Trials

Page 15 GAO- 01- 754 Women in Clinical Drug Trials

of safety and efficacy outcome data to detect differences between men and
women in their responses to drugs. NDAs were less likely to include
discussions of analyses of the safety and efficacy of drugs in women
specifically by comparing women who received the drug and a comparison group
of women.

Table 1: NDAs With Evidence of Sex- Related Analyses

(All figures in percent)

Analysis Analyzing differences between men and women

Analyzing differences between women receiving study drug and a comparison

group of women

Both safety and efficacy 72 42 Safety 81 44 Efficacy 89 78

Source: GAO?s review of 36 NDAs.

Fewer NDAs included analyses of pharmacokinetic data by sex, even though
analysis of pharmacokinetic data is explicitly recommended in the 1993
guidance. We found that 42 percent of NDAs presented outcome data for these
early studies for both men and women. Seventy- five percent of the NDAs we
reviewed had some evidence of an analysis of pharmacokinetic data for sex
differences.

Many of the NDAs we reviewed reported differences in men and women?s
responses to drugs, but fewer reported these differences to be statistically
significant (see table 2). For example, while one- half of the NDAs reported
drug safety differences between men and women, less than one- fifth of the
NDAs reported statistically significant sex differences in drug safety. 24
We found no evidence that any of the sex differences reported in any NDA on
any dimension- safety, efficacy, or pharmacokinetics- even when
statistically significant, were judged to be clinically relevant by either
the

24 Some of the NDAs that did not report significant sex differences failed
to describe any statistical tests. Failure to describe a statistical test or
report a significant difference does not necessarily mean that the
difference is not statistically significant. For example, in table 2, we
report that 50 percent of NDAs reported a sex difference in drug safety and
that 17 percent found these differences to be statistically significant. Of
the remainder, 28 percent conducted a statistical test and found that the
difference was not significant and 6 percent did not report a statistical
test. When Reported, Analyses

Sometimes Found SexRelated Differences

Page 16 GAO- 01- 754 Women in Clinical Drug Trials

NDA sponsors or the FDA reviewers, and no dose adjustments based on sex were
recommended.

Table 2: NDAs That Reported Differences Between Men and Women.

(All figures in percent)

Reported differences between men and

women Reported statistically

significant differences between men and women

Differences in safety 50 17 Differences in efficacy 42 14 Differences in
pharmacokinetics 58 28

Source: GAO?s review of 36 NDAs.

Some NDA sponsors also reported differences in either safety or efficacy
between women receiving the drug and women in a comparison group (see table
3). About one- fifth of the NDAs reported statistically significant
differences in safety between women taking the drug and a comparison group,
and about one- half found statistically significant differences in efficacy.

Table 3: NDAs That Reported Differences in Drug Response Between Women Using
the Test Drug and Women in the Comparison Group

(All figures in percent)

Differences reported between women using the test drug and women in a
comparison group

Statistically significant differences reported between women using the test
drug and women in a comparison group

Safety 36 19 Efficacy 69 53

Source: GAO?s review of 36 NDAs.

Apparent sex differences in pharmacokinetics, and sometimes safety and
efficacy, may be due to differences in weight between the sexes instead of
other biological differences. At a constant dosage, individuals who weigh
less have a higher exposure to the drug than heavier individuals, and, on
average, women weigh less than men. The potential for higher drug
concentration or exposure can lead to an increased risk of adverse events
Sex Differences Often

Attributed to Weight, but Sex- Related Dose Adjustments Not Recommended

Page 17 GAO- 01- 754 Women in Clinical Drug Trials

for women. 25 In our sample of NDAs, 36 percent reported pharmacokinetic
differences based on weight, whether or not sex differences were also
reported. Twenty- five percent of NDAs reported apparent sex differences in
drug response between men and women that were attributed to weight, not sex.
In these cases, the sponsors reported sex differences in drug response but
then noted that the differences disappeared when weight was taken into
account. In all of these cases of weight- related differences in men and
women?s responses to drugs, the sponsors asserted that no dose adjustments
were necessary based on sex. For two intravenously administered drugs and
one injectable drug the NDA did indicate dose adjustments based on weight
for all patients. 26

FDA has not effectively overseen the presentation and analysis of data
related to sex differences in drug development. There is no management
system in place to record and track the inclusion of women in clinical drug
trials or to monitor compliance with relevant regulations, so FDA is unaware
that many NDA submissions fail to meet requirements. The agency also does
not routinely review the required tabulation of demographic data by sex in
the IND annual reports for drugs in development. Finally, FDA?s medical
officers have not been required to discuss sex differences in their reviews,
and we found that their reviews frequently did not address the results of
sex- related analyses conducted by NDA sponsors. Until recently, FDA has
also lacked procedures to determine whether the reviews of its medical
officers adequately discuss sex differences. We did not find, nor did we
look for, any evidence that FDA?s reviews of the NDAs we examined had
negative public health consequences. Such an examination was beyond the
scope of this study. Recently, FDA has taken steps to pilot test several
initiatives to address these management needs.

FDA does not know how many women are included in clinical trials for each
NDA or if NDA summary documents comply with the data presentation
requirements of the 1998 regulation. There has been no systematic attempt by
FDA to routinely collect and organize data on the

25 See J. S. Bertino Jr. and A. N. Nafziger, ?Pharmacokinetics of Oral
Fleroxacin in Male and Premenopausal Female Volunteers,? Antimicrobial
Agents and Chemotherapy, Vol. 40, No. 3 (March 1996), pp. 789- 791.

26 Other dosing adjustments not related to sex were based on factors other
than weight, such as body surface area and the medical condition of the
individual patient. FDA Oversight Needs

Improvement

Page 18 GAO- 01- 754 Women in Clinical Drug Trials

inclusion of women in clinical trials. Although FDA officials told us that
they believe that regulatory requirements are being met, FDA has no system
in place to provide information that would support that assertion. The
agency has not routinely tracked the required presentation of safety and
efficacy data from women participating in clinical trials for the drugs it
reviews.

FDA does not routinely review the required presentation of data about the
sex of study participants in the IND annual reports. As we noted earlier, 39
percent of the required IND annual reports did not include the tabulation of
demographic information about study participants mandated by the 1998
regulation. We found no evidence that FDA follows up with sponsors that have
not submitted annual reports- about 15 percent in our sample. A senior FDA
official told us that the agency does not rely upon the information in these
reports to monitor pre- NDA drug testing. According to this official, the
agency instead uses other reports submitted by the sponsors for which there
are no regulatory requirements to tabulate clinical trial participants by
sex.

FDA?s Medical Officer Reviews are important documents that detail FDA?s
evaluation of the safety and efficacy of new drugs. We found that FDA?s
medical officers have not been required to address sex differences in their
reviews, and many of the medical officers? reviews we examined did not
address the sex- related data and analyses included in the NDAs (see table
4). For example, FDA?s medical officers did not discuss in their written
reviews why reported differences between men and women in their responses to
drugs did not require dose adjustments. In some cases, apparent
contradictions in the NDAs about the role of sex or weight within the text
of a drug application were not addressed.

Table 4: Medical Officer Reviews Not Discussing Sponsor- Reported Sex-
Related Analyses of Differences in Drug Response

(All figures in percent)

No discussion of analyses of differences in drug response between men

and women No discussion of analyses of

differences in drug response between women using the test drug and women in
a comparison

group

Safety 61 81 Efficacy 58 75 Pharmacokinetics 44 n/ a a

Source: GAO?s review of 36 Medical Officer Reviews. a Pharmacokinetic
studies are usually performed using just the test drug.

Page 19 GAO- 01- 754 Women in Clinical Drug Trials

Since December 2000, FDA has pursued several initiatives that directly
address areas of concern related to the review of sex differences. First, to
help track the number of women in clinical trials and to monitor the
compliance of NDAs with data reporting regulations, FDA began pilot testing
a worksheet for reviewers to capture demographic information about the
participants in large- scale efficacy trials. Instructions for the worksheet
that will allow it to be used by all of FDA?s reviewers are being developed.
Second, to help ensure that its medical officers address sex differences,
FDA began pilot testing a standardized template for Medical Officer Reviews.
The template instructs medical officers to discuss sexrelated issues in a
standard format in all of their reviews. Third, an electronic training
package was recently implemented to provide information to FDA?s medical
reviewers on the guidance and regulations applicable to the review of sex-
related data and analyses included in NDAs. However, FDA does not require
reviewers to use the training package.

We found that women were a majority of the clinical trial participants in
the NDAs we examined and that every NDA included enough women in the pivotal
studies to be able to demonstrate statistically that the drug is effective
in women. While these findings are welcome, we also found three areas of
concern. The first is the relatively small proportion of women in early
small- scale safety studies. These early studies provide important
information on a drug?s toxicity and safe dosing levels for later stages of
clinical development, and many of the NDAs we examined found significant sex
differences in a drug?s pharmacokinetics, or how it is absorbed,
distributed, metabolized, excreted, and concentrated in the bloodstream.
Second, we are not confident that either NDA sponsors or FDA?s reviewers
took full advantage of the available data to learn more about the effects of
the drug in women and to explore potential sex differences in dosing. This
is because NDA summary documents are not required to include analyses of sex
differences, and some of them do not. Similarly, FDA?s medical officers have
not been required to discuss sex differences in their reviews, and many of
the reviews we examined did not include complete discussions of potential
sex differences. Third, FDA does not now have appropriate management systems
to monitor how many women are in clinical trials, to be assured that NDAs
and IND annual reports are in compliance with pertinent regulations for
presenting outcome data by sex and tabulating the number of women included
in ongoing trials, or to confirm that its medical officers have adequately
addressed sex- related issues in their reviews. While FDA has taken some
promising initial steps to address these deficiencies, it is important that
Conclusions

Page 20 GAO- 01- 754 Women in Clinical Drug Trials

the agency finalize the pilot programs it has underway and give sustained
attention to these management issues.

We recommend that FDA adopt management tools that will ensure drug sponsors?
compliance with current regulations regarding the presentation of data by
sex and that its reviewers? consistently and systematically discuss sex
differences in their written reviews of NDAs. Specifically, we recommend
that the Acting Principal Deputy Commissioner of FDA:

 Promptly implement management tools, such as the proposed demographic
worksheet and the standardized template for Medical Officer Reviews, that
will allow the agency to determine whether NDAs and IND annual reports are
in compliance with regulations that mandate the presentation of available
safety and efficacy outcome data for women in NDAs and the tabulation of
study participants by sex in IND annual reports.

 Fully implement the proposed template for Medical Officer Reviews or take
other actions to ensure that FDA?s medical officers consistently and
systematically consider and discuss sex differences in their written reviews
of NDAs.

We received written comments from FDA on a draft of this report (see
appendix III). FDA generally agreed with our findings. FDA did not comment
on our recommendations, but outlined additional steps it may take to monitor
the inclusion of women in clinical trials. FDA questioned our description of
comparisons between men and women, and comparisons between women taking the
drug and a comparison group of women, as two distinct types of analyses. FDA
pointed out that an analysis of sex differences implies that an analysis of
the drug?s efficacy in women has been completed because an analysis of sex
differences is a comparison of the drug?s efficacy in men and women. We have
clarified the text, but we continue to present information about both
analyses in order to accurately reflect the contents of the NDA summary
documents we reviewed. Finally, FDA pointed out that its efforts to improve
its management in this area have been underway for some time. In response,
we modified our description of FDA?s activities. FDA also made additional
technical comments that we have incorporated where appropriate.

As we arranged with your offices, unless you publicly announce the contents
of this report earlier, we plan no further distribution until 30 days
Recommendations for

Executive Action Agency Comments

Page 21 GAO- 01- 754 Women in Clinical Drug Trials

after its issue date. At that time, we will send copies of this report to
the Acting Principal Deputy Commissioner of FDA and to others who request
them.

If you or your staff have any questions, please contact me at (202) 512-
7119. Another contact and major contributors to this report are listed in
appendix IV.

Janet Heinrich Director, Health Care- Public Health Issues

Appendix I: Objectives, Scope and Methodology

Page 22 GAO- 01- 754 Women in Clinical Drug Trials

Our work addressed four questions: (1) what FDA regulations govern the
inclusion of women in clinical drug trials; (2) are the regulations being
followed; (3) are appropriate numbers of women included in clinical drug
trials to ensure the safety and efficacy of drugs for women; and (4) how
does FDA oversee the collection, presentation, and analysis of data related
to sex differences? Our work did not include an examination of post
marketing adverse events or negative public health consequences.

To assess FDA?s oversight of the collection, presentation, and analysis of
data related to sex, we reviewed the FDA Medical Officer Reviews for all
sampled NDAs. We also interviewed officials in FDA?s Center for Drug
Evaluation and Research, the Office of Special Health Issues, and the Office
of Women?s Health. We also interviewed officials from drug companies and an
industry trade association. To gain background knowledge on the issues
related to our work, we spoke with women?s health advocates and consulted
pharmacology experts. We conducted a literature review that included
relevant FDA guidance and regulations, FDA and IOM reports, medical journal
articles, prescription drug labels, and consumer advocacy publications.

Because FDA maintains no central source of data on the inclusion of women in
clinical drug trials, we sampled NDAs for new molecular entities (NME)
submitted to FDA from August 10, 1998 through December 31, 2000. Of the 82
original NDAs for NMEs submitted to FDA during this period, we examined all
36 that were either approved for marketing or judged approvable by FDA by
December 31, 2000, and that met our other selection criteria. We narrowed
our focus to only approved and approvable NDAs because these drugs are the
most likely to reach the public. We excluded diagnostic drugs used in
medical imaging, drugs for sex- specific conditions, pediatric drugs, and
drugs that were not approved for use in both men and women. We also did not
examine biologic products, such as vaccines. As a result of our sampling
criteria, the clinical drug trials for some drug classes that have been
cited by experts as including insufficient numbers of women were not well
represented. For example, our sample included only one cardiovascular drug.

We requested from FDA and reviewed critical summary documents for each NDA,
including the Integrated Summary of Safety, the Integrated Summary of
Efficacy, the Pharmacokinetics and Bioavailability Summary, and the FDA
Medical Officer Review. We obtained and reviewed other NDA documents only
when the summary documents referred to relevant information. We reviewed the
NDA summary documents because the 1998 Appendix I: Objectives, Scope and

Methodology NDA Sample

Appendix I: Objectives, Scope and Methodology

Page 23 GAO- 01- 754 Women in Clinical Drug Trials

regulations specifically require NDA sponsors to present data about drug
safety and efficacy in the Integrated Summary of Safety and the Integrated
Summary of Efficacy and because we were unable to review all of the
documents in each NDA (an entire NDA can contain as many as 250 volumes).
Our findings speak only to what was included in the summary documents or in
the supplemental documents we examined; we did not systematically review
other relevant data, such as data in clinical pharmacology reviews, that may
have been presented in NDA volumes other than the critical summary
documents.

In our reviews of the critical summary documents we collected data on (1)
the presentation of outcome data by sex, (2) the number of women
participating in clinical drug trials by drug development stage, (3) the
frequency and extent of sex- related analyses, (4) the detection of
sexrelated differences in drug response and their statistical significance,
and (5) the relationship between body weight and sex- related differences.
The decision rules we used to code the NDAs are presented in table 5. In
general, we coded the information we sought as present if there was any
mention of it in the summary documents.

Table 5: Decision Rules for Collection of Data From NDA Critical Summary
Documents.

Objectives Decision Rules

Coding presentation of outcome data by sex Presentation of outcome data by
sex for one study met our

criteria for regulatory compliance Tabulating number of trial participants
Participant numbers were tabulated for all trials in which data

were directly used to prove drug safety and efficacy Coding the number of
trial participants by phase

Unless otherwise specified in NDAs, trials with less than 50 healthy
volunteers were ?Phase 1,? 50 to 100 patients with a control group were
?Phase 2,? and more than 100 patients with a control group were ?Phase 3?

?Phase 1/ 2? trials were coded as ?Phase 1? and ?Phase 2/ 3? were coded as
?Phase 2? Coding sex- related analyses At least a one- line summary of the
results of the sex- related

analyses for one study met our criteria for sex- related analyses Coding
sex- related differences Reported sex- related differences for at least one
study met our

criteria for detecting sex differences in safety, efficacy, or
pharmacokinetics Differences that were reported as being ?clinically
significant? were not coded as being ?statistically significant? Coding
weight- related differences Reported weight- related differences were
recorded

Reported weight- related differences were coded as sexrelated differences if
the sponsor reported ?no sex differences when weight is accounted for?

Appendix I: Objectives, Scope and Methodology

Page 24 GAO- 01- 754 Women in Clinical Drug Trials

To determine if IND annual reports filed with FDA met the regulatory
requirement for tabulating the sex of enrolled study participants, we
randomly selected a sample of 100 IND applications that met our inclusion
criteria from FDA?s November 2000 listing of active commercial IND
applications. That listing included a total of 3,636 IND applications.
According to FDA?s management information system, 15 of the IND applications
in our sample had been withdrawn and were not active, and sponsors for 9 of
the IND applications were not required to submit annual reports because they
had not been active for a long enough period. We also found that FDA could
not find one of the annual reports (see table 6). Because we randomly
selected the IND annual reports we examined, our findings are generalizable
to the entire set of IND annual reports. However, because of the small size
of our sample, our estimate of the proportion of annual reports not
fulfilling regulatory requirements is not precise.

In our review of the remaining 75 IND annual reports, the reports were
considered to have met regulatory requirements if the numbers of enrolled
participants were reported by sex for at least one of the reported studies.
The regulation requires ?tabulation? of the data; for purposes of our review
we considered any presentation of the demographic data to meet the IND
regulatory requirements.

Table 6: Description of the IND Annual Report Sample IND annual reports
Number Description

Total 100 Initial sample 24 Submission not required

9 IND applications filed less than a year ago 15 IND applications withdrawn
Not used

1 Logged as filed, but could not be located by FDA Used 75 Tabulation of
data by sex required for regulatory

compliance 64 IND annual reports submitted 11 IND annual reports not
submitted

We weighted the percentage of women by drug class to compare the percentage
of women in clinical drug trials from our sample to that of our 1992 study.
In weighting the percentage of women in our study by the percentage of
participants in trials for each drug class used in the 1992 study, we were
able to control for differences in the types of drugs IND Sample

Comparison With Our 1992 Study

Appendix I: Objectives, Scope and Methodology

Page 25 GAO- 01- 754 Women in Clinical Drug Trials

sampled and compare the two studies as if our sample included the same
drugs. For example, participants in cancer drug trials made up 7 percent of
all participants in the 1992 study of clinical drug trials but only 5
percent of the participants in the small- scale efficacy and full- scale
safety and efficacy clinical trials we examined in this study. By weighting
our sample so that 7 percent of the study participants we found were in
trials for cancer drugs, for example, we can fairly compare the percentages
of women participating in clinical drug trials from our 1992 study to those
from this study.

In reviewing the 36 NDAs, we also collected information to determine whether
enough women were tested in the clinical drug trials to detect sex
differences. Standards for participation of women in clinical drug trials
have included nominal thresholds for women?s participation (e. g., in our
1992 report, we regarded NDAs that tested 250 or more women as having enough
women) and the representation of the sexes in numbers that are proportional
to those in the population for whom a drug is intended. For this study, we
adopted the perspective that the clinical trials should include a large
enough number of women to demonstrate the safety and efficacy of the drug
for women. To determine if enough women were tested in clinical drug trials
to demonstrate the drugs? efficacy in women, we generally conducted a power
analysis using the number of participants in, and outcome data from, pivotal
trials. 1 NDAs that reported a statistically significant improvement in
women taking the drug compared to women in a control group clearly had
enough women in the pivotal trials to meet this criterion. For NDAs that did
not report this analysis, we took the largest effect size presented in the
Integrated Summary of Efficacy (that is, the largest percentage improvement
for those taking the drug), the total number of women participating in the
treatment group for all of the pivotal trials, and the total number of women
participating in the comparison group for all of the pivotal trials. We then
calculated the critical ratio, and significance level, for that effect size
and that number of cases. We found that all of the NDAs we examined in this
way had enough women in the pivotal trials to demonstrate that the drug had
a statistically significant effect. We followed the convention that
statistical tests with a probability level less than or equal to .05 are
regarded as statistically significant.

1 Based on sample size and response rates, four drugs were determined to
have a sufficient number of women, so that power analyses were not
conducted. Power Analysis for Women

in Pivotal Trials

Appendix I: Objectives, Scope and Methodology

Page 26 GAO- 01- 754 Women in Clinical Drug Trials

We conducted our work from July 2000 through May 2001 in accordance with
generally accepted government auditing standards.

Appendix II: Estimates of the Number of Men and Women in Clinical Drug
Trials

Page 27 GAO- 01- 754 Women in Clinical Drug Trials

We were able to estimate the number of men and women who participated in the
clinical drug trials for the 36 NDAs in our sample by reviewing the NDA
summary documents and FDA Medical Officer Reviews. Table 7 represents the
estimated percentage of men and women who participated in the clinical drug
trials by drug development stage. Table 8 represents the estimated number of
men and women who participated in the pivotal clinical drug trials overall,
and, where available, in the treatment and comparison groups of the pivotal
trials. The data in both tables are grouped according to drug class. For
some NDAs, the sex of some or all of the participants was not specified by
clinical drug development stage or treatment group. Appendix II: Estimates
of the Number of Men

and Women in Clinical Drug Trials

Appendix II: Estimates of the Number of Men and Women in Clinical Drug
Trials

Page 28 GAO- 01- 754 Women in Clinical Drug Trials

Table 7: Estimate of Women and Men in Clinical Drug Trials by Drug Class NDA
Overall Small- Scale Safety Trials Subsequent Safety and Efficacy

Trials Total Percent

Women Percent Men Total Percent

Women Percent Men Total Percent

Women Percent Men Analgesics and Anesthetics (3)

A 28,815 66 34 813 23 77 28,002 67 33 B a 10,702 44 17 1, 531 14 18 9,171 49
17 C a 5,659 24 35 523 24 73 5,136 24 32

Anti- Infectives and Immunosuppressants (9)

A a 5,924 40 59 482 21 74 5,442 42 57 B a 6,578 52 44 490 28 72 6,088 54 42
C a 1,545 15 79 418 11 68 1,127 17 83 D 6, 860 51 49 722 34 66 6,138 53 47 E
a 4,272 53 45 274 17 83 3,998 55 42 F a 9,327 51 49 557 9 79 8, 770 54 46 G
2, 995 32 68 730 22 78 2,265 35 65 H 1, 673 21 79 675 27 73 998 16 84 I a
7,544 46 36 1,103 10 78 6,441 52 28

Cancer (5)

A a 1,195 34 53 202 21 32 993 37 57 B 3, 527 99 1 123 73 27 3,404 100 0 C a
1,472 4 5 40 50 50 1,432 3 4 D a 684 31 64 186 38 55 498 28 67 E a 927 51 48
184 45 55 743 52 46

Diabetes & Cholesterol (5)

A a 1,543 42 43 240 4 4 1,303 50 50 B 2, 455 40 60 155 8 92 2, 300 43 57 C a
4,689 37 53 529 11 89 4,160 41 48 D a 8,084 34 65 528 19 81 7,556 35 64 E 4,
465 43 57 720 23 77 3,745 47 53

Neuropharmacological (6)

A 3, 226 50 50 307 20 80 2,919 53 47 B 5, 480 83 17 352 31 69 5,128 87 13 C
5, 042 84 16 289 43 57 4,753 86 14 D a 5,833 52 37 391 31 69 5,442 54 35 E a
9,333 56 15 578 15 81 8,755 58 11 F a 955 26 39 104 0 100 851 29 32

Ophthalmological (5)

A 1, 557 58 42 82 44 56 1,475 59 41 B a 1,084 34 33 40 20 80 1,044 35 32 C
5, 238 52 48 22 50 50 5,216 52 48 D a 2,438 39 33 34 41 59 2,404 39 33 E a
988 46 44 271 39 61 717 48 38

Appendix II: Estimates of the Number of Men and Women in Clinical Drug
Trials

Page 29 GAO- 01- 754 Women in Clinical Drug Trials

NDA Overall Small- Scale Safety Trials Subsequent Safety and Efficacy Trials
Total Percent

Women Percent Men Total Percent

Women Percent Men Total Percent

Women Percent Men Other (3)

A 1, 855 77 22 220 23 71 1,635 85 15 B 6, 895 52 48 207 17 83 6,688 53 47 C
a 5,847 66 28 1,443 28 72 4,044 85 15

Total a 176,706 52 39 15,565 22 67 160,781 55 36

Source: Estimated from GAO analysis of 36 NDAs and FDA Medical Officer
Reviews. a Indicates NDAs where the sex of some or all of the participants
was not specified by clinical drug

development stage (sum of percent women and percent men does not equal 100).

Appendix II: Estimates of the Number of Men and Women in Clinical Drug
Trials

Page 30 GAO- 01- 754 Women in Clinical Drug Trials

Table 8: Estimate of Men and Women in Pivotal Drug Trials by Drug Class
Overall Comparison Group Treatment Group Total Women Men Total Women Men
Total Women Men Analgesics and Anesthetics (3)

A a 19,082 B 3, 022 2,279 743 1,111 850 261 1,911 1,429 482 C 931 253 678
373 106 267 558 147 411

Anti- Infectives and Immunosuppressants (9)

A 1, 572 649 923 790 337 453 782 312 470 B 5, 829 3,258 2,571 2,102 1,201
901 3,727 2,057 1,670 C 736 128 608 366 67 299 370 61 309 D 1, 588 808 780
775 419 356 813 389 424 E 1, 346 670 676 443 228 215 903 442 461 F 7, 246
3,617 3,629 2,967 1,506 1,461 4,279 2,111 2,168 G 1, 295 438 857 291 109 182
1,004 329 675 H a 998 164 834 386 66 320 385 75 310 I a 5,644 3,021 1,556
2,508 1,836 672 2,145 1,302 843

Cancer (5)

A 387 145 242 113 41 72 274 104 170 B 1, 176 1,176 0 597 597 0 579 579 0 C
592930 0 0 0592930 D a 1785894 0 0 01525894 E 287 118 169 103 45 58 184 73
111

Diabetes & Cholesterol (5)

A a 561 283 278 110 56 54 450 227 223 B 2, 090 961 1,129 715 324 391 1,375
637 738 C 2, 826 1,300 1,526 1,406 642 764 1,420 658 762 D 2, 635 932 1,703
753 233 520 1,882 699 1,183 E a 2,319 1,047 1,272 789 366 423 1,512 677 835

Neuropharmacological (6)

A 904 431 473 312 156 156 592 275 317 B a 2,319 1,987 332 549 463 86 1,768
1,522 246 C a 4,057 3,520 537 319 273 46 1,123 961 162 D 1, 289 803 486 428
263 165 861 540 321 E a 5,986 5,100 886 F 366 167 199 126 57 69 240 110 130

Ophthalmological (5)

A 305 167 138 25 17 8 280 150 130 B 388 194 194 193 94 99 195 100 95 C 2,
406 1,237 1,169 923 473 450 1,483 764 719 D 1, 127 583 544 470 242 228 657
341 316 E 609 344 265 207 130 77 402 214 188

Appendix II: Estimates of the Number of Men and Women in Clinical Drug
Trials

Page 31 GAO- 01- 754 Women in Clinical Drug Trials

Overall Comparison Group Treatment Group Total Women Men Total Women Men
Total Women Men Other (3)

A 484 453 31 164 155 9 320 298 22 B 3, 177 1,766 1,411 1,597 915 682 1,580
851 729 C 881 731 150 288 240 48 593 491 102

Total a 86,105 38,817 27,113 22,299 12,507 9, 792 34,858 19,012 15,846

Source: Estimated from GAO analysis of 36 NDAs and FDA Medical Officer
Reviews. a Indicates NDAs in which the sex of participants was not specified
for some 0--= 09or all of the pivotal

studies overall, the comparison group, or the treatment group.

Appendix III: Comments From the Food and Drug Administration

Page 32 GAO- 01- 754 Women in Clinical Drug Trials

Appendix III: Comments From the Food and Drug Administration

Appendix III: Comments From the Food and Drug Administration

Page 33 GAO- 01- 754 Women in Clinical Drug Trials

Appendix III: Comments From the Food and Drug Administration

Page 34 GAO- 01- 754 Women in Clinical Drug Trials

Appendix IV: GAO Contact and Staff Acknowledgments

Page 35 GAO- 01- 754 Women in Clinical Drug Trials

Martin T. Gahart, 202- 512- 3596 Lisanne Bradley, Emily J. Rowe, Robert M.
Copeland, Lawrence S. Solomon, Anh Bui, and Jenny C. Chen also made major
contributions to this report. Appendix IV: GAO Contact and Staff

Acknowledgments GAO Contact Staff Acknowledgments

Related GAO Products Page 36 GAO- 01- 754 Women in Clinical Drug Trials

Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks
for Women (GAO- 01- 286R, January 23, 2001).

Women?s Health: NIH Has Increased Its Efforts to Include Women in Research
(GAO/ HEHS- 00- 96, May 2, 2000).

Women?s Health: FDA Needs to Ensure More Study of Gender Differences in
Prescription Drug Testing (GAO/ HRD- 93- 17, October 29, 1993).

National Institutes of Health: Problems in Implementing Policy on Women in
Study Populations (GAO/ T- HRD- 90- 50, July 24, 1990). Related GAO Products

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