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withdrawn from the U.S. market in recent years induced potentially fatal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 group6

 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, §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’

 10See “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.

11General 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

 12See 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.

13We 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

 14A 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.)

15Regulations 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.)

16Clinically 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 Drugs17 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.

 17Federal Register, Vol. 58, No. 139, pp. 39406-39416, July 22, 1993.

18In 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.

19Federal Register, Vol. 63, No. 28, pp. 6854-6862, Feb. 11, 1998.

20While the Federal Food, Drug, and Cosmetic Act (21 U.S.C. §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

 21These 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

 22These 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.)

23Our 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

 24Some 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

 25See 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.

26Other 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/aa

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

Ba 10,702 44 17 1,531 14 18 9,171 49 17

Ca 5,659 24 35 523 24 73 5,136 24 32

Anti-Infectives and Immunosuppressants (9)

Aa 5,924 40 59 482 21 74 5,442 42 57

Ba 6,578 52 44 490 28 72 6,088 54 42

Ca 1,545 15 79 418 11 68 1,127 17 83

D 6,860 51 49 722 34 66 6,138 53 47

Ea 4,272 53 45 274 17 83 3,998 55 42

Fa 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)

Aa 1,195 34 53 202 21 32 993 37 57

B 3,527 99 1 123 73 27 3,404 100 0

Ca 1,472 4 5 40 50 50 1,432 3 4

Da 684 31 64 186 38 55 498 28 67

Ea 927 51 48 184 45 55 743 52 46

Diabetes & Cholesterol (5)

Aa 1,543 42 43 240 4 4 1,303 50 50

B 2,455 40 60 155 8 92 2,300 43 57

Ca 4,689 37 53 529 11 89 4,160 41 48

Da 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

Da 5,833 52 37 391 31 69 5,442 54 35

Ea 9,333 56 15 578 15 81 8,755 58 11

Fa 955 26 39 104 0 100 851 29 32

Ophthalmological (5)

A 1,557 58 42 82 44 56 1,475 59 41

Ba 1,084 34 33 40 20 80 1,044 35 32

C 5,238 52 48 22 50 50 5,216 52 48

Da 2,438 39 33 34 41 59 2,404 39 33

Ea 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

Ca 5,847 66 28 1,443 28 72 4,044 85 15

Totala 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)

Aa 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

Ha 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 59 29 30 0 0 0 59 29 30

Da 178 58 94 0 0 0 152 58 94

E 287 118 169 103 45 58 184 73 111

Diabetes & Cholesterol (5)

Aa 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

Ea 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

Ba 2,319 1,987 332 549 463 86 1,768 1,522 246

Ca 4,057 3,520 537 319 273 46 1,123 961 162

D 1,289 803 486 428 263 165 861 540 321

Ea 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

Totala 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).

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