NEJM Editorial

Women in Clinical Trials -- A Portfolio for Success

Just a decade ago, in September 1990, public and political concern about
the underrepresentation of women in major clinical trials, especially
trials focusing on cardiovascular disease, resulted in the establishment of
the Office of Research on Women's Health by the National Institutes of
Health (NIH).

The mission of the office was to set an agenda for research on women's
health and to ensure that women and members of minority groups would be
included in clinical research funded by the NIH.

Three years later, the NIH Revitalization Act required that the NIH
strengthen its policies to ensure not only that women and members of
minority groups would be included in clinical trials but also that, if
scientifically appropriate, they would be included in adequate numbers to
allow valid analysis of differences according to sex and race or ethnic
background in the effects of therapies.

By many measures, these efforts have been successful, as indicated in the
article by Harris and Douglas in this issue of the Journal.

After reviewing all clinical trials on cardiovascular topics that were
funded by the National Heart, Lung, and Blood Institute between 1965 and
1998, the authors found that women were enrolled in trials at rates that
exceeded the prevalence of cardiovascular disease among women in the
general population and that the proportion of women in such trials had
increased over time.

Even after excluding single-sex trials, the authors found that the
enrollment of women in mixed-sex clinical trials was still consistent with
the prevalence of cardiovascular disease among women.

This finding is in accord with a recent report by the General Accounting
Office on women in all NIH-funded studies.

Women represented 61.9 percent of all subjects enrolled in NIH-funded
extramural trials in 1997; after the exclusion of single-sex protocols,
women accounted for 52 percent of the subjects.

With regard to specific types of cardiovascular disease, Harris and Douglas
found that the rates of enrollment of women in studies of coronary artery
disease and hypertension were similar to the prevalence of these diseases
in women.

In contrast, women were consistently underrepresented in studies of heart
failure, with little or no improvement over time.

In describing these changes, which are encouraging overall, the authors
note that much of the increase in the enrollment of women in clinical
trials involving cardiovascular disease has been due to the initiation of
two large single-sex trials, both investigating the primary prevention of
cardiovascular disease, rather than to across-the-board increases in the
enrollment of women in such trials.

They conclude that single-sex trials should not be the solution to the
systemic problem of the underrepresentation of women in cardiovascular trials.

Their caution is appropriate. But the question remains, should single-sex
trials be used as one of the strategies in the epidemiologic arsenal for
addressing sex-specific issues?

To answer this question, we must keep in mind the overarching purpose of
increasing women's participation in clinical trials -- to gain better
information about women's health -- while considering the two different but
complementary goals that underlie the NIH guidelines: the representation of
relevant populations and the assessment of possible differences in
treatment effects.

With respect to the first goal, it is important to ensure that a population
at risk for a particular disease or receiving treatment for it is
represented in the relevant clinical trials.

This applies not only to women but also to elderly persons, members of
racial or ethnic minorities, and other populations.

Only when this goal is met will clinical decision making for women, for
example, be based on direct findings in women rather than on an
extrapolation from the findings in men.

The second goal, assessing possible differences in the effects of
treatment, is equally important from a scientific perspective.

It is also more difficult to achieve than the goal of representation.

To determine definitively whether an intervention or therapy affects women
and men differently, adequate numbers of both men and women must be
included in the trial.

This issue is not always relevant to a therapy or intervention, as there
are often more similarities than differences between the effects of
treatment in women and in men.

But if the sex-specific effects of an intervention are to be evaluated,
then the mere representation of women will not be sufficient.

The trial must include a large enough number of women to ensure that the
study has the statistical power to evaluate the effect of the intervention
in each sex and to compare the magnitude of these effects.

The logistic problems in attaining this second goal are substantial.

For example, in the late 1980s, an analysis of data from the all-male
Physicians' Health Study showed a clear benefit of low-dose aspirin on the
risk of a first myocardial infarction, but the numbers of strokes and
deaths due to cardiovascular causes were too small to determine the effect
on these outcomes.

The Women's Health Study, one of the two large, single-sex, randomized
studies of cardiovascular disease initiated in the past decade, was
designed to evaluate the benefits and risks of low-dose aspirin and vitamin
E in the primary prevention of cardiovascular disease (and cancer) in women.

Because the base-line rate of cardiovascular disease is so much lower in
women than in men, a preventive therapy that could be evaluated in a sample
of 22,000 men over the age of 40 years in the Physicians' Health Study
required a sample of 40,000 women over the age of 45 years in the Women's
Health Study.

Even if the Physicians' Health Study had included 20,000 women and 20,000
men, it would not have had adequate statistical power to determine whether
low-dose aspirin reduced the risk of cardiovascular disease in women, let
alone to determine whether the magnitude of the effect differed between
women and men.

This point illustrates one of the dangers of conducting a trial with a
sample that is too small: it could have not just a null result but an
uninformative null result.

That is, the lack of a statistically significant effect may be due either
to the ineffectiveness of the therapy or to the inability of the study to
detect an effect because the sample is too small.

Underpowered trials can do great scientific harm if their results are
misinterpreted as demonstrating that an intervention has no effect; often,
in fact, it may have an effect but the sample is simply too small to
determine whether it does.

When sex-specific differences are to be evaluated in a trial, the crucial
question is how best to achieve this scientific goal.

A single approach is unlikely to be effective in all situations, and a
variety of approaches must be considered.

For example, in the Antihypertensive and Lipid Lowering Treatment to
Prevent Heart Attack Trial, funded by the National Heart, Lung, and Blood
Institute, the investigators enrolled a disproportionately high percentage
of black participants in order to be able to evaluate the effect of each
therapy in blacks, who are at particularly high risk for hypertension.

On the other hand, the Women's Health Initiative combined two approaches,
the use of a single-sex trial plus the inclusion of sites with large
minority populations, in order to obtain adequate representation of women
of different racial and ethnic backgrounds.

The choice of the research design must always be driven by good science,
and the inclusion of relevant populations must be addressed in developing
the research design that is most appropriate to the scientific objectives
of the study.

The increased participation of women in clinical trials should not lull us
into relaxing our efforts in this area.

For example, as Harris and Douglas point out, women have historically been
underrepresented in clinical studies of heart failure, with little
improvement during the past decade.

Since slightly more women than men have congestive heart failure, it is
important to determine whether there are unique scientific issues or
barriers to the enrollment of women that can be addressed in order to
obtain direct evidence of the effects of therapies for heart failure in women.

In addition, the recent report by the General Accounting Office noted that
in the case of non-sex-specific studies, the investigators either did not
analyze the data according to sex or omitted the results of such analyses
from the findings published in medical journals.

The authors of the report concluded, "NIH needs to expand its focus beyond
simple inclusion and to ensure that, when it is scientifically appropriate,
researchers conducting clinical trials enroll populations and analyze study
data in ways that enable them to learn whether interventions affect women
and men differently."

No single study design is appropriate for answering all questions.

Gathering the best information on women's health requires a portfolio of
approaches.

Both single-sex and mixed-sex trials, if well designed and conducted, will
provide much-needed data for use in improving the cardiovascular, and
general, health of women.


Julie E. Buring, Sc.D. Brigham and Women's Hospital Boston, MA 02215

The New England Journal of Medicine
August 17, 2000
Vol. 343, No. 7
Copyright 2000 by the Massachusetts Medical Society.
All rights reserved.
"http://www.nejm.org/content/2000/0343/0007/0505.asp"

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