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The Mismeasure of Woman

Women and Clinical Trials

Sanyin Siang,, July 21, 2000, Issue 83

Advocates for including women in clinical trials have seen progress at the level of funded research. Now they are focusing efforts on getting the resulting data properly analyzed to uncover relevant clinical differences between the sexes.

Medical research is like Swiss cheese, with the holes being data on women's health. But as two recent studies show, the problem may now be more at the publications end than at the funding stage. A May 2000 report by the Government Accounting Office (GAO) on the funding practices of the National Institutes of Health (NIH) documented increased attention to research on female-prevalent conditions and dramatic progress in including women in clinical trials. The second study, a review by the Society for Women's Health Research (SWHR) of publications in four leading medical journals, reveals that journals lag far behind when it comes to publishing analyses by sex.

Historically, women have been excluded from many clinical trials for a number of reasons. These include a perceived difficulty in recruiting and retaining women for studies, the confounding effects of female hormonal changes, and a desire to protect a potential fetus. Because of the last reason, the U.S. Food and Drug Administration (FDA) further exacerbated the situation in 1977, when it barred women of childbearing age from clinical trials. Hence, for nearly a decade and a half, many medical research studies, including breast cancer trials, were done almost entirely on men.

Attempts to remedy the situation occurred in the 1985, when a U.S. Public Health Service (PHS) task force examined women's health and how the issue was addressed within the Department of Health and Human Services. The need for improvements prompting NIH to establish a policy that urged the inclusion of women in clinical trials. However, inconsistent implementation across NIH institutes led a 1990 GAO report to conclude that lack of compliance with guidelines and continued exclusion of women from clinical trials existed. Following that scathing report, Congress passed the NIH Revitalization Act of 1993, mandating the inclusion of women and minorities in clinical trials. In the same year, the FDA rescinded its restrictions on the participation of women of childbearing age. Finally, in 1994, NIH published proposed guidelines and revised its grant application form to help researchers comply with the new policies.

"Because women were overlooked as research subjects for so long, there are critical data gaps for the diseases and conditions that are unique to or prevalent among women," noted Regina Vidaver, a molecular biologist and coauthor of the SWHR study. "Studies are being conducted to fill in this information, but data on women's unique health concerns remain incomplete."

Now, nearly a decade after its initial study, GAO revisited the issue of women's health research at NIH and reassessed NIH's progress in implementing the inclusion policy. To do so, GAO Report author, Janet Heinrich, and GAO staff interviewed officials, reviewed documents and analyzed NIH's grant tracking data for all human subject studies funded during fiscal year 1997. They also analyzed NIH's expenditures for fiscal years 1993 to 1999. They compared NIH-wide and individual institute spending on women's health research with amounts for research on men and research on both women and men. They also examined NIH funding for conditions that are unique to or more prevalent in women.

The results were promising. The report documented that female participation in NIH-funded clinical research in fiscal year 1997 exceeded 50 percent, even when female-only or male-only studies were removed from the data set. Spending on women's health conditions grew by 39 percent between 1993 and 1997. This compares with a 23 percent increase on men's health research and 27 percent increase on research that affects both women and men. The figure outpaced NIH's own budget increase of 29 percent. Spending on female prevalent conditions such as osteoarthritis and breast cancer increased by nearly 80 percent and 60 percent, respectively.

"We are very gratified that the GAO thinks we are doing a good job," stated Ruth Kirschstein, acting director of NIH. "There is always room for improvement and we are going to continue to work very hard in this area." Kirschstein served as cochair of the PHS task force and as the first acting director of the NIH's Office of Research on Women's Health (ORWH). Already, the benefits of the improvements are surfacing. "With early detection and new therapies, we will begin to see and are seeing a decrease in mortality for breast cancer," commented Kirschstein, a survivor of that disease.

NIH's improved track record can be attributed to the accomplishments of ORWH, established in response to the 1990 GAO Report, working in collaboration with the NIH institutes and centers. The office uses its budget to leverage increased funding for research on women's health and supported extensive training and education programs on the inclusion policy for staff members, investigators, and institutional review boards (IRBs).

NIH also implemented a data tracking system for grants to monitor data on inclusion of women and minorities in clinical trials and to ensure that grants follow inclusion and sex-based analysis guidelines. "When the new law went into effect in 1994, researchers expected many hurdles, " remembered Vivian Pinn, director of ORWH. "What I have found is that in speaking in public areas all across the country about the need for women to participate in studies, we have women who express excitement about wanting to learn how they can participate in clinical research." According to Pinn, for fiscal year 1997, there were 3.75 million women in extramural clinical research compared to 2.3 million men.

One of the best examples of the great strides in this arena is the success of NIH's Women's Health Initiative, now based in the National Heart, Lung, and Blood Institute. The three-part project involves:

(1) A randomized clinical trial to look at the role of hormone replacement therapy, calcium, and vitamin D supplement, and dietary considerations in preventing cardiovascular disease, osteoporosis, and colon and breast cancers.

(2) An observational study to look at predictors of disease.

(3) A community prevention study.

The large-scale project has recruited 68,000 postmenopausal women for its clinical trials study and more than 100,000 women for its observational study, a feat when it comes to prevention studies since this type of research necessitates recruitment of healthy subjects. "This study has been exciting in that the women participating are helping us get information that will help their daughters and granddaughters. They understand that the long-term benefit will be for future generations," explained Pinn.

Other organizations also continue to address the issue of recruitment and retention of women in clinical trials. Earlier this year, SWHR launched a three-year campaign, Some Things that Only a Woman Can Do, to educate women about the importance of participating in research. The project Web site provides a fact sheet on health conditions that affect women, answers to common questions about medical research, and links to medical research studies on the Internet. Web site users can also email their questions to an expert and order a free educational kit. Another component involves collaboration with minority advocacy groups to reach their constituencies and translation of the education kit into Spanish. The campaign is a partnership among nearly a hundred other groups, including universities, hospitals, and industry.

When it comes to publishing research results and analyzing the data by sex, the study by SWHR in the June 2000 issue of the Journal of Women's Health and Gender-Based Medicine revealed less positive progress. Study authors sifted through thousands of research articles in the New England Journal of Medicine, the Journal of the American Medical Association, the Journal of the National Cancer Institute, and Circulation from the years 1993 to 1998. They assessed the papers for inclusion of women, funding source, type of study, sex-relatedness of the diseases, and sex-based analysis of study outcome. They discovered that among the NIH-funded non-sex-specific studies, approximately 20 percent published each year failed to include women, and of those that do, only 25 to 30 percent analyzed the data by sex differences. These numbers did not change significantly over the five-year time period.

"The discovery that men and women may react differently to drugs and treatment came about almost by accident," explained Vidaver. A literature review conducted by SWHR in 1998 revealed that sex and gender differences extend to a range of diseases and disease treatments, including the presentation of heart disease symptoms, drug reactions, rates of lung cancer, and susceptibility to illnesses such as depression, autoimmune diseases, and osteoporosis.

An example that highlights the importance of female inclusion and sex-based analysis is a study assessing the efficacy of aspirin in preventing heart disease. Initial trials testing only males determined that aspirin in low doses helped to prevent heart disease. Now, as researchers conduct small-scale versions of the study on women, they discover that daily intake of low dose of aspirin in women may increase the risk for hemorrhagic stroke, a condition more prevalent among women.

"Too many people believe that the inclusion of women in clinical research is the end, when actually it is a means to an end of performing sex analysis. It is only when sex analysis of clinical research is performed as the rule, rather than as an exception, can we come to a full understanding of human biology," stated Vidaver.

Some studies have analyzed the results according to men and women, but found no differences. In such cases, the journals often do not want to take up space with negative results. "A single sentence does not seem to be a major imposition," commented SWHR study coauthor Sherry Marts. "But it may offer a significant amount of information."

Following the study, SWHR sent a letter to editors of 32 medical journals, encouraging revisions of the journals' publication guidelines to reflect the inclusion policy and to analyze research data by sex.

"Questions about the availability and analysis of data comparing women and men must become part of peer review and editorial decision-making," the letter stated. What the organization hopes for is a sentence in the publication guidelines similar to that currently documenting approval of a human subjects study by an IRB. Thus far, the responses from editors have been promising. One journal editor requested examples and advice regarding editorial policy.

The May GAO Report had also cited the need to track implementation of sex-based analysis guidelines as an area for improvement at NIH. In response, Pinn explained that much of the research funded after the 1993 policy has not reached the analysis stage. Furthermore, the progress made in NIH funding and grant review practices since the new policy is not yet reflected in the medical literature. Phase III clinical trials may take four or more years to complete and even longer before the results are peer reviewed and published.

As the old data sets from studies initiated before the 1993 NIH policy phase out, and studies under the new guidelines conclude, the number of published studies including women is expected to increase. An informal survey of all NIH institutes in late May showed that only 54 Phase III clinical trials funded under the new policy have reached completion and, of those, only 36 have been published or submitted for publication. However, Pinn agrees with the need to publish results of clinical trials that define similarities or differences between men and women.

Sex-based differences have captured the interest of other organizations. This year, the Institute of Medicine (IOM) convened a blue-ribbon committee to review and evaluate the current knowledge base about these differences. Along with research on humans, the IOM committee will investigate priorities for animal and cellular models that could determine the existence of sex differences.

The committee will develop recommendations for overcoming barriers to this type of study, make use of new opportunities in basic and applied research, and fill identified research gaps. The project, cosponsored by several groups including SWHR, NIH, ORWH, the National Institute of Drug Abuse, and the National Institute of Environmental Health Science, and PHS's Office of Women's Health, expects to publish its findings in spring 2001.

"The ultimate test of whether or not we are addressing women's health research will be determined by the progress in knowledge as well as the new findings, new questions, and new answers that arise," concluded Pinn. "That will not be documented in numbers. While we have seen lots of progress, there's still a lot that we need to investigate. That's the essence of the scientific inquiry."

Sanyin Siang works on a variety of issues at the intersection of science, ethics, and law at the Directorate for Science Policy Programs of the American Association for the Advancement of Science.

Michelle Flynn is a professional artist whose work may be seen throughout the United States and Canada. Until recently, Michelle was the staff artist for the magazine Warmwater FlyFishing from Abenaki Publishers.




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