Are women being adequately represented in clinical trials at the National Institutes of Health?
That simple question, pondered by Florence Haseltine, PhD, MD more than a quarter of a century ago, has led to sweeping changes in the way women are viewed on a physical, behavioral … and now … molecular basis.
Changing the Status Quo
In the mid-1980s, Haseltine was working at the National Institute of Child Health and Human Development, which focused almost exclusively on women’s health in terms of maternal issues. Haseltine, who coined the term ‘sex-based biology,’ began gathering friends and colleagues together to champion additional women’s health concerns including endometriosis and ovarian cancer. Quickly, the mission grew to encompass much broader issues that disproportionately or differently impact women beyond the narrow scope of gynecologic disease.
The result was the formation of the Society for Women’s Health Research (SWHR) in 1990. One of the people tapped to be part of that early volunteer board was Phyllis Greenberger, who agreed to go to Capitol Hill with Haseltine to speak to the Congressional Caucus for Women’s Health Issues. “It turns out there was a 1985 Public Health Service report that was written by two doctors at the NIH that looked at whether there was enough attention on women’s health issues and were women being included in research. We used that report as ammunition,” Greenberger recalled, noting the answer to both questions was a resounding ‘no.’
At the behest of Greenberger and other SWHR volunteers, several members of Congress asked the Government Accounting Office (GAO) to investigate the NIH’s inclusion of women. Greenberger noted at that time the focus was on the disease without consideration of gender … even when the disease in question was known to disproportionately affect women, such as osteoporosis. “Nobody had any sort of separate designation for women, and it was mostly men in clinical trials,” she said. Greenberger added the safety profiles and effectiveness data of many drugs were based on outcomes of the mostly young, healthy, white men who populated clinical trials.
In the aftermath of the severe birth defects that resulted from use of thalidomide and DES, women of childbearing years had been generally excluded from participating in pharmaceutical trials by a Food & Drug Administration (FDA) guideline released 13 years earlier. When NIH directors were effectively ‘called on the carpet’ as a result of the GAO audit, Greenberger said the excuse for not using more women (of any age) was pinned on hormonal changes that could make it more difficult to measure results, coupled with a belief that men and women were basically alike except for the reproductive system.
A Big Year for Change
By 1993, the volunteer group made the decision to formalize and become a 501(c)(3) organization. Greenberger, who viewed the daunting task of changing the status quo as “fun and challenging,” applied for the founding staff leadership position with SWHR. As president and CEO, Greenberger has witnessed tremendous change in how women are assimilated into biomedical research but still sees the long road ahead to fully embrace diversity from bench to bedside.
That same year, Congress passed the NIH Revitalization Act of 1993, which SWHR had worked tirelessly to get passed. The legislation mandated women and minorities be included in clinical research and required Phase III trials be analyzed by gender. In light of the changes at the NIH, the FDA rescinded its earlier guideline mandating the exclusion of women with childbearing potential.
Moving the Science Forward
Although 1993 was a landmark year in terms of new rules and regulations for women’s health, Martha Nolan, JD, vice president of Public Policy for SWHR, noted it was simply a starting point. “Just changing the law didn’t necessarily turn a switch and have everyone be in agreement,” she said. “There was a lot of pushback.”
One example of the uphill battle to institute change is evident in the amount of time it took to codify various women’s health initiatives across the federal government. The 1993 Revitalization Act made the Office of Research on Women’s Health at the NIH permanent. However, a number of other similar initiatives were soon launched across federal agencies such as the Substance Abuse and Mental Health Services Administration (SAMHSA) and CDC. The Women’s Health Office Act (WHOA) was an effort to make these new entities permanent.
“In 1994, then Rep. (Olympia) Snowe (R-Maine), who became Sen. Snowe, introduced this legislation for the first time,” Nolan said. “It became law in 2010 when it passed in the Affordable Care Act.” Greenberger added, “It took us 16 years to get the women’s health offices into law to protect them.”
It only took about one-third of that time to get the Institute of Medicine to acknowledge the validity of sex-based biology. The organization submitted a proposal to Congress to have the IOM chart the future of medical research in terms of sex in 1996. Five years later, “Exploring the Biological Contributions to Human Health: Does Sex Matter?” concluded that, indeed, it does.
“Phyllis’ effort between 1993 and 2001 was to try to change the scientific and medical practice perspective,” said Nolan. SWHR launched scientific advisory meetings designed to engage the research community in debate and discussion about the role of sex and gender differences in a variety of diseases and conditions including the autoimmune system, cardiovascular health and addiction.
Although getting more women into trials was certainly important, Nolan said it was only part of the battle. “Just including women in equal numbers doesn’t matter if you’re not analyzing for differences,” she noted. Who benefitted? Who got hurt? Was it equal among subgroups, or was one outcome more predominant among men or women? Drilling down in the data was crucial.
In fact, Greenberger noted, “A 2001 GAO report that was an investigation of the FDA found that eight out of 10 of the most recent drugs pulled off the market had disproportionate adverse effects for women.”
Recently, Nolan added, another victory was achieved in moving the needle on meaningful analysis by SWHR and other advocacy organizations. “In 2012, we managed to get an amendment attached to a ‘must pass’ bill – the FDA Safety & Innovation Act – on demographic reporting that forced the agency to really look at how well demographic subgroups were represented in drugs already approved and to what extent demographic analysis played in the approval process and issue a report … which it did in 2013.”
Since then, she said, an action plan has been crafted to explain how the FDA will address research gaps. “There are 27 points to that action plan, which gives us much to digest and work on with the agency,” she noted.
Drilling Even Deeper
“What we learned after the IOM report is it isn’t just clinical science, it’s basic research, too,” Greenberger said.
Nolan added, “Our priorities are a continued focus on both the FDA and NIH due to changes that have occurred over the last several years. One is the determination by the director of NIH that sex be a variable and be considered in pre-clinical research. This is wonderful … it’s something we’ve been focused on for quite some time.”
While recognizing it will take time to implement such changes, Nolan promised, “The key is they’re going to do it, and we’re going to make sure they do it.”
Similarly, SWHR’s attention on molecular diagnostics and precision medicine also aims to discover the benefits of drilling deeper to find genomic variations and mutations impacting women’s health and treatment options.
What started as a simple question about how women were plugged into medical research and discovery has turned into a 25-year journey toward better health for half the nation’s population. Although there are many more miles to go, the SWHR remains committed to its unwavering goal of optimizing women’s health through education, advocacy, and research.
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For more information on the organization’s work and upcoming initiatives, go online to swhr.org.
TAGS: Society for Women’s Health Research, SWHR, Florence Haseltine, Phyllis Greenberger, Martha Nolan, National Institutes of Health, NIH, Office of Women’s Health Research, Institute of Medicine, IOM, WHOA, Women’s Health Office Act, Sex-Based Biology, Gender Health Analytics
PHOTOS: Requested headshots of Phyllis Greenberger and Martha Nolan.
WEB: swhr.org
RELATED LINKS:
Exploring the Biological Contributions to Human Health – Does Sex Matter?
http://www.nap.edu/openbook.php?isbn=0309072816