It's a Man's World—and it Shouldn't Be

June 1, 2013

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-06-01-2013, Volume 22, Issue 6

Women should be represented more in studies and greater attention paid to their general health issues.

Nearly everyone involved in drug research in Europe is peering ahead at what advantages they might derive from the futuristically-titled Horizon 2020. This is the European Union's multi-billion dollar research program, which is due to start next year, supporting developments right across the science and technology spectrum through the next seven years. Some aspects of biomedical research and clinical trials will certainly benefit.

This columnist recently encountered an advocate of a very particular case for clinical trials support with a strong claim on the future—the special needs of women. Not just greater attention to classic women's diseases, but to the overlooked specifics in women's more general health issues. "The health of women has a direct bearing on the health of the future generation, their families, and communities, and ultimately, the health of societies," quotes Hildrun Sundseth, Board Member of the European Institute of Women's Health (EIWH), from the 2010 strategic paper of the NIH Office of Research on Women's Health. But this aspect of women's health is just not getting onto the male-dominated radar in clinical trials circles, she goes on. "Industry researchers would have us believe that they have a gender balance in their trials, but when one looks for the data, there is no robust analysis. The trouble is that this has to be considered in the set up of the trial, not just as a simple add-on consideration at the end to tick a box." She says that gender issues "have mostly been discussed in Europe as meaning 'give jobs to women scientists.' Important, yes, but I don't mind who studies the differences between x+y and x+x chromosomes, what we need is to know the differences."

It is no longer adequate to assume that the only significant difference is the reproductive system, she argues. Science should not limit itself to taking special account only of diseases related to the genito-urinary or mammary apparatus. "There is increasing awareness that sex differences are highly pervasive, operating at all levels from molecules to health delivery," she says. "Biological determinants of diseases are not necessarily the same in men and women."

She cites growing evidence that a person's sex may differentially influence genetic predisposition, the impact of both environmental and biological risk and protective factors, time of onset, symptoms, and the progression of many diseases. She notes some of the striking sex/gender differences in prevalence, progression, and outcome of diabetes, obesity, cardiovascular diseases, depression and brain disorders, infectious diseases, lupus and other autoimmune diseases, and cancer.

Many physiological and pathological functions are influenced by sex-based differences in biology, and this knowledge is increasing understanding not just of disease but also of the ability to intervene more effectively. Sex—or at any rate sexual differentiation—may influence the effectiveness of medication and its duration. But so far, little of this has impacted the way that clinical trials are planned, conducted, or evaluated. Europe has largely ignored the sex differences in biomedical research and clinical trials, she claims—"unlike the United States which, through the NIH Office of Research on Women's Health and the FDA Office of Women's Health, has a strong and long-standing commitment to studying the sex differences in biomedical research and advocating the participation of women in clinical trials to allow for sex, gender, and subpopulation analysis." Her voice is not alone. It is already three years since Nature argued that "gender inequalities in biomedical research are undermining patient care" and called for an end to the "sex bias in basic research and clinical medicine" (Nature, 465 (7299), June 2010).

Putting women in the picture

Sundseth recommends the inclusion of women in clinical trials in numbers that match the prevalence of the disease in the general population, and construction of trials in ways that permit a systematic analysis of sex differences. Mere adjustments in statistical analyses are insufficient, since these are designed to do no more than eliminate the possibility that sex is a confounding factor. She calls for separate stratified analyses for men and women that explore whether different secondary factors influence efficacy, treatment adherence and side effects. And recruitment of both men and women is only half the battle, since it is also necessary to ensure that even at the molecular level, both male and female cells are used.

The continued use of many more male subjects than females in both animal studies and human clinical trials is short-changing women's healthcare, she claims. Particularly since differences in the physiology of males and females, and in their response to disease, have been recognized for decades in many species — not least Homo sapiens. Hormones made by the ovaries are known to influence symptoms in human diseases ranging from multiple sclerosis to epilepsy. Yet male research subjects continue to dominate biomedical studies, with 5.5 male animal models used for every female in neuroscience, and women subjects remaining seriously under-represented in clinical cohorts.

EIWH has high expectations of Horizon 2020, and has compiled a list of priorities for its approach to biomedical and clinical research "to achieve optimal prevention, diagnostic and therapeutic practice for both sexes." It wants the EU program to advance understanding of the biological sex and gender differences in health and disease by exploring the complex interactions between the two. It urges studies of sex differences at basic cellular and molecular level, including in immunology, endocrinology, epigenetics, systems biology, and neuroscience. And it is calling for the creation of a strategic research plan for women's health for the next decade "to fulfil the promise of personalized medicine."

Not content with that, EIWH is also urging the establishment of a "European Office of Research on Women's Health," modelled on US practice with the NIH, so as to harness genomics, proteomics, and metabolomics in the examination of biological sex differences. Sex-specific research results should be made more readily available, women should be explicitly included in clinical trials in numbers statistically relevant to allow for systematic analysis of sex differences, and the European Union should require that trials include adequate representation of sub-populations and provide reports of gender and sex-specific data. Out of this, it hopes, it will be possible to identify and validate sex-specific biomarkers for disease risk and prognosis across the lifespan.

Lifespan issues

The lifespan reference is very deliberate. Sundseth points out that although women outlive men by an average of six years, the difference in years spent in good health is much less: for women 62.6 years, and for men 61.7 years. "As a result," she says, "more women spend their additional years burdened by chronic diseases, reduced physical or mental capacity, and eventually lose the ability to live independently, consequently requiring costly long-term care." There is a tendency for women, once past menopause, to become invisible to researchers. Yet, she says, this is precisely the time when chronic diseases set in. In this way, age joins with gender in unhelpful discrimination in biomedical research and clinical practice.

Already, the current lack of evidence about the effectiveness of medicines in women may result in withholding treatments that could be beneficial—or in exposing women to treatments that may be harmful. This situation is aggravated by age. By 2030, Europeans over 65 will account for 30% of the EU population. Women make up the largest segment of the older population and become the heaviest users of medicines. In such circumstances, it is hard to understand why women are not systematically included in clinical trials, Sundseth contends. And since older people take more than 30% of prescribed medicines and more than 40% of over the counter medicines, it is no surprise that older women have the highest risk of developing adverse drug reactions—costly to their quality of life and to healthcare budgets.

It will be a valuable contribution to Europe's struggle to cope with an aging population if better health for women results from greater investment in research on biological sex differences that affect health and disease, she argues. Success could also play into Europe's broader objectives of achieving innovation-based competitiveness at the international level. Since women's health is an issue that defies geographical boundaries, a smarter approach to women's health could help keep Europe at the forefront of innovation in biomedical research. "To contribute to public health and stay competitive in world markets, Europe's research needs to understand better how the biological sex differences can be applied to the next generation of medical interventions and therapies to fulfil the promise of personalized medicine," she says.

Of course, there may be legitimate reasons to skew the ratios, she admits—but the cumulative effect is harmful. It is time, says Sundseth, for women to take matters more into their own hands. "General clinical trial practice that considers one-size-fits-all will persist unless women themselves understand that they are at risk," she argues. "Women will continue to face gender and age blindness in biomedical research, unless they themselves are willing to become advocates for evidence-based gender-specific prevention, treatment and care of major chronic diseases."

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

download issueDownload Issue : Applied Clinical Trials-06-01-2013

Related Content:

FDA | Blogs