Women have been traditionally underrepresented in science not only as scientists, but also as experimental subjects. This lack of representation in both clinical trials (especially before the 1993 NIH Revitalization Act that required the inclusion of women and minorities in clinical trials) and preclinical basic research has had negative consequences for women’s health. There are well appreciated sex differences in the basic physiology and prevalence rates of many diseases. Even though cardiovascular disease is the most common cause of death in women, only 1/3 of the subjects in clinical trials on cardiovascular disease are women and less than 1/3 of those trials report the results by sex, meaning they may miss treatments that are promising for one sex but not the other. Women are more likely to suffer from a chronic pain condition than men and even though there is evidence of multiple sex specific pain pathways, 79% of animal studies in the journal Pain from 1996-2005 only used male animals. Sex differences in metabolism can mean that a dose that is effective in men is harmful in women, likely one of the reasons that women experience more side effects than men and that 8 of 10 drugs recently recalled by the FDA led to more serious adverse reactions in women.
Lately the under-representation of female subjects has been getting more attention. In April of this year, a group of senators requested a Government Accountability Office investigation into whether NIH funded clinical trials included appropriate analyses to determine if there were sex differences in the response to treatment. In March a National Policy Summit on the Future of Women’s Health and accompanying report highlighted both the advances in women’s health research since the 1993 NIH Revitalization Act and the many remaining areas of inequality in clinical research. The NIH recently announced plans to require that preclinical research on animal models and cell lines include subjects of both sexes, unless there is scientific justification for a single sex study (these guidelines will be phased in starting October 2014). The Research For All Act introduced in June by Rep. Jim Cooper and Rep. Cynthia Lummis would require the NIH to have guidelines for the inclusion of both sexes in preclinical research (in all cases except those which the NIH director deems unnecessary). This law would also require expedited clinical trials to include enough participants to test the efficacy and safety of the treatment in both sexes and for the NIH to report demographic information in their biennial report.
The new NIH guidelines attempt to address the huge bias in neuroscience, physiology and pharmacology studies to include only male animals or not to report the sex of the animals at all. A common justification for not including female subjects is a potential increase in variability that is caused by the estrous cycle (which would require monitoring of estrous cycle and subject groups for each stage of estrous). Recent meta-analyses have found similar variability in both sexes in response to a variety of pain tests and behavioral, molecular and physiological tests in neuroscience, suggesting that monitoring estrous cycle is unnecessary and that female mice are ‘now liberated for inclusion in neuroscience and biomedical research‘. There has been push back in the scientific community, though, with some arguing that the new guidelines will lead to a huge increase in research costs and time. Since NIH funding levels have stagnated in recent years, this is a cause for concern. It is unclear what will be considered sufficient justification for only studying one sex and whether additional resources will be available. For health issues where there are known sex differences or ones that disproportionately affect women, it is just good science to include female subjects, though.
Since the Research for All Act would require sex balance in NIH funded research, now would be a good time to express your opinions on these guidelines to your elected officials — and of course to remind them of the importance of federal funding in developing treatments for both men and women (to find your elected officials click here). Personally, I think an increased emphasis on the fact that sex is an important biological variable is a good thing, though I would like to hope that the scientific community could be persuaded to do this without a legal imperative. (Full disclosure: my lab is currently looking at both male and female animals, so I don’t have to change my research program and as a woman I have a vested interest in ensuring that treatments are tested in women)