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Will the current push for sex-specific analysis in pharma research inspire changes for dietary supplements, too?
Over in the pharmaceutical industry, the spotlight is searing hot again on whether women are adequately represented in clinical trials for drugs. This concern has persisted for decades, beginning in the 1990s and sparking the National Institutes of Health’s (NIH) Revitalization Act of 1993, a law that required the NIH to establish guidelines for including women and minorities in clinical studies, as well as two Government Accountability Office (GAO) reports in the early 2000s on the status of women’s research. Now, there’s a deadline looming. By August of this year, under what’s known as Section 907 of the Food and Drug Administration Safety and Innovation Act (FDASIA), FDA must publish an action plan with detailed recommendations on how to “improve the completeness and quality” of the way researchers analyze clinical data on demographic subgroups, including women and minorities, in studies on drugs, biologics, and medical devices. With the August deadline imminent, lawmakers and stakeholders are pushing hard for improvement.
The main problem isn’t an insufficient number of female subjects in clinical trials. Thanks to the efforts started in the 1990s, the number of women in Phase III drug studies is up these days. The problem is that many researchers are still not reporting outcome data according to sex. What does this mean? It means that, prior to releasing a drug, pharmaceutical companies may not have-or may not make public-the data necessary to warn consumers on how drugs may affect men and women differently. That information should be making its way onto drug dosage and warning labels, but, typically, it’s not.
The physiological differences between men and women can significantly manifest in drug reactions. Just last year, FDA made the makers of the sleep drug Ambien halve the dosage required for women, compared to the dosage for men. The reason? Women metabolize and eliminate the drug more slowly than men do, resulting in increased and potentially hazardous morning drowsiness after taking the drug.
Menstrual cycles and pregnancy can also affect how drugs behave in women. In fact, the physiological variations stemming from menstruation are one reason why some researchers in the past excluded women in drug trials. Also, diseases themselves impact the sexes differently in terms of risk, development, and symptoms-a fact that skews clinical trial outcomes.
Paving the way to what will hopefully be a step in the right direction for equality among sex analysis, lawmakers and activists alike have been busy encouraging FDA and the NIH to revamp U.S. research guidelines. In April, a group of senators wrote to FDA asking the agency to require greater analysis of sex differences in clinical trials for new drugs. That same month, members of Congress asked the GAO to take another look at how women are included in NIH-sponsored trials.
And now there is bipartisan legislation on the table pushing for sex-specific analysis. In June, Congressional members Jim Cooper (D-TN) and Cynthia Lummis (R-WY) introduced the “Research for All Act of 2014," a bill that would require “the inclusion and separate analysis of both male and female animals” in NIH-funded basic research, including studies that utilize tissues and cells, which would need to come from both male and female subjects.
NIH is listening. In an article published in the May 14 issue of the journal Nature, Janine Clayton, director of NIH’s Office of Research on Women’s Health, and Francis Collins, director of NIH, wrote that while over half of the subjects in NIH-funded human trials are now women, the same cannot be said for preclinical animal studies. This is set to change. According to Clayton and Collins, NIH will now require researchers to include female animals in basic research. “The NIH is now developing policies that require applicants to report their plans for the balance of male and female cells and animals in preclinical studies in all future applications, unless sex-specific inclusion is unwarranted, based on rigorously defined exceptions,” they wrote. The new policies are effective October of this year and represent the biggest movement NIH has made on this issue. NIH plans to issue training on “experimental design” to NIH staff, trainees, and those who receive NIH grants.
Achieving equality of the sexes in clinical analysis will require educating the science community at large. In their Nature article, Clayton and Collins wrote that reviewers of NIH grant applications “for the most part, are not attuned to this failure”-“failure” meaning the current lack of female subjects in animal trials.
Researchers may resist these changes at the start. “It’s going to take awhile for the mentality of researchers and scientists around the country and the world to recognize that research has to be done differently,” says Phyllis Greenberger, president and CEO of the Society for Women’s Health Research (Washington, DC), a group that has been instrumental in advocating for sex-specific analysis and women in research since 1990. Factoring gender analysis into a study requires building it into the study model from the very beginning.
Could a push for sex-specific analysis in pharma research inspire changes in dietary supplements research, as well? The conversation is certainly relevant, as lack of sex-specific analysis is a problem “across all disciplines of health research,” says Andrea Wong, PhD, vice president of scientific and regulatory affairs for the Council for Responsible Nutrition (CRN; Washington, DC).
In fact, Wong says, the lack of sex-specific research “can be magnified in the dietary supplement category because there’s a smaller pool of funding available for dietary supplements research compared to drug research…and, consequently, less money available to investigate sex-specific differences.”
Still, she says, it’s important that the supplements industry pursue sex-specific analysis to see how women and men respond differently to dietary supplement interventions, both in terms of safety and efficacy. Men and women have different needs when it comes to supplements, just as with drugs. “There are already differences between what men and women need for basic nutritional function,” Wong says. For instance, the Institute of Medicine’s dietary reference intakes (DRIs) already list different vitamin and mineral targets for each sex. And although the biological effects of supplements are less acute than drugs', sex-specific analysis is still important.
Still, few supplement studies are designed from the get-go to study both men and women. The ones that do tend to be large-scale studies. One such study Wong points out is the NIH-funded VITAL trial looking at the effects of vitamin D and omega-3 on cardiovascular health in both men and women. Another recently announced large-scale study on the heart health benefits of cocoa flavanols will also look at the effects of a multivitamin in both men and women. This study’s multivitamin arm will fill some knowledge gaps left behind by the NIH’s Physicians’ Health Study II, which only examined the effects of multivitamins on cancer in male physicians.
Sex-specific analysis is an important issue that all should be aware of, regardless of gender or drug/supplement affiliation. FDA’s August action plan for drug research will either be a step-or a leap-forward for women’s research. Greenberger and her team say that, depending on what the plan entails, it could be the biggest regulatory movement on this topic since 1993. Let’s hope so.
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