More than 20 years after requiring researchers to include women in clinical trials, the NIH is intent on adopting similar rules for investigators carrying out agency-funded preclinical studies that involve animals and cells.
NIH put some money where its proverbial mouth is on September 23, awarding $10.1 million in grants to 82 recipients toward sex-based data comparisons: They will add animals, tissues, or cells; add to samples that already include males and females; and/or analyze existing male and female datasets. The grants bring to $14.7 million the supplemental funding NIH has issued starting last year, when it awarded $4.6 million to some 50 grantees.
Earlier this month, NIH issued a request for researcher comments on:
How much consideration of sex affects the reproducibility, rigor, and/or generalizability of research findings;
Areas of science or phases of research conducted with animals—as well as with cells and/or tissues—presenting the greatest opportunity or need for considering sex;
Key impediments to considering sex as a biological variable in research;
Ways in which NIH can facilitate consideration of sex as a biological variable in agency-funded research.
Researcher comments are being accepted electronically through October 13.
“For many scientists, sex continues to be a blind spot,” Janine Austin Clayton, M.D., director of NIH’s Office of Research on Women's Health and the agency’s associate director for research on women’s health, told GEN. “We want scientists to think about sex when designing their studies. Scientists should ask, ‘Will my research be different in males and females?’”
Dr. Clayton said NIH will phase in new policies: “The first phase of the policy development is collecting information to inform the details, rollout, and timing of the policy. Details about the policy and implementation plans will become available as they roll out during the next year.”
NIH is catching up with other funding agencies worldwide. For its €70 billion (about $89 billion) Horizon 2020 research and innovation funding framework, the European Union’s application instructs investigators: “Where relevant, describe how sex and/or gender analysis is taken into account in the project’s content.” Since 2012, the Canadian Institutes of Health has required grant applicants to address how their study design accounts for sex and gender, requiring justification if only one sex is being examined.
“The current overreliance on male animals and cells in preclinical research obscures key sex differences that could guide clinical studies. By requiring a deliberate approach in considering sex in preclinical studies, we make sure men and women get the full benefit of medical research,” Dr. Clayton added.
Numerous studies have found data disparities by sex. One of the most recent was published August 28 in the journal Surgery. A Northwestern University team found that of 613 articles published in that journal and four others that included animal or cell research, 117 animal studies and 90 cell studies did not specify sex. 80% of the animal articles used all-male data, as did 71% of the cell articles. The cell results may be skewed by a smaller total number of articles compared with animal (118 vs. 531) and the fact, acknowledged by the study, that many of the cell articles used lines whose sex is hard or impossible to be determined.
“Although it is not practical to mandate that all research studies include equal number of males and females from inception, it is reasonable to require that all authors report accurately the number of males and females used in their studies, justify single-sex studies in their publications, and at least acknowledge the possibility of a sex bias in their results should there not be equal sex representation in their study population,” the study concluded.
Perhaps the most widely cited example of sex differences affecting drug development is Ambien. Last year, the FDA revised the product label to require a lower dose for women following reports of the drug’s delayed clearance rate compared with men, linked to greater risk of next-morning impairment.
Where animals or cells from both sexes are used, studies still often lack analyses of data that address potential sex differences—as an Institute of Medicine committee observed in Women’s Health Research: Progress, Pitfalls, and Promise (2010).
A Call for Parity
“Just as we have called for equity of pay and rights for women in the workforce, so must we call for sex and sex parity in research design and execution,” Teresa K. Woodruff, director of Northwestern’s Women’s Health Research Institute and a co-author on the animal/cell study, declared in a commentary published April 8 in PNAS.
The need for parity was questioned in a 2000 study showing more women than men were assessed (550,743 to 355,624) in 603 of 724 clinical trials published between 1985 and 1995 in five journals (Annals of Internal Medicine, British Medical Journal, Journal of the American Medical Association, The Lancet, and New England Journal of Medicine). Single-gender studies heavily favored women (365,135) to men (64,658). However in mixed-sex trials, men outnumbered women (290,966 to 185,608), according to “Gender Representation in Trials,” published by researchers from The Johns Hopkins University in Controlled Clinical Trials.
NIH has required clinical trials to include women and minorities since 1993, when President Bill Clinton signed the NIH Reorganization Act. Since then, participation in clinical trials by sex has climbed and “is now about 50–50, males and females,” Dr. Clayton said.
She and NIH Director Francis S. Collins, M.D., Ph.D. announced May 14 in Nature the agency’s plans to require female animals and cells in preclinical studies. They acknowledged that several journals now require authors to specify sex-related information—including Nature, The American Journal of Preventive Medicine, Clinical Orthopaedic and Related Research, Endocrinology, The European Journal of Neuroscience, The Journal of Physiology, PLoS Biology, and the 14 journals of the American Physiological Society.
“Although there has been an increase in researchers taking sex into account, it falls short of the transformative shift that is needed to overcome historical gaps in our knowledge of female biology,” NIH’s Dr. Clayton said.
Among those who agree is Irving Zucker, Ph.D., a professor of psychology and integrative biology at the University of California, Berkeley.
“The underrepresentation of females in preclinical animal research remains to be corrected,” Dr. Zucker told GEN. “It is presently the case that sex bias prevails in many biological disciplines, most prominently in neuroscience and pharmacology. It is imperative that the NIH articulate policies that will preferentially fund proposals from investigators whose research clearly lists the sex and gender of their samples, includes both sexes and analyzes data separately for each sex.
“In instances where human traits are known to vary with menstrual cycle, or are influenced by ovarian hormones, rodent animal models must be tested at several stages of the estrous cycle and the effects of gonadal steroids should be investigated,” he added.
Two years ago in Nature, Dr. Zucker and Annaliese K. Beery, Ph.D., now of Smith College, called for “stringent, strictly enforced measures, not voluntary appeals” to end the data disparity.
NIH’s $10.1 million is a welcome, if modest, start. “In the long run, it’s probably going to take a lot more than that to make this happen on a large scale,” Dario Dieguez, Jr., Ph.D., health/scientist administrator with the Society for Research on Women’s Health (SRWH), told GEN.
Dr. Dieguez acknowledges some research topics don’t lend themselves to studying both sexes—diseases that primarily affect one sex, such as prostate or ovarian cancer. In addition to criteria for such exemptions, he said, NIH will need to teach its new standards to investigators, as well as staffers who review and oversee agency grants.
NIH’s new rules should move researchers toward studying and analyzing sex differences in physiology and potential treatments, to address what Jesse A. Berlin, Sc.D., vp, pharmacoepidemiology at Johnson & Johnson Pharmaceutical Research and Development and Susan S. Ellenberg, Ph.D., of the Perelman School of Medicine at the University of Pennsylvania, observed in “Inclusion of Women in Clinical Trials” (BMC Medicine, 2008): “There is no question that some treatments do work differently in men and women, but the proportion of treatments for which men and women respond very differently is unknown.”