The National Institutes of Health (NIH) wants to encourage researchers to consider both sexes when conducting preclinical studies, according to Joan McGowan, PhD, director of the Division of Musculoskeletal Diseases at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
Dr. McGowan made the announcement during the “Musculoskeletal Sex Differences throughout the Lifespan Research Symposium,” sponsored by the AAOS, Clinical Orthopaedics and Related Research, the Orthopaedic Research Society, the Center for Musculoskeletal Health–University of California, Davis, and the Society for Women’s Health Research. The symposium was also sponsored by the NIH/NIAMS under Award Number R13AR066518. New policies will require researchers to use male and female cells and animals in preclinical studies, except in cases where sex-specific inclusion is not warranted.
Why include both sexes?
Since 1990, the NIH Office of Research on Women’s Health (ORWH), has been “leading the effort to develop policy that drives the inclusion of sex differences in research,” according to Dr. McGowan.
“In 1993,” she said, “the NIH mandated that enrollment of women and minority groups in clinical research be tracked. This effort has been very successful; in 2011–2012, more than 50 percent of those enrolled in clinical trials were women.”
The ORWH also instituted programs to encourage scrutiny of sex differences in research. For example, the Specialized Centers of Research on Sex Differences program awards funding to established scientists who integrate basic, clinical, and translational research approaches to incorporating a focus on sex and gender. In 2013, the ORWH made administrative supplements for research on sex differences available to current NIH-funded researchers who enhance their study designs to consider sex differences.
Even though differences have been found between men and women in areas such as the preventive effects of low-dose aspirin, researchers often do not factor both sexes into study design. As a result, the NIH is taking action.
“As our understanding of science evolves, so do our policies that govern research,” Dr. McGowan said. She cited a commentary by NIH Director Francis Collins, MD, and ORWH Director Janine Clayton, MD, which recently appeared in Nature (May 2014).
“The need to further consider both sexes in preclinical research generated quite a buzz in the research community,” she said.
The NIH, noted Dr. McGowan, “believes the study of sex differences will strengthen the science.”
The problem, she added, is that consideration of both sexes has been a blind spot in most studies that have led to clinical interventions.
Reproducibility of research
The increased emphasis on studying both sexes “is part of a larger effort to make sure that the work supported by the NIH is reproducible and generalizable,” said Dr. McGowan. “Basic, translational research needs to be able to move up the line to clinical application.
“The NIH is trying to improve reproducibility, particularly in preclinical science used to develop clinical protocols,” continued Dr. McGowan. She noted that the lack of reproducible results—as well as the lack of transparency in research findings—is a problem in all areas of research, rather than only in specific types of studies.
This issue was highlighted in a 2005 article by John Ioannidis, MD, “Why Most Published Research Findings are False”(PLoS Medicine).
“Dr. Ioannidis evaluated 49 of the most highly regarded research findings from the last 13 years, then followed up to determine whether the studies that uncovered possible interventions were reproduced,” explained Dr. McGowan. “He found 16 percent of the study findings were contradicted, while 16 percent of follow-up studies found much smaller differences than the initial studies.
“In addition, 68 percent of the initial studies remained either unchallenged or the findings could not be replicated, which is a really dangerous number,” she continued. “It may mean that the first study was not interesting enough for people to follow up on, but people still may be citing it because it’s in a reputable journal. Or, it may mean that the study couldn’t be replicated, and the researchers who couldn’t replicate the study didn’t publish the findings.”
Researcher misconduct is not a suspected cause, in most cases, of the lack of reproducibility in the medical literature.
“This problem is undoubtedly caused by many other things,” she said. “It might be that, for instance, an intervention may work in one sex but not the other.” Other possibilities range from researchers’ need for greater training in experimental design to the difficulties they face when attempting to publish negative data.
No matter the cause, lack of reproducibility is “unacceptable,” said Dr. McGowan.
“We should not be jumping into human trials without an extremely strong premise, and that’s what we hope to strengthen,” she said. “This is not a problem the NIH can solve alone. It’s going to take journal editors, other government agencies, industry, basic researchers, professional societies, and others to accomplish this.”
New policy on the horizon
Studies must evaluate both sexes, when appropriate, asserted Dr. McGowan, noting that the NIH is developing a policy to address this issue in preclinical studies.
Sex, she stated, is a fundamental biological variable.
“We at the NIH are going to take a deliberate approach to encourage researchers to consider that fundamental biological variable,” she said. “We think this will deliver better research.”
Dr. McGowan noted that the NIH “will begin phasing in policies over the course of the next fiscal year—which begins on October 1, 2014—requiring grantees to consider both sexes in preclinical research.
the use of animals in their experimental design, describe why they are using a particular species, and include the number and sex of the animals. For the immediate future, applicants should continue reporting this information. Over the next year, the NIH will issue notices explaining what new information should be included in applications and progress reports to address sex differences and the timing of these new requirements. Additionally, we will be developing guidelines for reviewers as they consider information about the sex of animals in their evaluation of applications.”
As noted on the ORWH website (www.nih.gov/women), the “NIH will also be making announcements about how the agency is working with the scientific community, including editors of scientific journals, to further consider the importance of sex differences in our research efforts.”
The website also reminds researchers that “current NIH policies will remain in effect for applications submitted in October 2014,” but urges applicants to “stay tuned for additional guidance on how NIH will be implementing policies for biomedical research applications involving animals and cells, reviewer guidelines, and progress reports.”
“We will only truly improve public health if we have confidence in the fundamental knowledge that serves as the basis for developing clinical treatments and interventions,” added Dr. McGowan.
Listen to a podcast interview with Dr. McGowan here.
Jennie McKee is a senior science writer for AAOS Now. She can be reached at firstname.lastname@example.org
- Clayton JA, Collins FS: Policy: NIH to balance sex in cell and animal studies. Nature. 2014 May 15;509(7500):282-3.
- Loannidis JP. Why most published research findings are false. PLoS Med. 2005 Aug;2(8):e124. Epub 2005 Aug 30.