The National Institutes of Health announced on Wednesday a new policy requiring that both sexes be represented among the subjects of preclinical biomedical research it finances involving animal and cell models.
More than two decades after requiring gender balance among human beings in the trials themselves, NIH leaders said they now realize that the same step should be applied to the laboratory experiments that inform those trials.
The policy reflects a widespread recognition of differences in how men and women differ in their responses to medical treatments, the NIH’s director, Francis S. Collins, and the director of the NIH’s Office of Research on Women’s Health, Janine A. Clayton, wrote in an article in Nature announcing the policy.
The change also represents another attempt by the NIH to counter a growing problem of biomedical-research studies that don’t fare well in attempts at replication, Dr. Collins and Dr. Clayton wrote.
"This move is essential, potentially very powerful, and need not be difficult or costly," they wrote.
The NIH will begin adopting the policy in October by training its staff and participants in its grant-review panels on how the requirement should be applied. Full enforcement will come shortly afterward, Dr. Clayton said in an interview. "It will be implemented very quickly, just in a rolled-out fashion so that it makes sense," she said.
Once in place, the policy will allow researchers to explain in case-by-case situations when it doesn’t make sense to include both male and female animals or cells in lab work, Dr. Clayton said. Aside from obvious situations such as ovarian or prostate cancer, however, those instances should be rare, she said.
"We will have rigorously defined exceptions—the exception will be truly an exception, not the rule," Dr. Clayton said.
The NIH last year began offering financial supplements to existing grant awards to add gender diversity. Once the new policy is in effect, the agency expects those payments to end. Gender balance will become standard, not "an add-on" with just a few females included at the end of a study, she said.
Enthusiastic boosters of the change, such as Irving Zucker, a professor of psychology at the University of California at Berkeley, question only why it took so long. "For me, it’s a dream come true," said Mr. Zucker, an author of studies showing the tendency among scientists to use male animal models, their routine failure to note the gender disparity in their published work, and the reliability problems that can ensue.
The NIH acknowledged the overall issue by establishing its Office of Research on Women’s Health, in 1990. Then, in 1993, Congress passed the NIH Revitalization Act, which required the inclusion of women in NIH-financed clinical research.
The delay in applying that requirement to preclinical research has been attributed to cultural inertia, combined with scientific concerns about the complexity of handling female animal models, given that the effects of an experimental treatment can vary daily during hormonal cycles.
A 2010 article in Science magazine described researchers as saying female mice and rats are more expensive to use because their four-day ovarian cycle requires costlier daily vaginal swabs to check for those hormonal effects, while giving scientists less-clear results.
Without such extra efforts, "the data are uninterpretable," Andrew S. Greenberg, a senior scientist and director of the Obesity and Metabolism Laboratory at Tufts University, told the journal at the time.
Contacted about the new NIH policy, Dr. Greenberg said: "Both sex and gender have important effects on physiology and pathophysiology in many studies. The influence of sex and gender in specific research studies should be reviewed on a case-by-case basis."
‘The Nail in That Coffin’
Mr. Zucker and a colleague, Brian J. Prendergast, a professor of psychology at the University of Chicago, published a study this year discounting concerns expressed in the Science article by showing that, over longer periods of time, male animal models have just as much variability as females in how they are affected by treatments.
The study put "the nail in that coffin," said Annaliese K. Beery, an assistant professor of psychology and neuroscience at Smith College who has worked with Mr. Zucker on similar studies of gender bias in research. "It’s an argument some people have used for not using females, but it’s not a good one," Ms. Beery said.
Meanwhile, studies in topics that include blood pressure, depression, and smoking cessation have repeatedly demonstrated the need to account for gender differences in human treatments, Dr. Clayton said. "Any 5-year-old can tell you boys and girls are different," she said.
As part of its new policy, the NIH also plans to step up efforts to encourage medical journals to include data about the gender of test animals and the gender of their cells, which have sex-specific variations, she said.
Dr. Clayton said she too could not explain why the NIH had taken 20 years to apply the concept to preclinical studies, though she said she had been leading the Office of Research on Women’s Health for less than two years and was determined to make it happen. She replaced Vivian W. Pinn, the office’s first full-time director, who served from 1991 until her retirement, in 2011.
In the 2010 article in Science, Dr. Pinn spoke skeptically of the idea. "I cannot foresee how a blanket policy requiring the use of male and female animals could be implemented or would work," she told the journal. "The research and how it’s designed has to be based on the science of what is being studied and the availability of models." Dr. Pinn did not respond to attempts by The Chronicle to locate her for comment on Wednesday's announcement.