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NIH to require sex-reporting in preclinical studies

The US National Institutes of Health (NIH) will require grant applicants to report the sex of animals and cells used in preclinical studies, officials said today.

The shift could help to reveal differences in the ways that diseases affect males and females. Depression, for instance, more often causes anger in males and hopelessness in females; failing to account for this type of variation can skew research results. It can also be dangerous — last January, the US Food and Drug Administration halved the recommended dose of the sleep aid Ambien for women. Although the drug has been available for 22 years, researchers only recently discovered that women who take Ambien are at increased risk of accident. 

The NIH has long recognized animal sex bias as a problem, says Janine Clayton, director of the agency’s Office of Research on Women’s Health (ORWH), who announced the agency’s new policy in a Nature commentary with NIH director Francis Collins.

A 1993 law requires that NIH-funded clinical trials include women, with few exceptions, and the numbers of participants recruited to such trials appear to have evened out over time. “If you look at NIH clinical research last year, over 50% of participants were women,” says Clayton. “It’s in the preclinical space where we haven’t seen a corresponding revolution.”

Much of this, she says, is due to a belief that the oestrus cycle affects the female animals’ physiology and throws off results; as a result, researchers tend to prefer male animals, though recent meta-analysis studies of literature have shown that this is not the case. (Some studies use female animals because they can be housed in groups, whereas male animals tend to fight unless given their own cages.)

Under the new NIH policy, which will begin to take effect in October of this year, grant applicants will have to describe how they plan to balance the sexes for cells and animals used in their studies. Clayton says that the NIH rules will not be so prescriptive as to require equal numbers of males and females, but both sexes must be represented. “This is more than a numbers game,” she says.

The NIH will monitor whether its grantees are complying with these plans “so we get pinged if there’s a problem,” says Clayton. There will be exceptions — research on reproductive organs, for example — but they will be few and far between.

In recent years, researchers have come to recognize the importance of sex differences in animal work, and many are actively including both sexes and reporting them in the methods of their papers, says Sherril Green, a comparative pathologist at Stanford University in California. She adds that pharmaceutical companies are also separating animals by sex early in the drug development process so as to avoid costly missteps such as the case with Ambien, which may have been avoided with more testing in women.

Yet the problem is bigger than just sex bias: factors such as age and genetic background can all greatly influence how an animal responds to a treatment. Brad Bolon, a veterinary pathologist at Ohio State University in Columbus, thinks the new NIH rules ignore the real problem. “By drawing so much attention to matter of sex, it avoids the whole crux of the issue,” which is too little transparency on the details of experimental design as a whole, he says.

Bolon also worries about added costs that may result from the new rules. To get enough statistical power to draw conclusions about each sex, researchers may need to double the number of animals used in the study. “Arbitrarily saying that research must be done in both sexes, especially early on, is going to take money out of testing truly novel hypotheses,” he says.

In recognition of such concerns, in 2013 the ORWH began offering funding supplements to grantees to allow them to add the appropriate number of animals to their studies. But Clayton says that this programme will probably be eliminated because investigators must now begin accounting for sex difference in their experiments from the very beginning.

Bolon says that a more direct way to persuade scientists to use both sexes in their research would be for journals to require reporting of certain variables in their methods sections. Many journals already have such guidelines, and Clayton says that NIH plans to work with journals so that sex reporting becomes the norm.

Editor’s note: a previous version of this story incorrectly referred to the “gender” of lab animals and cells rather than their “sex”.

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