Wednesday, May 28, 2014

A Move Toward Sex Equality in Preclinical Research | Pain Research Forum

Women suffer from chronic pain conditions in far greater numbers than do men, and recent research suggests that the basic biology of men's and women's experiences of pain might differ. Yet the overwhelming majority of basic pain studies are performed on male animals and male-derived cells. That is set to change, at least for researchers funded by the US National Institutes of Health (NIH), with new NIH guidelines mandating equal representation of both sexes in preclinical research. NIH director Francis Collins and Janine Clayton, director of the NIH's Office of Research on Women's Health, Bethesda, US, outlined the new policy in a commentary published May 14 in Nature.


According to the commentary, "The NIH is now developing policies that require [grant] 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," such as in research of diseases affecting only males or only females.


The move will surely benefit women in the long run, said Rebecca Craft, who studies sex differences in pain at Washington State University Pullman, US. "This [policy] is finally going to hold people's feet to the fire to test female [animals]," Craft told PRF.


Jeffrey Mogil at McGill University, Montreal, Canada, also praised the new policy, which he described as particularly relevant to pain research. "There are huge, striking sex differences in pain—big stuff, not just a little more or a little less of something," he said. "Robust evidence of sex differences is as good or better in pain than in any other field," Mogil told PRF.


Clinical study design has undergone a revolution over the past 20 years, since the NIH began requiring equal numbers of women and men in nationally funded clinical trials. For decades, women took prescription drugs that were tested solely in men. In some cases, that practice led to unforeseen side effects and risks for women from medications. Although the transformation to gender-balanced trials took years to implement, researchers today hail it as a great achievement in medicine.


Now the NIH has taken the next step toward gender equality in science by requiring equal sex representation in animal experiments, and in work done with cells. The change is particularly important to pain researchers, said Craft, considering that "a number of pain syndromes are much more common in women." Without testing female animals, she added, "you are really not modeling the phenomenon very well."


Mogil echoed that sentiment. Whether or not there are sex differences that affect pain on a cellular level, "there are sex differences in the circuitry, and that is all you need to have the biology be robustly and fundamentally different between males and females," Mogil said.


The news has some researchers worried that the change might come with high costs, but Mogil said that fear is unfounded. "There is no downside and no tradeoff. We have everything to gain and very little to lose at all," he told PRF.

For example, if twice the animals will be required, that could double the price of breeding, housing, and tracking the animals. But Mogil doubts the new decree will drastically change research costs. "If you're using 12 animals, for example, you just use six male and six female," Mogil said, and track the data separately, "and combine again if there are no sex differences."


"I don't think six animals per sex is enough," to reveal subtle sex differences, Craft said, but then, that is not the purpose of the policy. "This is definitely a start. What we need to know most is when there are big differences … which would leap out at you, even with that small sample size."


The new rule could affect the progress of target validation and drug development. "For agents based on mechanisms determined from experiments performed on males, there is the possibility the biology is less relevant to females," said Mogil.


Researchers have stayed stuck in the rut of studying predominantly male animals and cells mostly out of convention. A single sex animal pool, researchers reasoned, would yield more reproducible results. And until recently, clinical trials overwhelmingly tested drugs on men, so it made sense to stick with male animals at the preclinical stage. "Until funders or journals start requiring it, no one is going to change," Craft said. The new guidelines will provide that push, she added.


A popular misconception also contributed to the historical male dominance, Mogil said. "People resisted before because they thought that data would be more variable in females." But as he demonstrated years ago (Mogil and Chanda, 2005), "that idea is empirically false. If anything, there is more variability in males. So what people were worried about all this time turns out to be wrong."


For researchers daunted by the thought of embarking on a new experimental paradigm built around equal representation of male and female animals, Craft suggests two papers for guidance (Greenspan et al., 2007Becker et al., 2005), and the NIH will reportedly provide training materials as part of the rollout of the new policy. The change will mean more work for researchers unfamiliar with female biology, Craft said, but that will be a worthy investment indeed.


Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California, US.