Investigators agree that both males and females should be included in preclinical studies, but should the National Institutes of Health require it?
The Basic Science Research Dinner at the 2015 Annual Scientific Meeting of the American Pain Society, held May 13-16 in Palm Springs, California, US, featured a panel of four researchers who took part in a debate on the forthcoming policy of the National Institutes of Health (NIH) for sex equality in preclinical research. The new policy was outlined by the NIH in May 2014 (see PRF related news article). The final form of the policy, which has not yet been made publicly available but is expected to begin to go into effect in October of this year, will require that NIH-funded researchers use female alongside male animals in preclinical studies, and even use primary cells and tissues derived from animals of both sexes. The vast majority of current preclinical studies, including those in the pain field, use exclusively male animals.
The session moderator, Benedict Kolber, Duquesne University, Pittsburgh, US, began by laying out some of the potential contributors to the sex differences in rodents and in humans that have been observed in pain studies, including endocrine, genetic, and cultural/social factors. He pointed out that the NIH Revitalization Act, requiring that women and minority subjects be included in clinical trials, passed in 1993. “We only had to wait 22 years to finally consider the preclinical world,” he said.
The four panelists chosen to debate the topic were asked to state their position in turn, beginning with Rebecca Craft of Washington State University, Pullman, US, on the “for” side. Craft, who studies sex differences in opioid and cannabinoid sensitivity, said many pain conditions are two to six times more prevalent in women than in men (Unruh, 1996). “How well has animal research modeled that figure?” she asked. According to a paper by co-panelist Jeffrey Mogil, she said, “The answer is, ‘not that well’” (Mogil and Chanda, 2005). She conceded that all pain studies might not require animals of both sexes, but it makes sense for pain research, considering the sex differences in the prevalence of chronic pain. Craft also asked, “What is the cost of the status quo,” where clinical failures of analgesic drugs are the norm? Ultimately, she said, society as well as labs will benefit from the new policy, which will improve the translational chances of preclinical work.
Laura Stone, McGill University, Montreal, Canada, spoke out against the new policy. “We all know boys and girls are different,” Stone began, but the real question is whether the NIH should require researchers to use animals of both sexes. That depends in part on the aim of the research. While applied research, she said, is goal driven and generates knowledge as “a means to an end," basic research is driven rather by the thirst for knowledge itself. Stone called the requirement a bad idea and “a threat to investigator-based science. Trust us,” she said, “we [as scientists] need to decide how best to address the question of sex differences in our research.” She also argued that the requirement for more animals would eat up precious resources, perhaps leaving important studies undone.
Jeffrey Mogil, also at McGill University, rallied for the “pro” side. Everyone seems to agree that studies should be done on female animals—in principle, he said. But the problem is that very few labs are actually using both sexes, and that will not change without a government mandate of some sort. Many researchers eschew female animals “for fear of [their findings] being ruined by estrous-cycle variation,” Mogil said, which is a perfectly reasonable but empirically unfounded fear, he continued. Mogil sees three possible consequences of using animals of each sex rather than all males. “One, there are no obvious sex differences, and you go on your merry way. Two, there are huge, obvious differences, in which case your study just became more interesting.” In a third possibility, Mogil said, a small trend emerges, and investigators choose whether or not to follow up on that in the future. Mogil doubts that the NIH will require that researchers power their studies to specifically detect sex differences—which, he said, would be unreasonable and unnecessary.
The final panelist, on the “against” side, was Geoffrey Bove, University of New England, Portland, Maine, US, who also cited a lack of resources as a concern. In addition, he said that by splitting a sample size in two, studies would lose statistical power. Like Stone, he concluded that “we [as scientists] should be trusted to use both sexes when appropriate, but it’s not always appropriate.”
Bove also wondered, “How may other variables will we be required to test for in the future—Age? Obesity? Exercise level?” Stone echoed that concern, wondering whether conditions such as osteoarthritis, which affects mainly older adults, should be studied only in aged rats. “I’m sensitive to the ‘slippery slope’ argument,” said Mogil, but these other factors come in gradations that are difficult and cost prohibitive to study, whereas sex “divides animals into exactly two levels.” Sex differences are easier to study than any of these other variables, he assured the audience. Researchers on the panel and in the audience, however, did agree that differences between the various genetic strains of animals might be even more important to consider than sex differences, and should be considered in pain research.
One audience member suggested that the best solution might be to require researchers to report in their grant proposals their reasoning for the sex of animals they will use, but Mogil reported that that strategy has failed in Canada. “We can all agree on the need for cultural change, but it won’t happen without teeth.” What exactly those teeth will look like remains to be seen, and pain researchers on both sides of the argument will be eager to get a look at the new policy come October.
Editor’s note: What are your views on NIH’s policy of sex equality in preclinical research? What do you think of the points raised by the debaters? Share your thoughts with the PRF community by leaving a comment below.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.
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