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More on Addressing Sex Differences in Pre-clinical Studies

You likely saw the recent Nature policy article, in which NIH Director Francis Collins and NIH Office of Research on Women’s Health Director Janine Clayton discussed ways that NIH is addressing sex differences in research. As our understanding of science evolves, so do our policies that govern research. This commentary cites several studies that highlight the need to further consider sex differences in preclinical research and describes how NIH will enact new policies to expand the consideration of sex differences in research studies using animal models and cells. The article generated quite a buzz in the community, and I wanted to take this opportunity to explain the roll out of our implementation plan.

As you saw in the article, we stated that we will begin phasing in policies over the course of the next fiscal year (which begins October 1st), requiring grantees to address inclusion of both sexes in preclinical research. Under current policy, applicants proposing work in vertebrate animals must justify 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, we will issue Guide notices that will explain 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 the information about the sex of animals in their evaluation of applications.

This is an important step towards strengthening our understanding of sex differences—and more broadly—towards improving the overall rigor of NIH-supported research. Earlier this year, in this blog and in a Nature commentary by Francis Collins and NIH Deputy Director Larry Tabak, we discussed how NIH is working to enhance the reproducibility of biomedical research. In addition to considering sex differences, rigorous research studies must address critical experimental design elements, such as blinding, randomization, and sample-size calculations. As you know, NIH’s mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability. 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.

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15 thoughts on “More on Addressing Sex Differences in Pre-clinical Studies

  1. While I appreciate the intent, this mandate seems out of touch with the reality that many investigators are not appropriately skilled/resourced to interpret and follow through on data collected from such studies. This means that these studies could be under-powered to observe real differences and data gathered may not be able to be appropriately interpreted/exploited for future work. If this is a true priority for NIH (and I agree that it should be), why not initiate/expand RFAs, etc for new, well-justified sex-based projects with investigators that have the expertise to execute the work in a substantive way (money talks and people will pull together to do the work correctly)? Not all valuable, NIH funded projects have male/female differences underpinning their biology so why make a mandate? Honestly, this seems like a feel good response instead of a rationale approach to tackle real biological questions about sex differences in disease and therapy.

    • With all due respect, the argument proffered has remained the same for several decades and precluded studies of both sexes. It is indeed likely that many parameters do not differ – problem is, we don’t know which. It has also been a habit in human studies to include both sexes and then lump the data. Not good either. In the best of all worlds the data are the dat and they should be reported – possibly providing hints for future work. I would argue from experience that often while a basal property may not differ by sex, the response to a stimulus will. If we all say “well the basal properties did not differ therefore I can lump the response data” we will a) miss the real story and b) spend lots of time confused as to mechanism as c) guess what, there can be more than one path from start to finish and differ by sex. I applaud the approach of us continuing to do our work, just to include the second sex – if we drop that sex, then PLEASE make sure that the conclusions realize that only one sex was studied and formulate sex-based hypotheses. That was wonderfully cathartic :)

  2. The use of rodents as a model involves a number of tradeoffs to start with, compromising physiological relevance for economy and scale. Not surprisingly, although mouse are a better model than C. elegans or drosophila, many drugs that work in mice subsequently fail in human clinical trials. Is it over-determining to mandate evaluation of sex-specific differences in mice, given the already partial correspondences between mice and man?

  3. I look forward to the transparency, openness and genuinely interactive process that will “rigorously define” the exceptions that will be permitted.

    I also look forward to your defined steps to be taken to ensure that study section reviewers get on board with these new initiatives. We are cognizant of the ways in which peer review (collectively) fights your initiatives. For example, Zerhouni mentioned years ago that when the ESI affirmative action policies were put in place, study sections responded by further punishing ESI applications with poorer scores. The bias was not fixed, it was entrenched. This tells us that simply letting the community know that sex-differences research is the new black will not necessarily produce the result you hope for in terms of application scores.

  4. If findings in animal models are poorly extrapolated to human health and disease, why study sex-differences in animals?

  5. What if the phenomenon you are studying only occurs in one sex? Are we obligated to figure out why that is the case instead of trying to determine the mechanisms and conditions under which it occurs in the one sex? That is, if we have data showing female rodents do not show a certain response, but males do, are we obligated to try to figure out why?

  6. For this to work and not just create more busywork to no purpose, there needs to be an understanding and acceptance of when cell gender is irrelevant and hence the policy should not apply. Obvious examples are hybridomas used to produce MAbs, cell lines used to make recombinant proteins, most likely the cells used to produce viruses, etc, etc. Sure, some primary cell systems will be hormone-sensitive, and sorting out the biology here is relevant. But please focus on systems where there truly is a case for gender differences, and define exclusions where there are overwhelming grounds to consider cell gender an irrelevancy. Mandates are often bad ideas, because they lump the “innocent” with the “guilty”, so to speak. Common sense is almost always an important tempering factor…

  7. Apropos to the last comment, how will these changes be viewed in the context of grant applications and funding. Proposing to do the same studies you’ve published before now in females to test these differences while clinically relevant is mechanistically boring. I fear study sections will punish this simple question. Additionally, as NIH cuts everyone’s budgets, how will all these additional animals be paid for to assure the work is done>

  8. How will gender equity in pre-clinical models be supported.? Including male and female rodents will increase budgets at a time when there isn’t enough money to fund exceptional proposals. Funding rates are so low it seems like this is not the best time to implement this new policy.

  9. I find the focus of this effort rather odd. How is a 4- to 6-day mouse estrus cycle and 18- to 21-day gestation possibly relevant to humans? That is not why we use rodents – we use them because they are useful for modeling particular aspects of disease while limiting genetic variability as a confounding factor, because their is a plethora of reagents, and because of the wide availability of transgenics, NOT because they are exact photocopies of human diseases – they can never be that. And if you look carefully at the literature, a majority of rodent investigators that purchase mice from commercial vendors almost exclusively use females because they are less agressive so easier to handle and far less likely to fight – personally I find that more of an issue than under-usage. Perhaps it might be worth consulting the lab animal community before instituting such biologically-baseless and frankly stupid changes?

  10. I concur with the many voices saying that the new mandate is illogical even for many in-vivo studies. But the real head-scratcher is the apparent mandate for cell-culture work. Are we really expected to find a male equivalent to the HeLa cell and double-up all our experiments with same? I hope NIH has some scientists guiding this policy who can see the ludicracy of that proposition. One cannot find equivalency in ANY two cell lines– even two clonal expansions from the same tumor– due to chromosomal aneuploidy and genome instability. Even primary cultures are prohibitively difficult to parse by sex. My endpoints cannot be determined without cultures large enough to be obtained from pools of rat and mouse fetuses. If I am expected to genotype the fetuses prior to placing them in culture, the additional lag time will result in the death of a large fraction of the cells (certainly involving some sort of biological selection). And that’s to say nothing of the additional cost (of the genotyping and all other consequences).

    This entire policy seems short-sighted and poorly conceived. But a requirement to separate all cell-culture studies into male and female experimental arms would be unbelievably ignorant.

  11. Please clarify what is meant by “preclinical research”. According to the FDA website, the purpose of preclinical research is “to develop adequate data to undergird a decision that it is reasonably safe to proceed with human trials of the drug.” Is the new NIH policy being considered for ALL NIH-supported animal work or just preclinical; that is, will basic, mechanistic research be exempt?

  12. I think this is an important step towards strengthening our understanding of sex differences, but i`m not sure if it can be implemented in the present reality… How will gender equity in pre-clinical models be supported? It`s really a good question.

  13. Some practical consideration of costs is warranted. If I am studying lung cancer and using cohorts of 6 females per cage, what happens when I have to add 6 males? They must be housed separately because of fighting, so now I have 7 cages per sample point instead of one. The maintenance charges increase 7x, not just 2x, and the size of animal facilities must increase accordingly. This means higher overhead, less time and money for mechanistic studies, and fewer personnel supported by a grant. If there is really some reason to suspect sex differences in lung cancer etiology, why not issue an RFA instead of forcing all lung cancer researchers to address it superficially, and slowing progress in all other cancer research?

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