New article: “Making a ‘Sex-Difference Fact’”
By Marina DiMarco and Kelsey Ichikawa
This week, the GenderSci Lab has a new paper out in Social Studies of Science, “Making a ‘Sex-Difference Fact’: Ambien Dosing at the Interface of Policy, Regulation, Women’s Health, and Biology (open access).” The paper analyzes the first drug ever to be issued with an FDA mandated differential dose for men and women on the drug’s label. That drug, Ambien, became a hallmark example for advocates of sex difference biology, including the NIH’s decision to require comparisons of “male” and “female” materials in all preclinical research.
The product of a year of intensive research by our interdisciplinary team including gender studies, STS (science and technology studies), philosophy, history of science, and biomedical science scholars, this paper demonstrates that the FDA’s 2013 decision to halve the recommended dose of Ambien for women is the result of a contested regulatory approval process rather than settled science. We trace the making of this “sex difference fact” through federal science policy, media reports, and women’s health advocacy.
When the FDA recommended sex-specific dosing for Ambien (aka zolpidem) in 2013, the decision was touted as giving long overdue attention to sex differences in drug safety and efficacy. Since then, Ambien dosing has been widely cited as a classic example of clinically relevant sex differences and a motivation for studying sex differences in drug regulation and biomedical research. As noted above, it was repeatedly and prominently used to justify the NIH Sex As a Biological Variable (SABV) policy mandating the inclusion of male and female materials in all federally funded preclinical research. Regulators and women’s health advocates argued that sex differences in how people metabolize zolpidem are straightforwardly linked with higher rates of adverse effects of the medication in women, such as driving accidents and emergency department visits.
“The case of Ambien/zolpidem is a gold-star example of this bias and hype.”
Meanwhile, it has never been clear that high doses of zolpidem put women at greater risk than men. Rather than a regulatory judgment based on scientific consensus, the FDA’s decision to halve the dose of zolpidem for women was a contingent event in which drug manufacturers and regulators used sex groupings to mollify persistent drug safety concerns, in the specific context of an ultimately successful attempt to achieve regulatory approval of one formulation of zolpidem, Intermezzo.
Despite this, zolpidem became a touchstone “sex difference fact,” circulating widely, now detached from the scientific disagreements that accompanied the production of this regulatory decision.
A core mission of the GenderSci Lab is to counter bias and hype in sex difference research, and enhance public discourse surrounding the sciences of sex and gender. The case of Ambien/zolpidem is a gold-star example of this bias and hype. Today, it continues to be widely invoked as a justification for the priority of sex-based biology for addressing sex and gender disparities in health. We hope that our article helps readers understand the process by which contested and weak sex difference claims become widely accepted as simple facts, and open up discussion about the premise that biological sex is a simple, stable set of properties that make sexes inherently different from one another and drives patterns of health inequity.
Read the full article and share on social media here.
Key takeaways:
The FDA’s 2013 decision to halve the dose of Ambien for women was not based on settled science, but was a contingent outcome of a contested regulatory approval process.
The case of zolpidem is an example of how decontextualized circulation of sex difference claims between regulators, women’s health advocates, and the media helps to produce “sex-difference facts” resistant to correction.
The FDA’s decision to introduce sex-based dosing foreclosed an important conversation about the evidence required to establish a biological sex difference and the importance of biological sex differences relative to other gendered, social, and demographic pathways in addressing health inequities.
Key take-homes about zolpidem and sex differences:
Zolpidem is not a demonstrated case of biological sex differences producing disparities in adverse drug effects.
Controlling for body weight reduces much of the observed sex difference in clearance rates, and females’ lower clearance rates do not reliably predict higher adverse effects like car accidents.
The FDA also recommended that prescribers suggest lower doses of zolpidem for males.
After reviewing evidence, no other national regulatory agencies aside from those of the US and Canada have required sex-specific dosing regimes for this drug.
Sex differences in zolpidem metabolism have been studied since the inception of the drug and the consensus of the pharmacological literature does not support sex-based dosing.
When citing the zolpidem example, scientists and researchers should directly consult papers with pharmacological data rather than secondary literature, media reports, or advocacy materials that reference zolpidem.
Update September 2023:
Our research team found the FDA’s 2012 and 2013 review of data for other formulations of Zolpidem. In addition to evidence from the Intermezzo review, FDA cites re-analysis of pharmacokinetic/pharmacodynamic data suggesting impairment at higher pharmacokinetic levels (as measured by the Digit Symbol Substitution Test), and epidemiological studies about sleep aids and impairment as the motivation for their decision.
You can read the full review behind the 2013 decision here.
You can find the FDA’s Medical Review of Intermezzo here.
Statement of Intellectual Labor
Marina DiMarco wrote the first draft. Kelsey Ichikawa and Sarah Richardson revised and edited the blog.
Recommended Citation
DiMarco, M. and Ichikawa, K. “New article: “Making a ‘Sex-Difference Fact.’” GenderSci Lab Blog. 2023 May 17. genderscilab.org/blog/new-article-making-a-sex-difference-fact