Does sex matter when pharmaceutical companies determine the recommended dose for drugs?

Blind Spots

We know at Lost Women of Science that history has a blind spot when it comes to women, as evidenced by our database of more than 325 brilliant, and largely forgotten, female scientists. As Unger’s statement suggests, science shares the same blind spot. By centering on men for so long, medical research developed a habit of ignoring women. This ‘“one size fits all” approach overlooked female-specific physiology and led to biased care. Our previous blog post explores what happened with heart disease, for example. The situation is even more grim when it comes to female-specific conditions, which, aside from cancer, receive just 1% of research funding, according to a 2022 report from McKinsey & Company.

Former director of the Office of Women's Health Research, Janine Clayton, told the New York Times in 2013 that Ambien was “just the tip of the iceberg,” adding that there are “a lot of sex differences for a lot of drugs,” some known, some not. 

The Ambien saga sparked important conversations about equity and representation in medical research, but it didn’t resolve the core issue. According to Kathryn Sandberg, then director of the Center for the Study of Sex Differences in Health, Aging and Disease at Georgetown University, 90% of researchers were still using male animal models in basic science research. According to recent analyses, sex bias in preclinical research is still a problem more than a decade later.

Although the news about Ambien shocked the American public, few doctors were surprised. Many of their female patients had been complaining about Ambien-related drowsiness for years yet doctors kept on prescribing it. The New York Times reported that according to IMS, a healthcare information and technology company, as many as 60 million people picked up prescriptions for sleeping pills in 2011, two years before the FDA updated dosage guidelines. Two-thirds of those prescriptions were for drugs containing zolpidem, the active ingredient in Ambien.

Ulterior motives

Over the years, several studies have challenged the safety data cited by the FDA in its 2013 decision to change dosage guidelines. In 2019, researchers countered that there is no scientific evidence supporting the dose reduction in women and that cutting dosage might lead to underdosing in some cases. Another study in 2021 claimed the original analysis of the zolpidem did not provide sufficient evidence to justify the change, based on their own research data. Then in 2023, a group of researchers published an article in Social Studies of Science claiming that the FDA’s decision to insist on sex-specific dosage for Ambien was a “contingent outcome of the drug approval process,” suggesting that the change was motivated by external factors - namely commercial interests.

Their argument hinges on the story of another drug–a sleep aid called Intermezzo also produced by Transcept Pharmaceuticals. 

Intermezzo was designed for middle-of-the-night risers, but the FDA rejected it for fear that the effects might not wear off by morning. On a quest to bolster safety claims, Transcept turned to women, arguing that women metabolize the active ingredient, zolpidem, slower than men. Therefore, halving their dose should mitigate concerns about drowsiness. Convinced, the FDA approved Intermezzo and reevaluated Ambien, which is also zolpidem-based.

The news website Vox followed up on these studies with an investigation in which experts weighed the risks of oversimplifying differences between the sexes. It argued that sex is just a “coarse proxy for other mechanistically relevant features like body weight or hormones.” 

We still don’t know exactly why some drugs affect women differently. Seeing as male and female biology differ in so many other ways, it should come as no surprise that they do. And even if the drowsy women weren’t a dead giveaway, it shouldn’t take something going wrong to realize that these differences matter. 

Due diligence

This past summer, Lost Women of Science aired a season about Frances Oldham Kelsey called the Devil in the Details. In that story, Kelsey, a medical reviewer at the FDA in the 1960s, reviewed the application for a drug called thalidomide. Although it was already on the market in Europe, Kelsey questioned whether thalidomide was safe for pregnant women and people who might become pregnant. To make a long story short [please go listen to the full season as it’s great], it wasn’t. Kelsey is credited with protecting innumerable American women and their children from horrific defects linked to the drug. 

Her heroic actions have a complicated legacy, which also touches on the dosage issue. The FDA tightened regulations and sidelined women in many drug safety studies after the thalidomide scare. Decades passed before the agency realized that might cause more harm than good in some cases. 

Slight twist: While the FDA’s Unger framed what happened with Ambien in 2013 as a natural consequence of scientific inquiry, I’d argue that these stories say more about society. Sure, just as pharmaceutical companies need to study the effects of drugs on all potential users, regulators and medical reviewers should be aware of commercial interests at stake. Drug applications must include complete, transparent data. But beyond that, the scientific community needs to address the underlying equity issues that limit the quality of care available to women and minority groups in the U.S. This can lead to whole groups of potential users of new medicines being  overlooked as products are readied for the market.