New Study Shows Sex Biases in Drug Dosage Trials Lead to Overmedicated Women

Results of a new study published in the journal Biology of Sex Differences showed an association between sex biases in drug dosage trials and the overmedication of women.¹

According to the study investigators from UC Berkeley and the University of Chicago, women are more likely than men to experience adverse drug reactions (ADRs) from medications as clinical trials have historically focused on men.¹

The study evaluated data from several thousand medical journal articles and found conclusive evidence of drug dose gender gaps from 86 different FDA-approved medications, including but not limited to antidepressants, cardiovascular, and anti-seizure drugs and analgesics.¹

“Women have a nearly 2-fold greater risk than men for exhibiting ADRs across all drug classes and are significantly more likely to be hospitalized secondary to an ADR,” study authors wrote. ²

Until the early 1990s, women had been excluded from drug trials for concerns about exposing pregnant women to drugs that risked damage to their fetus. While the US National Institute of Health (NIH) Revitalization Act of 1993 required enrollment of women in federally supported phase 3 clinical trials, the historical remanence of sex biases in medicine and the exclusion of women in drug dose clinical trials remain prevalent factors for gender inequality in pharmacokinetic (PK) study today.²

A 2018 review of 107 NIH funded randomized control trials (RCTs) incorporating both men and women showed that only 26% reported at least 1 outcome by sex or included both sexes as a covariate, whereas 72% failed to include an analysis by sex at all.²

Investigators also found that in upwards of 90% of the cases analyzed, women experienced worse ADRs, including nausea, headache, depression, cognitive deficits, seizures, hallucinations, agitation, and cardiac anomalies.¹

Of the 668 medications for the 20 most common treatment regimens in the United States, 46%, or 307, of them show considerable sex differences in ADRs, according to the investigators.²

The study findings argued that doses should be based on milligram/kilogram body weight or titrated to the desired clinical effect rather than a “1-size-fits-all” basis, which leads to higher exposures in women.²

Study authors offered several recommendations to address sex biases and limitation in drug dose gender gaps, including:²

1. The FDA should make available PK data in order to reveal PK sex differences and lead to corrective action that may reduce ADRs in women
2. Clear evidence of sex differences in PKs should be available on drug labels; AEs should include known sex differences
3. “One dose fits all” should be replaced with lower initial doses for women; when applicable, medications should be administered on a body weight adjusted basis (mg/kg) for both sexes
4. Considerable understanding of clinically relevant sex differences in drug treatment should be a component of the board certification process for health care providers
5. The Department of Health and Human Services (HHS) should prioritize sex equality as a long-term goal
6. Pharmaceutical companies should offer increased attention for sex-appropriate dosing early in the drug development process

“When it comes to prescribing drugs, a 1-size-fits-all approach, based on male-dominated clinical trials, is not working, and women are getting the short end of the stick,” said study lead author Irving Zucker, PhD, a professor emeritus of psychology and of integrative biology at UC Berkeley.

References:

1. Anwar Y. Lack of females in drug dose trials leads to overmedicated women. News Release. Berkeley News; August 12, 2020. Accessed August 18, 2020. https://www.drugtopics.com/view/maximizing-adherence-packaging-for-patient-health-and-pharmacy-growth.
2. Zucker I, Prendergast BJ. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biology of Sex Differences. 2020; doi: https://doi.org/10.1186/s13293-020-00308-5.