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In January 2013, FDA told manufacturers to lower the dose of zolpidem for women, and suggested a 10 mg to 5 mg for immediate-release products (Ambien, Edluar, and Zolpimist) and from 12.5 mg to 6.25 mg for extended-release products (Ambien CR). That was based on evidence the drug is metabolized more slowly in women, which makes the side effect of next-day impairment more likely in women than men.
Ambien was approved 20 years ago, at a time when researchers evaluated drugs differently for men and women. Different in that there was a fundamental belief the only difference between the sexes was the reproductive system. In a recent broadcast from 60 Minutes on gender differences in drugs, Larry Cahill, a neuroscientist at the University of California Irvine, said he “used to share his field’s assumption that males and females outside the reproductive system were fundamentally the same.” But he’s changed his outlook, in part due to the Ambien difference in metabolism by gender, which becomes a textbook case of the incorrectness of that thinking. He says, basically, that for 20 years, women have been overdosing on Ambien.
To be sure, for many years, the call for more adequate population representation in clinical trials is often made. Minorities are under-represented in clinical trials—Hispanics account for only 7.6% and African-Americans 15%, according to the NIH. And even older persons may be excluded from clinical trials.
Interestingly, the 60 Minutes report echoed what was told attendees at an early March event “Charting the Course: A National Policy Summit on the Future of Women's Health,” which focused on disparities in research, diagnoses, treatments and outcomes between men and women for heart disease, lung cancer, depression, and Alzheimer’s. That information related to animal studies and said that 38% of stroke and 45% of anxiety and depression studies used female animals. The 60 Minutes broadcast offered insight by researchers who said animal studies are primarily performed on male species to adjust for the variable of female hormones.
Dr. Thomas Hochadel, COO of Cognitive Research, a full-service contract research organization that specializes in Central Nervous System (CNS) product development, looks back over the history of research and sees one logical explanation for the gender disparity, and that is thalidomide. “You have to remember that after thalidomide, no one wanted to take the risk of testing drugs in women where it could cause birth defects. Even today, in clinical trials, women of child-bearing years must use birth control and also be regularly tested for pregnancy as part of a trial.”
Between thalidomide and the previous scientific belief that men and women are essentially the same except for reproduction, there apparently remains a gender gap in clinical research. Even though 20 years ago, in 1993, the NIH adopted its National Institutes of Health Revitalization Act of 1993 Subtitle B—Clinical Research Equity Regarding Women and Minorities, and was the first official call for population equity in research. But as mentioned, getting to that point 20 years later hasn’t always worked, or been easy.
Hochadel observes that sponsors definitely are more aware of the need to include more women, especially in the neuroscience trials, or in trials were drug-drug interaction for impairment must be weighed, and is seeing an uptick in those readily prepared to address those safety concerns in clinical trials.
As scientific developments evolve, and the use of biomarkers for targeted medicine increase, will the need for gender and population equality in clinical trials naturally decrease? Hochadel says no. “Personalized or targeted medicine using biomarkers will assist in defining the target efficacy population—gender, race, disease sub-type—and some population differences in pharmacokinetic parameters relating to safety and efficacy. It will refine, but not supersede the drug development process and the call for gender equality in examining the safety and efficacy of new drugs in development.”
FDA Drug Safety Communication
Health Summit, WAMC