The (Un)fairer Sex?

Historically, clinical trials have been conducted in men – usually white men. Women of child-bearing age were excluded based on risks to the fetus should they fall pregnant, and there was a general belief that – beyond the reproductive system – men and women were biologically the same. Though women are still underrepresented in clinical trials in many diseases areas, times have changed. New research has opened our eyes to the myriad differences in how men and women respond to disease, and the drugs prescribed to treat it.

A well-publicized case in point was last year’s relabeling of popular sleep aid zolpidem (Ambien) at the request of the US FDA, which halved the recommended maximum dosage for women based on new evidence from clinical trials and adverse event reporting. Apparently, women eliminate zolpidem 45 percent more slowly than men, leaving them more vulnerable to next-day impairment, as well as rare side effects like sleepwalking and even sleep-driving. If the new labeling is correct, women have been habitually overdosing on zolpidem for the past 20 years. In fact, the differences in metabolism between men and women were known when the drug was approved, but at the time there was no evidence that it would matter. FDA’s Sandra Kweder told US TV show 60 Minutes, “If I saw this today, in light of today’s science, I think we would go back and try to tease this out a little bit further. But I think at the time this was generally [...] business as usual for what you saw in clinical pharmacology studies.”

Biased clinical trials are only half the problem; preclinical development work is still largely carried out on animals and cells of a single sex – most commonly male. The reason? To reduce variation by eliminating the hormonal cycle of female animals. The trouble is that female animals and cell lines are not biologically the same as those of the male. By excluding one sex in the early stages of research into new therapeutics, we are missing an opportunity to identify differentiation that could bring us closer to the ultimate goal of truly personalized medicine – potentially reducing risks and saving lives. In this month’s Upfront, we explore new rules that require all NIH-funded research to include both male and female subjects wherever possible.

Clearly, including both sexes in all preclinical and clinical research is not without its challenges, and requires cooperation from governments, researchers and physicians. But in the long run, a deeper understanding of the differences can only benefit us all.

Charlotte Barker
Editor

I’d like to know what you think – what is your organization doing to avoid sex bias in preclinical and clinical studies? What are your main challenges? Contact me at: [email protected]