By Dr. Kelly O'Connell
Pre-clinical animal studies are essential to drug development and provide a wealth of mechanistic, therapeutic, and safety-related information. The resulting data ultimately help propel drugs into the phases of clinical trials to hopefully yield new safe and effective therapeutics for humans. As consumers of these drugs, we naturally expect that the endpoints of those clinical trials apply broadly and yield therapies that work for all patients. Though a natural assumption, it is a flawed one. In truth, the foundation of our understanding for nearly every available therapy (from drugs to devices) is based on sex-specific studies which almost exclusively use male animal models.
A popular news story from a few years ago exemplifies the significance of sex-specific responses to even a common medication. Zolpidem (trade name Ambien) is a relatively common sedative that physicians prescribe to help patients sleep. Over many decades, companies encountered volumes of unanticipated complaints from people waking up “groggy” the morning after taking a pill. After an investigation, blood tests revealed pharmacokinetic differences in the way men and women metabolized the active zolpidem metabolite1. Women metabolized the drug about half as fast as men, extending the effects of the drug for twice as long leading to women being overly sedated the following morning. As a result, gender-specific dosages of Ambien were implemented to reflect this new information.
To many people with research backgrounds, the overwhelming use of male animal models will not come as a shock. As a previous bench scientist myself, I almost exclusively used male mice and rats in my cardiac studies. Why? We are conditioned to reply that “the estrous cycle in females is difficult to exclude as a confounding factor to the outcomes of the study, therefore, female animals are excluded.” Researchers have known about differences in sex-specific responses for a long time but there is a growing appreciation of the lack of understanding and funding in this area.
In 2014, the NIH announced a funding push to support agencies and researchers dedicated to examining sex-specific responses in a variety of diseases2. In fact, the institute now requires all submitted applications to consider sex as a variable in their research3. An ongoing debate surrounds this decision, as many researchers question the necessity of a blanket statement in all research disciplines to include biological sex as a variable. Experimental design challenges and budget constraints also complicate this issue. Nevertheless, the facts are telling: in a 2009 survey of animal research in the fields of neuroscience, pharmacology, and others, Beery and Zucker found that 8 out of 10 studies included male animals only4.
It might be easier to assume male and female responses are the same, but without adequate data, this can’t be verified. What we do know, is that relying on male only preclinical and clinical studies, without scientific justification, at best ignores potential differences in half the population and at worst, may cause real harm.