More than 125,000 people die every year from properly prescribed drugs, according to Harvard's Center For Ethics. That's not counting overdoses, misprescribed meds or people who misuse drugs. These "unintended consequences" are the fourth leading cause of death in the United States.
There are also about 2.7 million reactions to drugs each year, reactions that are so severe they require hospitalization. Newer drugs are more likely to cause a reaction, and women are more often affected than men. In fact, eight out of 10 drugs that were pulled from the market from 1997-2001 caused more negative side effects in women. That might be because women typically need less of a drug (but are typically prescribed the same amount as men), or because of gender factors affecting the drug's effect on the body.
Researchers aren't entirely sure why women have more negative reactions than men. But there's a key detail in the drug-creation process that might help explain why: the gender of most mice in drug-testing trials.
Gender bias in the lab
Until 2014, the majority of animals used for the trials of new drugs were male mice in a ratio of about 5.5 male mice to every 1 female mouse. In that year, the National Institutes of Health issued a decree requiring both male and female mice to be used in equal numbers in drug testing. But that means all drugs approved before 2014 (meaning most of what's on the market now) probably were never tested on female mice.
But why? The reasons for focusing almost exclusively on male mice include that female mice are supposedly more difficult to work with in a lab setting; female mice go through an estrus cycle, which can influence results depending on where they are in their cycle; and in behavior and neurobiological tests, female mice that have reproduced may display maternal protection behavior that can "skew" results.
As Brook Borel writes in Spectrum News, there have been issues with this standard protocol and the drugs that have resulted from it. One such example is Ambien or zolpidem: "Many women metabolize the drug so slowly that it is still in the bloodstream the morning after a dose, leaving them too impaired to drive or to do other tasks that require mental acuity. It took more than a decade after zolpidem launched for the FDA to formally address the issue; in 2013, it halved the recommended dose for women."
Here's a video that explains the story in more detail:
But the bias doesn't end with mice.
When it comes to drug trials on people, women are underrepresented. Even though women make up 51 percent of the population, women commonly represent 20 percent or less of the people studied when drugs come to the human trial stage. This is despite a 1993 National Institutes of Health Act requiring that all NIH-funded Phase 3 clinical trials include women (with exceptions for drugs that are for men-only, of course). Part of the reason women were initially not included in experimental trials was concern about a drugs' effects on reproduction or on the women's developing fetuses — but that kind of information is important to know. Women now take a number of medications during pregnancy that have never been tested on pregnant women in controlled circumstances. So if there are problems, they will be difficult to suss out.
"Pregnant women get sick, and sick women get pregnant," Francoise Baylis, a professor of bioethics told Slate, pointing out the obvious problem with designing drug trials around the realities of human existence. In the guise of protecting pregnant women from the side effects of medications during trials, we are exposing them in real life, when nobody is following up on the potential issues.
The problem with male-only trials
This exclusion of women is both dangerous and just plain bad science.
As OB/GYN Dr. Teresa Woodruff wrote in an editorial for the journal Nature, leaving women out means that information is lost, including "... everything from variations in gene expression between male and female mice, to a higher susceptibility to adverse drug reactions in women compared with men. Moreover, hormones made by the ovaries are known to influence symptoms in human diseases ranging from multiple sclerosis to epilepsy."
In some experiments, women are specifically not included because researchers are concerned about how women's hormonal cycles will affect the results. While that seems to make sense when you're looking for specific information in a trial, the combination of thousands of tests in which women's biology is excluded means that, “Medicine as it is currently applied to women is less evidence-based than that being applied to men,” according to Woodruff.
Both the 1993 mandate for females to be used more in experiments and the 2014 change that requires female mice to be used only apply to research done with NIH money. And despite the 1993 mandate, an analysis showed that many researchers simply ignored it: Only 24 percent of drug trials included equal numbers of men and women.
Naturally, some scientists disagree with all of this, complaining that being forced to use both sexes will be more difficult. "Modifying experiments to include both males and females costs money and requires a duplication of time and effort — time that researchers might not have to spare or that might be better spent conducting other research — that is rarely practical or scientifically warranted," writes R. Douglas Fields in Scientific American. This kind of thinking makes it clear why so many trials fail to meet the standards set by the NIH for gender parity in research subjects.
It's true that, depending on the experiment, including more female mice and female humans will cost more money. But as Janine Clayton, director of the NIH Office of Research on Women’s Health, told Spectrum, "In the long run, money can be saved when scientists study both sexes early in basic and translational science."
And of course, you can't put a price on the loss of lives that are directly tied to unforeseen and misunderstood prescription drug reactions.