Sex, drugs and clinical trials
It usually begins with a rat. A chemical cocktail is injected into its veins. If all goes well, the potion will speed through the animal’s body, killing its target with such gusto that it will be worth the risk of infusing the unfamiliar chemical into a human. All the while, hopeful scientists document possible side effects, be it twitching or perhaps death. Finally, the drug goes on sale for human use. But a serious problem has emerged in this pharmaceutical fairytale. For decades, scientists have favoured testing their chemicals on male specimens – from the first rat to the final human guinea pig. As a likely outcome, women are now one-and-a-half times more likely to develop an adverse reaction to prescription drugs than men.
The side effects can be mild, such as headache, nausea or dizziness, but they can sometimes lead to death. Eight of the 10 drugs withdrawn from the US market between 1997 and 2000 posed a greater risk to women than men. Meanwhile, zolpidem, a widely prescribed insomnia drug, was being sold to women for 11 years before the US Food and Drug Administration realised the dosages were too high. In 2013, the FDA halved the bedtime dose for women, after announcing that the drug remained in their system for longer than in men, meaning that women might be waking up still drugged.
While more scientists are beginning to acknowledge the role that a person’s sex can play in their body’s response to a drug, Dr Katie Flanagan, at Monash University in Melbourne, says many in the medical community remain unmoved. Male lab rats still dominate. And few studies consider sex in their analyses, she says. A recent report from the FDA found the disparate representation of women in clinical trials to be “worrying”. “To move mass thinking takes time,” says Flanagan. “You can’t change the minds of medics quickly.”
Females weren’t always excluded from scientific experiments. “We had a long tradition where sex differences were considered,” says Londa Schiebinger, a professor of science history at Stanford University. In the infamous Newgate prison experiment in 1721, surgeon Charles Maitland made incisions in six condemned criminals – three males and three females – and rubbed smallpox pus into the cuts, in a demonstration of the benefits of inoculation.
Some time in the 20th century, however, the tide turned. It’s unclear why, but some cite work on rats in the 1920s, which showed that a female’s behaviour changed throughout her cycle because of hormonal fluctuations. Scientists feared that these uneven hormones would interfere when trying to interpret the consequences of new drugs. This dogma still pervades medical thinking, despite several reports showing that the behaviour of male and female rodents is as varied as each other, notwithstanding those pesky hormones. “In any case it’s not a reason to not study females,” says Schiebinger. “Think about how dangerous it is to release drugs onto a population of women with menstrual cycles without testing it on them.”
Nevertheless, the final blow was struck in 1977 when the FDA published new guidelines excluding women of childbearing age from participating in early clinical trials. Since the US drives the consumption of prescription drugs, the pharmaceutical industry worldwide followed their demands. It would take more than a decade to reconsider.
Highlighting the “growing concern” about the lack of data on the side effects of drugs on women, in 1993 the FDA reversed its policy. The US National Institutes of Health, the largest source of funding for medical research worldwide, soon followed suit. These days “enrolment in NIH-funded clinical trials is about 50-50 men and women,” says Dr Janine Clayton, NIH associate director for research on women’s health.
But some researchers claim that this even-split figure is misleading. They argue that it is the result of a few large single-sex studies, for example those that have looked into breast or cervical cancer, and is not representative of clinical trials across a broad spectrum of diseases. A recent review of 80 clinical trials on the treatment of acute coronary syndrome found that only 27.7 per cent of the subjects were women, despite females comprising 41.5 per cent of those affected. When The Saturday Paper asked the FDA to clarify, the organisation responded: “There is no single ‘right’ target number or percentage for subgroup analysis.” So-called “subgroups” include sex, race and age. “Stakeholders have told us that information about demographic subgroups is not easily accessible.”
Questions are also being raised about drugs currently on the market, some of which would have been approved during the female blackout period of the 1980s. Giovannella Baggio, a professor at the National Research Centre for Gender Health and Medicine in Italy, wants a “re-do” of particular clinical trials to include women. The FDA deems this move unnecessary because drug-related adverse events are already recorded once a drug hits the market. So if a potential safety concern is identified, the FDA may take regulatory action. The 11-year delay on reducing the dose for zolpidem, however, highlights issues with this process.
There are many reasons why drugs might affect males and females differently. Females have a higher percentage of body fat than males, which can influence how certain drugs are distributed throughout the body. There are also sex differences in the enzymes of the liver that break down some drugs, which explains why some medications, such as antihistamines, are cleared faster in men than women. The lingering drugs may lead to a greater vulnerability to side effects. Even on a genetic level some medications have distinct responses in men and women. “Once you accept that these differences exist, they exist at almost every level,” says Peter Rogers, a professor of women’s health research at the University of Melbourne.
Similarly, sex differences have been described for almost every commercially available vaccine in use. According to Flanagan, females tend to mount more effective immune responses to measles, hepatitis B, influenza and tetanus vaccines, while males have better responses to yellow fever and meningococcal A and C vaccines. Women also experience more adverse reactions to vaccines than men. These responses are likely to be due, in part, to differences in sex steroids, particularly testosterone, oestradiol and progesterone, which can bind to immune cells and change the way they function. New studies of vaccination have found that genes associated with immune cells are expressed differently in males and females. Frustrating the matter is that despite sex differences often being found when the data is reported, a recent review in The Lancet Infectious Diseases noted that when it comes to vaccines, most studies still do not document male and female responses separately.
Despite these variations we still have some way to go before understanding what needs to be done. Many drugs on the market have dose recommendations regardless of sex, but more research will be needed to understand if advising different doses for men and women is the key to overcoming problems. Still, Rogers and Flanagan suspect that, like zolpidem, there are medications where doses should be changed in consideration of the patient’s sex.
Looking at differences in male and female responses has the potential to improve health outcomes for all patients. According to Flanagan, in some cases, males and females may respond to drugs in opposite ways. “When you analyse the sexes together their responses can cancel each other so you miss all of that useful data,” she says. For example, last year researchers at Yale University reported that the drug guanfacine could reduce alcohol and cocaine cravings in females, but not males. Had the trial not teased out sex factors, the female response might have been lost in the statistical scrum.
Meanwhile, there is still no NIH policy mandating the use of male and female animals in preclinical trials. This is problematic given that a survey of almost 2000 animal studies found there was a male bias in eight out of 10 scientific disciplines – a bias that has increased in the past 50 years. The survey, conducted by researchers at the University of California, found that while women are diagnosed with anxiety and depression twice as often as men, less than 45 per cent of animal studies into these disorders used female rats. Similar patterns were noted for research into thyroid diseases and stroke.
After decades of bias, Flanagan believes that change is coming and more scientists are appreciating sex differences. “But like all big paradigm shifts,” she says, “it takes time.”
This article was first published in the print edition of The Saturday Paper on Mar 28, 2015 as "Sex & drugs & rats in roles". Subscribe here.