16 Nov 2015

Gender imbalance in drug testing

Women are often not included in drug trials, skewing the results, says Norman Swan.

Most drug safety testing is done on males - potentially leaving females at risk.Credit: Tom Merton / Getty Images

The 21st century is all about personalised medicine. Have genome; have custom-made treatments.

All very well, but there’s a glaring omission – if you’re a woman. 

From mice to humans, the subjects of medical research are mostly male. A 2010 Nature editorial “Putting Gender on the Agenda” estimated the ratio of male to female experimental animals in neuroscience is an astounding 5.5 to one. True: with clinical trials, crude analysis of the participation rates sometimes shows that women outnumber men, but when you remove trials on female-specific conditions, male dominance reappears.

The critics argue that there’s a problem from beginning to end. Animal research that tests new drugs before they go into humans is biased toward males. 

Then in early stage human trials, that determine safety and dosage, male-female differences are ignored. Furthermore, because we have invested so little in post-marketing surveillance – in which new drugs are monitored after going on the market – female-specific complications or treatment failures are only detected by chance.

A long list of treatments are prescribed for women with little

evidence of what works best. 

Some researchers say the result is a long list of treatments prescribed for women with little or no evidence of what doses work best, whether the safety profile is the same, or even if they are effective. 

There are good reasons to think women do not respond to medical treatments the way men do. For starters, they do not have the same set of genes. Men have genes specific to the Y chromosome and women get a double dose of the genes on their X. And even the genes that are identical can operate differently through what are called epigenetic effects – in which experience alters how genes behave. Clearly the experience of being a woman is different to that of being a man. 

One obvious factor is the sex hormones. Oestrogen, progesterone and testosterone all influence how the metabolism works, for instance how drugs are broken down in the liver. That means the rate at which drugs are cleared from the bloodstream – and hence their functional doses – can differ between the sexes.

Occasionally, problems emerge. A recent example was a sleeping pill called Zolpidem or Stilnox, which women eliminate more slowly than men. That led to cases of women with impaired alertness the morning after taking the pill and “sleep-driving” with disastrous effects. 

In 2013, the US Food and Drug Administration called for a 50% reduction in bedtime doses of the drug, especially in women.

Why do researchers use more males than females? 

Fundamentally because the female of the species is more complex. Her body changes as she ovulates, menstruates or becomes pregnant. To sort out these influences in a drug study would require more subjects and longer durations, making the process much more expensive. 

In addition, researchers may be nervous that a woman will become pregnant during a drug trial and expose her foetus to unknown risks. 

Women also live longer and develop heart disease more slowly, which means that testing a new heart drug will also incur a larger sample size and cost. 

And then there’s the difficulty of recruiting enough women. Because women are more likely to be carers, they may be less likely to have time to participate in a trial. Some of these reasons are real, some imagined, but they all strengthen the argument for more female representation. If the research results are more trustworthy, the extra cost may be worth it.

It’s not a new issue. For many years agencies in the US have tried to ensure better female participation in drug trials – with limited success. Changing research practices isn’t easy but solutions include: that funding bodies insist on gender balance; greater awareness of the issue on ethics committees; and drug regulators asking for gender-specific data.

Women would do well to take matters into their own hands. The next time they visit a doctor they might consider asking whether the drug they are being prescribed has been adequately tested in women. This should give a powerful impetus for change.

Norman Swan is a doctor and a multi-award winning producer and broadcaster on health issues.