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#DemandDiversity: For International Women's Day, we ask... why do women often suffer from more side effects than men?

Women are largely prescribed exactly the same treatment regimens as men, with no account for the underlying differences in physiology and drug metabolism between the sexes.

For a large proportion of the last century, medicine has been tested on predominantly on males at every stage of the drug development process. This includes the use of male cells in biomedical research, the use of male animals in animal studies, and predominantly male patients in clinical studies. The result? Medicine and healthcare that has been designed and perfected in men, is then applied to women.

For a long time, the physiological differences between men and women were hugely oversimplified to their reproductive organs, leading to women’s healthcare being referred to as ‘bikini medicine’. However, we now know that women differ from men in far more ways than their reproductive organs. In reality, every cell in the body has a sex. And this inherently changes the way a person’s physiology develops, which then impacts the way they metabolise and react to drugs too. Yet, when you read the back of a standard packet of aspirin, the recommended dose varies between adult and child, but never between men and women. So, women are largely prescribed exactly the same treatment regimens as men, with no account for the underlying differences in physiology and drug metabolism between the sexes.

But why is this such a problem?

For starters, women typically react worse to medications, with women having a greater chance of developing adverse events to medication than their male counterparts. Between 1997 and 2000, the FDA retracted 10 drugs that were on the market. Out of these 10, 8 were removed because of unforeseen health consequences that disproportionately affected women. Most of these drugs caused cardiovascular-related side effects in women, with the development of Torsade’s de Pointes (TdP) — a potentially fatal irregular heartbeat — being the most common complication. It turns out, women are more predisposed to developing arrythmias like TdP. Further to this, the tests used to diagnose cardiac diseases function differently between men and women. This means that the symptoms displayed in women can be significantly different, and can go undiagnosed as a result. For example, women experience different symptoms for heart attacks than men. Men will experience severe chest pain, whereas women often complain of symptoms likened to indigestion, fatigue and shortness of breath. It’s likely that this contributes to the fact that women are more likely to die within the first year of having a heart attack.

More recently, the sleep-inducing drug Ambien has had regulatory changes in dosage for women. It was found that women metabolise the active drug much slower than men, resulting in women waking up in the mornings with the active drug still in their body, leading them to cause car accidents whilst driving in the mornings. The discovery of the differences in metabolism and the consequent changes in dosage recommendations were made in 2013, but the drug was originally approved for use in 1992. How was a drug approved for use nearly 3 decades ago, but the differences in metabolism between men and women were only discovered 7 years ago? Worryingly, over 40 million doses of Ambien were prescribed during 2013 in the U.S. alone, which begs the question — how many women were over-medicated as a result of this?

How is this not discovered before drugs are approved?

This all goes full circle back to women being underrepresented in clinical trials. If women were adequately represented, and the data for the differences in metabolism for drugs between the sexes documented and analysed, these differences would have been identified and accounted for prior to drug approval.

Why are women underrepresented in clinical trials?

Women have historically been underrepresented in clinical trials for a host of reasons, but this can, at least in part, be attributed to the thalidomide experience. Prior to 1977, women were excluded from clinical trials by choice, as their fluctuating hormone levels made it difficult to get consistent data — men are homogenous, so trials with a larger proportion of male participants made it easier to get a clean sample of data with no anomalies. However, after the mass administration of thalidomide to pregnant women, and the consequent serious birth defects in thousands of children, women of childbearing age were banned from participating in clinical trials until 1993. Now we see why the side effects of Ambien were only discovered after approval: it was approved in 1992, before the ban was lifted. So, this shows us that representation of women in clinical trials is absolutely critical.

Are women still underrepresented now?

At first glance, it appears that women are fairly represented in clinical trials, as they have made up 49% of participants overall since 1993. However, once these trials are divided up into specific diseases the underrepresentation becomes clearer, especially in the fields of cardiovascular diseases, hepatitis, HIV, chronic kidney disease and digestive diseases. Further to this, studies often don’t fairly represent the real-world breakdown of patients according to sex, meaning that despite women being more likely to use the drug, they aren’t being represented.

Further, despite improvements in representation, pharmacokinetic properties of drugs are usually not stratified by sex. But why’s this an issue? Papers show that without researchers looking at different responses to a drug by sex, it’s not possible to identify the differences in efficacy, safety and adverse events. So, even if women are represented in clinical trials, there’s no use in obtaining data on sex if you aren’t going to use it.

Then, what’s the aim here?

The aim is to achieve fair representation of women in clinical trials. And, where they’re already represented, the industry needs to ensure trial data is analysed by sex. It’s unrealistic to believe that drugs will have a unified effect across the sexes when there are so many differences between them. Women’s anatomy and physiology deserves to be studied with the same intensity as men’s, from biomedical research in the labs, to being fairly represented in clinical research studies.

This blog was first published here.

5th March 2021

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