Are women’s lives at risk from drugs tested by men?

Using ‘male’ crash-test dummies to determine how men and women would fare in car accidents has been blamed for the dismal injury record for women on the roads.

Although men are more likely than women to be in a car crash, when women are involved in an accident on the road they are almost twice as likely to become trapped in a vehicle, according to a study of more than 70,000 people in the UK, published in the journal BMJ Open last month.

Alarmingly, previous studies in the U.S. have revealed that women are also 47 per cent more likely to be seriously injured than men, 71 per cent more likely to be moderately injured and 17 per cent more likely to die.

Yet for decades, only crash-test dummies representing a man around 5 ft 8 in tall and weighing 12 st were used in safety trials, and even now ‘female’ dummies are little more than a scaled-down version of the original, rather than an anatomically correct representation.

Hormone fluctuations throughout adulthood have also been cited historically as a reason for excluding women, as scientists argue this makes women more difficult to study

Generally speaking, women have smaller and less muscular bodies, with different sex hormones which make their ligaments more lax, leaving them more prone to certain injuries. It means, say scientists, that men are better protected than women when it comes to road safety.

And this is just one shocking example of the systemic bias women face when it comes to potentially life-saving research.

For decades, women have been either omitted entirely from the testing of new medicines or included only in small numbers.

Instead, as with the crash-test dummies, scientists have relied on data from studies carried out predominantly on men — typically the ‘reference man’, who is Caucasian, aged 25 to 30 and weighs 11 st — and applied them to women and people from other ethnic backgrounds.

Tsar to tackle inequalities costing women’s lives

Take heart disease — probably the worst-offending area. Although women make up 47 per cent of the 7.6 million people in the UK with heart disease, they accounted for just 28 per cent of participants in 500 key heart trials carried out between 1996 and 2015, according to a Canadian study, published in Circulation: Cardiovascular Quality and Outcomes in 2018.

This simple and very convenient approach — using male data for females — we now know undermines the way millions of women are treated for potentially life-threatening illnesses, such as heart disease and cancer.

For example, it is estimated that a woman having a heart attack has around a 50 per cent greater chance of misdiagnosis compared with a man, according to research by the University of Leeds in 2018.

Women are also less likely to receive potentially life-saving treatments for a heart attack in a timely manner, less likely to be admitted to a specialist heart ward and less likely to be prescribed drugs to help prevent a second heart attack.

As a result, it is estimated that 8,200 women in England and Wales died between 2002 and 2013 simply because they didn’t have the same care as men, the research found. In fact, Chris Gale, a consultant cardiologist who carried out this study, warned that this could be an underestimate, as not all heart attacks were recorded in the research.

These alarming statistics — and the low profile of other issues such as the menopause and female infertility — prompted the Government earlier this month to appoint Dame Lesley Regan, former president of the Royal College of Obstetricians and Gynaecologists, as its first Women’s Health Ambassador for England.

Her job will be to tackle the inequalities that are costing some women their lives.

‘This is an important opportunity to get it right for women and girls, and make a real difference . . . by addressing the inequalities that exist across society,’ she said.

For while our DNA may be 98 per cent identical, key biological differences between the sexes — from organ size to body composition — mean we are poles apart.

For example, men are on average taller and heavier, with greater muscle mass and, literally, thicker skins; while women’s bodies tend to be smaller, with 10 per cent more body fat and regulated by a different set of hormones.

These fundamental physiological differences mean they respond in different ways to medication.

For instance, it takes longer for a female body to clear drugs from its system because they become ‘trapped’ in its higher levels of body fat, and it processes them more slowly because the liver and kidneys are smaller.

This means that when a woman is prescribed a dose based on what works best for a man, they’re more at risk of adverse effects and, in some cases, need a different dose.

‘When it comes to prescribing drugs, a one-size-fits-all approach, based on male-dominated clinical trials, is not working and women are getting the short end of the stick,’ says Irving Zucker, a professor of psychology and integrative biology at the University of California, Berkeley.

In 2020, Professor Zucker carried out a review of more than 5,000 studies and found that when men and women are given the same dose of a drug, women experience side-effects such as nausea, heart problems, headaches and seizures nearly twice as often.

This is because, at the same dose, women had higher concentrations of the drug in their blood, and it took longer for the drug to be cleared from their bodies.

And the damning review — which was published in the journal Biology of Sex Differences — found that this was happening with more than 80 commonly prescribed medicines taken by millions of people in the UK every year.

They included antidepressants such as fluoxetine; painkillers such as morphine and oxycodone; and heart medication such as the beta-blocker propranolol, widely used on the NHS to treat high blood pressure, heart rhythm problems and even anxiety.

Professor Zucker called for dose reductions for women where there is evidence that taking the same amount as a man causes side-effects. Yet this rarely happens.

In 2013, U.S. medicines regulator the Food and Drug Administration (FDA) did just that for the sleeping pill zolpidem, once researchers found that after eight hours, the recommended 10mg dose resulted in 15 per cent of women still having enough of the drug in their system to leave them drowsy in the day, putting them at greater risk of road accidents. In men, however, the figure was only 3 per cent.

The FDA recommended the dose for women be reduced from 10mg to 5mg.

But this is a rare event. Indeed, the move proved controversial among some scientists and this reduction in dosage has not been introduced in the UK or elsewhere in the world.

Maternal deaths due to lack of data

Meanwhile, the exclusion of women from clinical trials continues. In a recent example, pregnant women were not included in the initial Covid vaccine trials.

While this was understandable — given the hypothetical risk to babies in the womb — it had catastrophic consequences, according to Marian Knight, a professor of maternal and child population health at the University of Oxford.

‘With no data, when the vaccines secured an emergency licence they couldn’t be recommended for pregnant women — and that was interpreted to mean they weren’t safe for pregnant women,’ she says.

‘A subsequent inquiry into maternal deaths during this period, which I carried out, showed that more pregnant women than usual died during the pandemic, with an additional 34 women dying from Covid to the end of October 2021. The majority of pregnant women who died from Covid were unvaccinated.

‘Undoubtedly, some of these deaths could have been prevented if pregnant women had been included in clinical trials and we had collected data more effectively.’

Trials should include the same proportion of women who are affected by the disease in question, argues Natalie DiPietro Mager, a professor of pharmacy at Ohio Northern University in the U.S., who wrote a paper on the issue in 2016 in the journal Pharmacy Practice.

‘If you don’t study a drug in women, you don’t know if it works well or not and whether there are safety issues,’ she told Good Health.

Astonishingly, some of the biggest studies ever carried out on serious, potentially fatal, conditions, such as heart disease, did not feature a single female in their volunteer ranks

Missing out on new treatments

Last year, a U.S. study of more than 20,000 clinical trials, involving more than five million patients between 2000 and 2020, identified six areas where women remain under-represented relative to the numbers affected — cancer, neurology, immunology, urology, cardiology and haematology, reported the journal JAMA Network Open.

This, the researchers said, is concerning because cancer and heart disease are the leading causes of death among women.

Around 24,000 women die from heart disease each year in the UK, and 78,000 from cancer.

The researchers said this also means women more often than men miss out on the chance to access cutting-edge treatments through trials.

So why are women not taking part in — or being actively excluded from — clinical trials?

One major reason is that, following the thalidomide scandal in the 1950s and 1960s, when a drug for morning sickness in pregnancy caused severe limb defects in thousands of children worldwide, women of childbearing age were barred from trials until the early 1990s, amid fears of similar side-effects.

Hormone fluctuations throughout adulthood have also been cited historically as a reason for excluding women, as scientists argue this makes women more difficult to study.

And there are other logistical barriers too, says Professor Knight. ‘If you have young children and must attend appointments for a trial that are outside of school hours, and you’re not allowed to take your children with you, you may decide it’s too much trouble,’ she says, adding that pregnancy should not be a barrier to taking part.

‘We should be justifying the exclusion of pregnant women in clinical trials, not the other way round. Pregnant women should be given a choice to take part.’

Changes to make trials inclusive

Astonishingly, some of the biggest studies ever carried out on serious, potentially fatal, conditions, such as heart disease, did not feature a single female in their volunteer ranks.

One was the landmark U.S. Physicians’ Health Study, which started in 1982 and provided key evidence over 30 years that low-dose aspirin decreases the risk of a first heart attack (by 44 per cent). It had 22,000 participants; every single one was a man.

Similarly, the seminal Multiple Risk Factor Intervention trial, which launched at the same time and looked at how lifestyle factors such as smoking and diet influenced the risk of developing heart disease, included no women in its almost 13,000 participants.

Yet both helped to shape treatment guidelines around the world for all heart disease patients — male and female.

Dr Vijay Kunadian, a consultant interventional cardiologist at the Freeman Hospital, in Newcastle upon Tyne, says: ‘It’s very frustrating — we can’t simply take findings from men and apply them to women. It is not as simple as that.’

But things are changing — more than half of the volunteers in the recent Covid vaccine trials in the UK were women.

And later this year, the Government will publish its Women’s Health Strategy, which is expected to demand routine collection of data in clinical trials to show if women and men respond differently to new drugs. At the moment this is voluntary.

‘We are committed to ensuring clinical trials are representative of the affected population,’ says Professor Lucy Chappell, chief scientific adviser for the Department of Health and Social Care.

The Medicines and Healthcare products Regulatory Agency, the UK’s medicines watchdog which also oversees medical trials, is considering new laws to ensure more women and ethnic minorities are included in trials. Until then, critics say, we should make better use of the data we have.

Research from the U.S. shows 72 per cent of trials fail to include any breakdown by sex in their results — so they have no data on whether women are affected differently to men.

Professor DiPietro Mager adds: ‘A lot still needs to be done, not just in enrolling women in clinical studies but analysing the findings.’

Under the microscope

TV presenter and author Fern Britton, 64, answers our health quiz

Can you run up the stairs?

Yes I can, although I do have a little tweak of arthritis in my right knee. But I try to walk 5km a day near my house in Cornwall. I also have an electric bike but, just before lockdown, I hefted a large bin bag into the wheelie bin and did something to my right shoulder.

I had some physiotherapy and got referred to a surgeon. To my surprise, and relief, he diagnosed arthritis as well as possible bone spurs and a tear to the rotator cuff (the group of muscles that holds the shoulder joint in place). He said I’d need a shoulder replacement. I cried because someone was taking me seriously. It won’t happen for about 18 months but cycling is out of the question in the meantime.

Any family ailments?

My father had three hip replacements and my mother and sister have had one each. I’ve bucked the trend with my shoulder.

Any vices?

A weakness for butter.

Pop any pills?

I went through the menopause in my late 40s and I’ve been taking HRT ever since to regulate any mood swings. I had a hysterectomy six years ago and switched to a different HRT, oestrogen-only (called Zumenon), because of the surgery. I also take Nurofen if my shoulder is keeping me awake at night.

Ever have plastic surgery?

No, but I did have a bit of Botox a few years back to deal with my frown lines. Maybe one day I’ll decide to get rid of the gooseflesh under my chin.

Had anything removed?

The hysterectomy apart, my appendix when I was ten.

Ever been depressed?

I was diagnosed with depression when I was 22. I called it ‘the black dog’. The way I describe it now is the dog is in permanent kennels; I no longer even hear him yowling at night. But after the hysterectomy, I contracted sepsis and nearly pegged it. That brought on another bout of depression.

I was given an anti-depressant called citalopram, which gradually gives you an overview of whatever the problem is without you being stuck right in the middle of it. The episode took me two years to get over. I was very lucky not to lose fingers, toes, arms or legs.

Tried alternative remedies?

A girlfriend suggested a mix of turmeric and vitamins, which has helped with the creaky knee.

Any phobias?

I don’t like frogs. I don’t like the way they suddenly come at you. I had a pond put into the garden when I lived in Buckinghamshire as therapy to help get used to the frogs. Thunderstorms frighten me, too, even when I’m in bed. And I’m not good with heights.

Like to live forever?

No, because I’m not scared of dying. I’m interested to see what comes next.

The Good Servant by Fern Britton (HarperCollins) was published on June 9.

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