Differences between men and women have been ignored in COVID-19 vaccine and treatment trials

It seems obvious: there are biological differences between the sexes. Yet in medical trials, male and female bodies are often treated the same, with data from males extrapolated to females — often leading to devastating consequences.

COVID-19 affects men and women differently, yet sex-disaggregated data hasn’t been released for vaccination and treatment trials. This would show how many men and women were recruited and made it through to the end of the trial, and how the drug affected them separately.

This lack of data has led to mixed messaging around side effects, safety and efficacy of the vaccine, potentially fuelling vaccine hesitancy.

What’s the difference?

Generally, men have worse symptoms and a higher risk of death from COVID-19. Women are more likely to suffer from the long-term effects of COVID-19 and are more likely to experience adverse side effects after getting the vaccine.

Despite these notable differences, nearly two-thirds of studies on COVID-19 treatments and vaccine had less than 45% female participation and just 7% disaggregated their main outcome data by sex, leading to a massive sex gap in COVID-19 trials.

UNSW bioethicist Professor Jackie Leach Scully told Crikey there are huge differences in how men and women react to medicines due to body size, which affects what dose women should be given. Receiving a larger dose than necessary of the vaccine could lead to increased adverse effects. Fat distribution also has an impact on metabolising medicine, as does immunity.

“Women have different immune responses. We know that they do from the fact that they tolerate pregnancies,” she said. Women also make up 78% of people affected by autoimmune diseases.

Environmental and behavioural biases also played a part, Leach said. Women are more likely to work in frontline health services and therefore more likely to be first in line for the vaccine, creating a larger sample size. Women are also more likely to visit a doctor to report the longer-term consequences of COVID-19 such as brain fog and fatigue, she said.

Little oversight

Australia falls behind other developed nations when it comes to implementing sex and gender analysis in health and medical research. There’s no legislation requiring trials to recruit women in Australia — the closest thing we have is guidelines on ethical conduct from the National Health and Medical Research Council. But these, according to some experts, are pretty muddy.

“A lot of [those guidelines are] open to interpretation,” says Amy Vassallo, a research fellow in the Global Women’s Health Program at The George Institute for Global Health.

“[There are] still trials being published that actively exclude women from research recruitment, or perhaps recruit men and women at baseline but don’t report loss to follow up or sex disaggregate their findings.”

This can lead to vaccine hesitancy, Vassallo warned.

“It creates data blindness, which means that we can’t give accurate information about what you can expect to experience when you have this intervention, and that lack of accurate information will lead to variations.”

In the UK, changing recommendations for those who breastfed or were pregnant created “confusion and hesitancy”, Vassallo said. Prime Minister Scott Morrison’s comments that the AstraZeneca vaccine is safer than the pill when it comes to the risk of blood clots didn’t help clear the air.

Australia isn’t alone in its limited sex-based medical requirements: one study found that out of 45 national medical funding agencies across 36 countries, just 15 had polices about the inclusion of women.

A massive impact

A lack of sex-based data has had a huge impact on medicine. In the US across the 1970s and ’80s, women were left out of clinical research studies following the thalidomide scandal that killed and harmed foetuses. Only in 1993 did it became mandatory for women and ethnic minority groups to be included in clinical trials.

Senior research fellow at Auckland Bioengineering Institute Kelly Burrowes told Crikey many researchers looked for a “uniform cohort of subjects”, leading women to be excluded due to their hormonal cycles. Female mice are often excluded from experiments too — even when testing drugs designed for women. This can all lead to misinformation and misdiagnosis for women.

The “classic” symptoms of a heart attack are mostly true only for men, following a study designed by and with the majority participation of men. Autism is under-diagnosed in women due to a lack of research into how women exhibit behaviours. Certain hip and joint replacements have been designed for and tested on men, leading to pain and limited function. Women’s pain — previously deemed “hysteria” — is often ignored by the medical community. The experience of women who had vaginal mesh implants has been dismissed.

COVID-19 has renewed the push to have sex-disaggregated data, and have more women both participate in and conduct medical research trials. But progress has been slow, hampered by non-existent or inefficient policies by governments and medical research bodies.