We know that men and women have different metabolic systems. We know that diabetes, one of the diseases particularly singled out as being relevant to this discovery, also affects men and women differently,102 and that it is a greater risk factor for cardiovascular disease in women than in men.103 But despite all this, the paper’s authors consistently failed to acknowledge any relevance of sex differences to their research. They cited animal studies that had similarly been conducted in all male populations, and perhaps most shockingly of all, in a section specifically looking at ‘limitations with the present investigation’ they completely failed to mention the fact that the study was all-male as a potential drawback, only referring to their ‘relatively small sample size’.
There have been some attempts to force researchers to properly represent females in medical research. Since 1993, when the US passed the National Institute of Health Revitalization Act, it has been illegal not to include women in federally funded clinical trials. Australia’s main funding body made similar rules for the research it funds,104 as has the EU, which in fact went even further, also requiring both sexes to be studied in preclinical animal studies. This requirement did not come into effect in the US until January 2016,105 which is also when the NIH introduced the requirement that the data in trials it funded be disaggregated and analysed by sex (unless there is a compelling reason not to).106
Other positive developments include the German Society of Epidemiology which has for more than a decade required researchers to justify including only one sex in any study where the results could potentially affect both sexes;107 and the introduction of the same by the Canadian Institutes of Health in 2012, as well as mandatory questions about the consideration of sex and gender in the study design. Some academic journals also now insist that papers submitted for publication should provide information about the gender of participants in clinical trials, for example.108
Trailing behind everyone is the UK, whose main funders ‘make no substantive reference to, or requirements regarding, the consideration of gender in research design and analysis’,109 and despite the at-risk population of women suffering more morbidity and mortality,110 UK research funding for coronary artery disease in men is far greater than for women. Indeed, such is the dearth of gender-based clinical research from within the UK, that Anita Holdcroft, emeritus professor at Imperial College London, has written that for cardiovascular treatment, ‘it is pertinent to use studies from North America and Europe where these issues have been investigated’.111
Still, while the situation in the UK is dire, significant problems remain elsewhere. For a start, the evidence we’ve just seen on the representation of women in trials suggests that these policies are not being rigorously enforced. And, indeed, this is what analyses of the NIH have found. Four years after the NIH announced their first policy calling for the inclusion of women in medical trials, a report was released by the GAO which criticised the NIH for having ‘no readily accessible source of data on the demographics of NIH study populations’, making it impossible to determine if the NIH was enforcing its own recommendations.112 By 2015 the GAO was still reporting that the NIH ‘does a poor job of enforcing rules requiring that clinical trials include both sexes’.113
There also remain plenty of loopholes for US drug manufacturers who don’t want the cost and complication of including unharmonious females with their messy hormones in their neat clinical trials, because the rules only apply to NIH-funded trials; independent drug manufacturers can do whatever they want. And the evidence suggests that many of them do: a 2016 paper found that ‘a quarter of the drug manufacturers in an industry survey did not deliberately recruit representative numbers of women as participants in drug trials.’114 When it comes to generic drugs, the FDA only specifies ‘guidelines’ rather than rules and, as we’ve seen, these guidelines are being roundly ignored. And the NIH policy on including female subjects in clinical trials doesn’t apply to cell studies.
Then of course there’s the issue of legacy drugs. Two million women per year take Valium for conditions ranging from anxiety to epilepsy, and it was aggressively marketed towards women for decades.115 And yet, a 2003 paper points out,116 this ‘mother’s little helper’ was never tested in randomised clinical trials with female subjects. A 1992 survey by the US General Accounting Office (the Congressional watchdog) found that less than half of publicly available prescription drugs had been analysed for sex differences.117 A 2015 Dutch paper baldly states that ‘The specific effect on women of a huge number of existing medications is simply unknown.’118
There is clearly a long way to go, and we must begin to address these gaps as a matter of urgency, because while they remain open, women (who ingest approximately 80% of pharmaceuticals in the US119) are dying. Some drugs used to break up blood clots immediately after a heart attack can cause ‘significant bleeding problems in women.’120 Other drugs that are commonly prescribed to treat high blood pressure have been found to lower men’s mortality from heart attack – but to increase cardiac-related deaths among women.’121 Statins, which are regularly prescribed around the world as a preventative measure for heart disease have mainly been tested in men and recent research from Australia suggests that women taking statins at higher dosages may face an increased diabetes risk122 – which in turn is a higher risk factor for cardiovascular disease in women than in men.123 In 2000 the FDA forced drug manufacturers to remove phenylpropanolamine, a component of many over-the-counter medications, from all products because of a reported increased risk of bleeding into the brain or into tissue around the brain in women, but not in men.124 Drug-induced acute liver failure has also been reported more often in women,125 and certain HIV medications are six to eight times more likely to cause an adverse drug reaction (ADR) in women.126
In 2014, the FDA released a database of ADR reports between 2004-13 which showed that women are far more likely than men to experience an ADR: more than 2 million were recorded for women compared to less than 1.3 million for men.127 Although around the same numbers of men and women die from an ADR, death is ninth on the list of most common ADRs for women, compared to first on the list for men. The second-most common ADR for women (after nausea) is that the drug simply doesn’t work at all, and data on the number of deaths that occur as a result of the drug failing to work is not available. We do know, however, that women are more likely to be hospitalised following an ADR,128 and more likely to experience more than one.129 A 2001 US study found that 80% of drugs that had been recently removed from the market caused more ADRs in women,130 while a 2017 analysis points to the ‘large number’ of medications and medical devices removed from the market by the FDA that posed greater health risks to women.131