Changing the Standard “Norm” of Medical Trials

Key Takeaways From This Article:

• Women and people of color were excluded from clinical trials and medical research for decades, creating a vacuum of medical knowledge in regards to women’s health and their interactions with drugs 
• It wasn’t until the 90s that the US officially began mandating requirements that made clinical trial testing more representative of the patient population
• Although the medical community has made great strides in equalizing research trials between genders, many drugs are still being prescribed based on symptoms alone, without considering other very important vitals such as gender, height, weight, and lifestyle. Much work is still needed to overhaul this system to provide more accurate and safer care for patients

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For many decades, there is one important variable that has been missing in disease and drug research—gender. For a long time, researchers focused their studies on typically white males as the ‘norm,’ arguing women were too expensive as research models due to their fluctuating hormones. But despite not being an active part of clinical drug trials, women are later prescribed the same medication as men without sufficient research having been done on how this medication may affect them. This kind of exclusion has rippled down to how women receive medical care and treatment and for a long time, prevented women from properly advocating for their own medical health. 

When studying disease or the medications used to treat said disease, a lot of variables must be considered. Lifestyle, age, height, weight, genetic history, race, all the way down to blood type. All of these variables affect how a disease may progress or how a drug may take effect. Although it was not mandated, it was an understood practice that most medical researchers used young white males as the standard ‘norm’ in any kind of medical trials. This meant not only were women excluded but also men of different ethnicities as well. Researchers just assumed that whatever drugs worked on the ‘norm’ population, the results would carry to everyone else–an assumption based on nothing more than a dismissive attitude towards race and sex that wouldn’t hold up in current scientific labs. Then this practice of excluding women from medical trials became law when the thalidomide tragedy exploded in Europe, causing thousands of malformed babies and stillborns. In 1975 the National Commission for the Protection of Human Subjects and Biomedical and Behavioral Research promulgated a new rule which included pregnant women as a vulnerable research subject. In 1977, the FDA followed with the guideline “General considerations for the clinical evaluation of drugs” which essentially banned women of ‘child-bearing potential’ from participating in early phase clinical research, except for life-threatening conditions.

This term ‘child-bearing potential’ was intentionally ambiguously worded so that researchers and doctors could interpret it as broadly as they wished. Many researchers took the term to mean not just pregnant or planning to become pregnant women but any woman capable of becoming pregnant. This included premenopausal single abstinent women, women using contraceptives, or women with sterile partners. Advocacy groups criticized the 1977 FDA guideline by arguing that trial participation should be focused on a woman’s independence to make decisions and determine fetal risk during pregnancy. By excluding women like this, it took away not only a woman’s independence to advocate for her medical health but also prevented them from benefiting from medical research as their male counterparts did. 

Gender, or more accurately, sex-based biology and the study of it is incredibly important, especially when it comes to the understanding of disease and disease treatments. We understand that lifestyle, environment, and behavioral differences all can play a crucial part in how certain drugs can affect a person or how certain diseases can develop. If those variables are so important in understanding a person’s medical make up, then the biological differences at the molecular and cellular level must be just as, if not more, important. Sex differences can be observed in various disease states in prevalence, diagnosis, severity, and outcomes. There are diseases that disproportionately affect women over men, such as breast cancer and heart attacks. Symptoms can present differently depending on sex. Sexually transmitted infections, for example, can present differently in women than men. Yet for a long time, these kinds of biological differences were not taken into consideration during research or clinical trials. 

You can still see the remnants of this kind of gender bias everywhere in medicine. For example, the physiological differences between men and women may translate into differences in how a drug treatment may affect a patient. Women typically have lower body weight than men but most drugs are often prescribed by dosage rather than patient sex. So when women take the same dose of a drug as a man, they are receiving a higher level of drug and therefore more susceptible to side effects. For example, it was found that the same dose of the drug zolpidem (a sedative to treat insomnia found in immediate release forms like Ambien) in women as in men caused two times the drug levels due to differences in metabolism. This accounted for the potential driving impairment the morning after taking the medication. In 2014, the FDA initiated distinct weight-based dosing for women and men. At the time, zolpidem was the only medication to have dosing based on sex.

It wasn’t until 1993 when the FDA released the guideline, “Guidelines for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs,” that the 1977 guideline was reversed. This new guidance lifted the ban of women of ‘child-bearing potential’ from participating in early phase research and left the decision to researchers and women themselves. The guideline further stipulated that clinical trial participants should be representative of the patient population that is likely to be prescribed the drug once approved. In 1994, the FDA also created an Office of Women’s health by Congressional mandate. The OWH has two overarching goals: 1) to protect and advance the health of women through policy, science, and outreach and 2) to advocate for the participation of women in clinical trials and for sex, gender, and subpopulation analyses. 

This movement towards more inclusion and gender equality not only represents fairness but also saves lives. An analysis of ten prescription drugs the were withdrawn in the market from 1997-2001 found that eight posed “greater health risks for women,” mainly because of adverse drug events due to known pharmacodynamic differences (e.g., three drugs like the antihistamine Seldane and Hismanal were withdrawn due to risk of torsades de points, a potentially fatal arrhythmia) or because of greater exposure of women to these drugs (e.g., four drugs like the appetite suppressant Pondimin and Redux were prescribed to more women than men). 

There have been great strides made in including more women in drug testing and disease research trials. But the strides are not all evenly made across all diseases and drugs. For example, there are now more studies and more women participating in studies that are more sex-specific. Substantial progress in prevention and diagnosis has been made for diseases such as breast or cervical cancer. But in other areas such as lung cancer, Alzheimer’s disease, or cardiovascular disease, less progress has been made, even though the leading cause of mortality in women has been cardiovascular disease since 1989. There are small clinical trials showing potential treatments for cardiovascular disease in women. The Women’s Health Initiative and Women’s Health Study have conducted trials using vitamin D and omega-3 supplements or HMG-CoA reductase inhibitors for cardiovascular disease prevention. These are all promising trials but unfortunately, these trials don’t have nearly enough women enrolled to fully understand how well these treatments would work. And the reliability of these trial conclusions is in question due to the insufficient statistical power. Meaning, because of the historical lack of women in medical research, women don’t have access to decades of statistics on female health and biology like men do. So for many female-centered clinical trials, there is no foundational ‘norm’ from which to work from. 

But as the medical world is coming to realize how crucial understanding biological differences is to medical research, more and more efforts are being made to make clinical research an inclusive space. The National Institutes of Health (NIH) and the Office of Research on Women’s Health (ORWH) outlined a plan to expand gender-biology studies with six main goals: 

1. increase sex differences research in basic science studies
2. incorporate findings of sex/gender differences in the design and application of new technologies, medical devices, and therapeutic drugs 
3. actualize personalized prevention, diagnostics, and therapeutics for girls and women
4. create strategic alliances and partnerships to maximize the domestic and global impact of women’s health research
5. develop and implement new communication and social networking technologies to increase understanding and appreciation of women’s health and wellness research
6. employ innovative strategies to build a well-trained, diverse, and vigorous women’s health research workforce 

But change comes slow. And the slow change can be seen affecting women now, during the COVID pandemic. With vaccine rollouts currently happening or about to happen in many countries, women are again finding themselves excluded from medical research. Many of the COVID vaccines have not been tested on pregnant women. This is a common practice for most vaccine trials because researchers find testing on pregnant women too ‘complicated’ for trials. There are more variables to account for. But this is a practice that only hurts the population and in a time of pandemic, it can almost cripple us. According to the US census, three quarters of healthcare workers are women with 85% of them as nurses. The CDC estimates about 330,000 healthcare personnel could be pregnant or postpartum at the time of vaccine roll out. In a time when our hospitals and healthcare workers are stretched to the very limit, we cannot afford to lose even a handful of nurses. How can we potentially leave 330,000 healthcare workers unvaccinated during a global pandemic? 

This crisis has made it even more abundantly clear just how important it is that we change the way we approach medical biases in research. Many groups, including the FDA, NIH, academia, Congress, and advocacy groups, now have an interest in ensuring appropriate enrollment of women in clinical trials and sex-specific analysis of the data. And after seeing the world fall to a global pandemic, there has been a noticeable shift in philosophy in how to best protect the public’s health. The medical world now realizes that by excluding women of ‘child-bearing potential’ they are not protecting women but hurting them. With new guidelines, policies, and organizations encouraging researchers to increase gender equality in medical research, women’s health research will only improve in quality by great leaps in the coming years. 

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