Of Mice and Men
Why You Should Care About The Exclusion of Women From BioMedical Research
Despite a growing recognition of the need to include more women in medical research for over 3 decades, the disparities in medical trials continue to negatively affect women’s health care in the US. Unfortunately, the warning that “the historical lack of research focus on women’s health concerns has compromised the quality of health information available to women as well as the health care they receive” in the1985 report by the US Public Health Service Task Force on Women’s Health still rings true today.
Historically, this discrepancy existed for several reasons.
There are obvious concerns about harming pregnant women and their offspring, and this led to a catastrophic exclusion of women from medical research. Additionally, researchers have found that it’s easier to study men, who don’t have pesky hormonal cycles that can affect results. And lastly, there is the cost. Because female physiology is more complex than that of men, typically more women are required in a study, or the study needs to run longer to account for the differences that could be attributable to the myriad of physiological differences between women and men.
But it is these very differences that exist in our physiologies that should not be shunned or avoided, but instead explored and understood. Within the pharmaceutical industry, there has been a historical assumption that studies on men could apply to women without modification. No one has been asking the questions — should dosages, formulations, or combinations — be different for women?
The thalidomide scandal around the world in the late 1950s — early 1960s cemented the idea in both the medical community and society that drugs could be dangerous in pregnancy. In 1960, FDA pharmacologist Frances Kelsey withstood intense pressure from the pharmaceutical industry, refusing to approve the request to market the drug in the US stating “further tests were needed”. Her astute scrutiny of the application, in the midst of what in retrospect became a worldwide scandal, is commendable. Unfortunately, her exact wish was for more testing. This was not heeded, and the fallout that followed is still with us today.
Rightly so, the disaster prompted the FDA to intensify regulations for testing and licensing drugs. Congress unanimously passed legislation in 1962 requiring companies to prove efficacy, to disclose all side effects identified in testing, and to obtain consent from patients participating.
Then, in 1977, still reeling from the societal backlash, the FDA released further clinical trial guidelines that excluded women of “childbearing potential” from the early phases of most clinical trials. The guideline went a step further, recommending the exclusion of women who used contraception, who were single, or whose husbands had had vasectomies.
The intense protectionist climate that existed at this time led to the eradication of women from all areas of clinical research. This interestingly led to the exclusion of female animals from all forms of medical research too. It simply became easier to not have to deal with female hormonal cycles in any capacity.
But as all pendulums swing, in the 1980s the US Public Health Service Task Force on Women’s Health began to recognize that this this sweeping exclusion of females from medical research was harming women’s health in our country. This led the NIH in 1986 to enact the Inclusion of Women and Minorities in Clinical Research Policy.
Despite this policy urging researchers applying for NIH funding to include women and minorities in studies involving human subjects, a 1990 study of NIH grant applications found that about 20% of them didn’t even provide information about the sex of the study population.
And so in 1990 the Office of Research on Women’s Health (ORWH) was born in response, and Congress enacted a law mandating the inclusion of women in medical research. While having a branch of the NIH dedicated solely as the focal point for women’s health research at the National Institutes of Health did increase the inclusion of women in studies, unfortunately, sex-specific analysis of the data did not follow.
Almost 3 decades later, a 2018 review of 107 NIH-funded randomized control trials (the gold standard for medical research) highlighted this disparity. It found that only 26% of studies that enrolled both men and women reported outcomes by sex, or included both sexes as a covariate. And 72% simply did not include sex in their analyses.
This means that although women were in the studies, no one was looking at the data to evaluate it for any differences that might exist between women and men.
When we don’t think to ask the questions, we are completely blinded to the answers.
For example, women experience side effects, or adverse drug reactions, nearly twice as often as men. Many potential explanations for this include biological, psychological, and cultural factors.
Are women metabolizing or absorbing medications differently from men? Are they more likely to be on more than one medication at a time? Are they more likely to report side effects? Or is it all of the above, or something else?
We know there are many reasons why women and men may handle drugs differently. Women generally weigh less, have smaller organ size, and a higher percentage of body fat — all of which affect the absorption and distribution of drugs. Women have a slower gastric emptying time and lower gastric pH, decreased renal clearance of drugs, lower plasma volume, and total body water differences, all of which can affect a drug’s distribution.
Not to mention responses to drugs can also be impacted by physiological changes during the menstrual cycle. The striking hormonal variations that women go through across days and weeks in the course of the normal menstrual cycle vary widely compared to men who only have diurnal hormonal variations.
And then there is the significant transition that occurs with menopause. We are just beginning to unpack an understanding of this normal physiologic transition, and how healthy women are impacted. Studies to evaluate women’s response to medications before, during, and after menopause are not routine.
All of these differences in how a person’s body interacts with medication exposure are known as pharmacokinetics (PK). So even though we know that there are very real sex-based differences, unbelievably they have historically not been considered when evaluating a medication for side effects.
A 2020 study by University of Chicago and University of California, Berkeley researchers suggests that women are being widely overmedicated because drug dosages are calculated based on studies that do not take into account differences between men and women. Because even though women are included, no one is evaluating whether when drugs are handled differently it might cause different side effects.
They scoured almost 5500 papers to identify drugs that showed a sex difference in PK and then compared it to data on differential sex-based side effects in that drug. Essentially, they asked the question — if a drug is knowingly metabolized differently in men and women, is there then a corresponding difference in the side effect profiles reported in men and women who are using that medication?
The study found that sex difference in PKs was linked to a similar sex difference in adverse drug reactions for women 88% of the time. Their results suggest that “elevated drug concentrations and decreased elimination times are far more prevalent in women than men and present a quantifiable and major health risk for women.”
While that information is telling, what is perhaps more sobering about this study is that they only found 86 drugs to include. They included only drugs that showed slower PK metabolism in women AND had significant sex differences in side effects.
Because while there were many more drugs with striking sex differences in adverse drug reactions, they could not include them because they did not have available PK data. Unfortunately, this type of pharmacokinetic information is included in only a small minority of approved drug labels.
Looking at the more than 2500 compounds listed in the Physicians Desk Reference (PDR), fewer than 4% present their pharmacokinetic data on their label. Yet across the board, women report twice as many adverse drug reactions as men.
Even drugs brought to market specifically for women, still base some of their findings on testing done in men. One seemingly ridiculous example of this is a 2017 study looking at the pharmacodynamic effects of alcohol use and Addyi (a drug specifically marketed for female hypoactive sexual disorder). Strikingly 23 out of 25 study participants in this subset were men!
While arguably the advances and changes in recognition are important, the sad reality is that it will take many years for us to change the clinical impact this has had on women’s health care. For example, a woman with cardiovascular disease today is given the ‘standard treatment’ that was developed in the 1980s, on testing done on men. But since 1984, the number of deaths attributable to heart disease in women has exceeded those for men. Could this mean that women need to have ‘standard’ cardiovascular treatments developed that work better in women?
Again. When we don’t think to ask the questions, we are blinded to the answers.
We know that women are different than men. Our physiology is more complicated due to the intricate hormonal changes that occur every month for women of reproductive age, and the drastic transition that occurs when we go through menopause. Instead of ignoring or avoiding these differences because they are complicated or expensive, it is time to start actively acknowledging and studying these variables.
In honor of Women’s History Month, President Biden signed an Executive Order on Advancing Women’s Health Research and Innovation earlier this week. The order seeks to strengthen the development of, and promote interagency alignment and consistency on, research and data standards to enhance the study of women’s health. It will devote “key investments” of $200 million to fund interdisciplinary women’s health research, with a specific focus on galvanizing new research on women’s midlife health.
Among many things, this new legislation will require investigators to
1) explain how their proposed study designs will consider and advance our knowledge of women’s health
2) consider women’s health, during the evaluation of research proposals that address medical conditions that may affect women differently or disproportionately
3) report regularly on their implementation of, and compliance with, research and data standards related to women’s health
This is just one more step that will continue to bring us closer to being able to ask the right questions, and hopefully start getting the answers needed to advance women’s health care in this country to where it should be.
In the writing of this article, I use the words women, and female to refer to those persons born with XX chromosomes. I have chosen to discuss this in strictly biological terms while understanding that many of the same issues discussed here may apply to persons with XY chromosomes who identify as women, or to persons with XX chromosomes who identify as men.
