To understand what the exclusion of women from clinical trials really means, you must first know that clinical research is the overarching term that encompasses four different things, according to the National Institutes of Health: epidemiology, which improves understanding of a disease through studying patterns, causes and effects of health and disease in specific groups; behavioral, which improves understanding of human behavior; health services, which examines how people access health care providers and services; and clinical trials, which evaluate the effects of an intervention and health outcomes. Clinical trials, which are the heart of all medical advances, study things like new drugs or drug combinations, new surgery methods, new medical devices, new ways to use existing treatments, new ways to change behaviors to improve health, and new ways to improve quality of life for people with acute or chronic illnesses.
Clinical trials are designed by starting with a clinical research question that researchers want to address. There are two strategies for framing the question, but the most common is null hypothesis testing—where something is assumed to be true and researchers test subjects to find evidence to disprove it. This can be constructed through looking at the presence of an effect or difference between groups. The trials are classified into phases based on the objectives, but Phase I trials—conducted in humans—take small sample sizes (i.e., less than 20), may use healthy human participants, and are used to investigate how a drug moves through and impacts the body, as well as toxicity. Phase II trials aim to identify an optimal dose of the drug and safety issues. Finally, Phase III trials generally involve many study participants and are meant to confirm effectiveness of an intervention (these are typically conducted by pharmaceutical companies for marketing purposes).
When researchers are selecting individuals to enroll in a trial, they consider the target use of the intervention (i.e., a new drug treatment) to ensure it will be desirable to that test population. Early phase trials tend to select participants that are more homogenous since it’s easier to reduce response variation and isolate effects this way; however, later phase trials are focused more on heterogenous populations that will mimic the response in a broad population that will be using the intervention.
While clinical research dates back all the way to Biblical times, the first randomized control trial (testing a treatment for tuberculosis) was carried out in the 1940s. In 1964, the World Medical Association articulated guidelines on using human subjects in research in what’s known as the Declaration of Helsinki—which has undergone a series of updates, with the latest being in 2013. However, men were treated as the “medical norm” until 1993—around the time many millennials were born—when Congress passed the NIH Revitalization Act, which mandated the inclusion of women (as well as minorities) in clinical trials.
Why (and how) women came to be included in clinical trials
Women were historically excluded from clinical trials for a few main reasons, says Sara Crystal, MD, a board-certified neurologist and an advisor to Cove, a telemedicine platform that provides consultation on migraines. Among them: bias; the assumption that there were no significant sex differences in regard to medication response, and therefore no need to study women separately; concern over having to adjust for women’s fluctuating hormone levels; and concern over reproductive effects.
The passage of the Revitalization Act had been a long time coming, however. It was largely influenced by the many civil liberty movements taking place, as well as the popularity of powerful literature, like the book Our Bodies, Ourselves, which addressed women’s reproductive health and sexuality. Efforts that led to NIH’s inclusion policy occurred simultaneously with those to establish the NIH Office of Research on Women’s Health, and a full decade prior, in 1983, the Public Health Service Task Force on Women’s Health Issues. (In fact, NIH had established the policy for including women in clinical research seven years earlier, in 1986, which urged researchers applying for NIH funding to involve women in their studies.)
Natalie Dipietro Mager, PharmD, MPH, an associate professor of pharmacy practice at Ohio Northern University College of Pharmacy, co-authored a study that examined the history and progress of women’s inclusion in clinical trials for prescription drugs. She notes in the study that while there is recognition today of the need to include women sufficiently in clinical trials, in previous decades, the consideration of men overshadowed women in clinical research design and conduct.
Prior to the women’s health movement of the late 1960s and 1970s, some medical research practices led to inaccurate understanding of the human body as a whole, says Regine Douthard, MD, MPH, senior program officer with NIH’s Office of Research on Women’s Health.
“Many clinical trials ran under an unspoken assumption that the only difference between women and men was their sexual and reproductive organs,” Douthard explains. “Women were, in essence, considered small men.”
"Many clinical trials ran under an unspoken assumption that the only difference between women and men was their sexual and reproductive organs. Women were, in essence, considered small men." — Dr. Regine Douthard
What are the problems created from omitting women from clinical trials?
It’s easy to sit back and think: This all changed 27 years ago, and we’ve come a long way since then. While this is true to a degree—a 2019 study found that women today make up about 49 percent of participants in clinical trials—it’s impossible to ignore the problems that omitting women from these studies in the past created, many of which still stand today. “It’s hard to say that studies have been entirely negated [as a result of women included in clinical trials],” says Dipietro Mager.
One big issue being discovered is that some diseases present differently in men and women. Take heart disease, for example: Men’s presentation of cholesterol plaque in the arteries looks different than women’s, says Dipietro Mager. As a result, heart disease is underdiagnosed in women. “The bulk of cardiovascular clinical trials research has been predicated to men, and this has, in my opinion, served as a medical disservice to women with cardiovascular disease,” says Kecia Gaither, MD, MPH, FACOG, a double board-certified OB/GYN.
There’s also data that shows women are treated less aggressively for heart disease than men and aren’t taken as seriously in hospitals, she adds, and as a result, women with heart disease are having worse outcomes than men. For example, a study from 2000 found that women are seven times more likely than men to be misdiagnosed and discharged from the hospital while having a heart attack.
A second big issue with omitting women from clinical trials has to do with prescription dosages. There are very few drugs that have overt dosage directions that are different for men and women, says Dipietro Mager. “Because men and women have different composition in terms of body fat, and women in general may have smaller frames than men, we don’t know whether there should be a difference in dosage,” she says. One of the few prescription drugs that does have differences on the label for men and women is the sleep aid Ambien, with a recommended initial dose of five milligrams for women and five to 10 milligrams for men.
There have also been studies showing how aspirin affects men and women differently. And in 2001, the FDA reported that eight of the 10 prescription drugs it withdrew from the U.S. market in 1997 were found to have posed greater health risks for women than men.
The future of women's health is tied to clinical trial inclusion
The NIH Revitalization Act of 1993 was a good start to understanding women's health. Since then, the FDA has also implemented a policy of encouraging inclusion in clinical trials (specifically with regard to prescription drugs) to ensure participants are representative of the broad population of patents who will be exposed to these drugs. (FYI: The FDA has jurisdiction over clinical investigations involving FDA-regulated products such as drugs, biologics and medical devices; for clinical investigations conducted or supported by NIH, both the FDA and the U.S. Department of Health and Human Services have joint jurisdiction.)
It’s worth noting that in 1977, following the tragedies caused by the use of two prescription drugs for morning sickness that turned out to be damaging to embryos, the FDA had recommended against including women of child-bearing age in early phases of drug testing, except for life-threatening illnesses. A new FDA guideline issued in 1993 was the first time the regulating body lifted the restriction on women, allowing them to be included in early-phase clinical trials. Five years later, the FDA published its final rule requiring new drug applications for drugs and biologics to examine and include data on safety and effectiveness by gender, age and race.
In a draft dated June 2019, the FDA published further guidance on diversity in clinical trials, and has published several other guidance documents on topics such as collection of race and ethnicity data in clinical trials and reporting of age-, race- and ethnicity-specific data in medical device clinical studies. The FDA Center for Devices and Radiological Health also issued guidance around gender-specific evaluation of data on medical devices in 2014. (It’s worth noting, however, that while including demographic subgroups as participants is strongly encouraged, there is no statutory requirement by the FDA to include these subgroups as participants in clinical trials.)
Even though these measures have helped grow representation of women in clinical trials, the same study reporting that 49 percent of participants are now women also found that women are still underrepresented in major medical research areas such as cardiovascular disease, hepatitis, HIV/AIDS, chronic kidney disease, and digestive disease. But again, there are signs that things are improving; a new study published in February this year reported that among cardiovascular trials conducted between 2010 and 2017, men still predominated overall, but the representation of women varied with disease and trial characteristics, and has improved in clinical trials examining stroke and heart failure.
Now, there are also advocacy groups advocating for women’s equality in clinical research. For example, Shikha Jain, MD, FACP, a board-certified hematology and oncology physician on faculty at Rush University Medical Center in Chicago, co-founded the Women in Medicine Summit last year. The summit is a multinational conference that’s focused on empowering both women and men to close the gender gap in medical research on a personal and national level. “My hope is that when we move forward and realize more and more the fact that this discrepancy still exists,” says Dr. Jain, “that physicians will make a concerted effort and be intentional in including men and women [in clinical trials] equivalently.”
What still needs to be done
One of the main reasons that women still aren’t being included often enough in clinical trials is that they simply aren’t offered the opportunity as often as men. There might be a preconceived notion that they aren’t interested in the trials or don’t have the time, "so the challenge is changing the perception that we shouldn’t include women in trials," says Dr. Jain.
Dr. Gaither says one way this can be accomplished is by having more education available to the public, whether it be by commercials, radio, or social media, explaining how you can engage in clinical trials. “I believe that the more diverse individuals participate in clinical trials, the better [we can learn] what works best for whom—ultimately improving health for all,” she adds.
Equally as important is including minority women, who as a subgroup continue to be vastly underrepresented in clinical trials. “That is a huge, huge issue,” says Dr. Jain. However, physicians are working with these populations to bring them opportunities to be part of trials—as well as destigmatize the way trials are perceived in general.
Many patients worry that being part of a clinical trial means they’ll be experimented on, says Dr. Jain. But trials differ, and participating in a trial means you’ll get the standard of care (or better) with the chance of to not only improving your trajectory in your disease process, but also potentially improving other patients’ potential outcomes by learning from your response to the treatment. Also, you don’t have to be sick to be part of a clinical trial; many trials are looking for healthy participants. (To find opportunities, check ClinicalTrials.gov or check with your local health department.)
Natasha Bonhomme, chief strategy officer for Genetic Alliance, a nonprofit health advocacy organization based in Washington, D.C., says that many times, women are still leaving their doctor visits with more questions than answers—and that the public in general is not very knowledgeable about clinical trials, often unaware until someone close to them is hit with a health crisis. “People don’t really understand that what we can learn from clinical trials really drives what we get in our healthcare system,” Bonhomme says. “A medical intervention doesn’t just show up out of nowhere; it takes decades of research, clinical trials, and investment—and that’s a great thing, but not a great thing when half the population is basically left out.”
The solution to designing more trials that include representative groups has to be a multi-pronged approach. “The impetus is going to be on physicians to educate, on the researchers creating trials to ensure there are intentional ways in which diverse groups of individuals should be recruited, and intentional patients who are asking the important questions and understanding the benefit not only for them but science and medicine in future,” says Dr. Jain.
A major upside to leveling the playing field when it comes to clinical trials is an improvement in the entire health-care system. Research shows that investing in women’s health, leading to healthier women and children, creates a healthier and more productive society for all. “It’s important for us to have as much information as possible, and also to have everyone feel like they are part of the medical and health care system and that it’s responding to them,” says Bonhomme. “It affects all of us.”
The bottom line, says Dr. Jain, is that more conversations need to be had and more work needs to be done. Now that we’ve identified the lack of inclusion of women in clinical trials in the past as a problem, the important next step is both doctors and patients taking steps to actually implement solutions. “We need to be intentional in how we’re moving forward,” she says. “The more that it’s discussed and addressed, the more we will be actually seeing changes.”
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