Inclusivity and diversity are being discussed in various areas of society, forcing professionals in many industries to consider whether their working environments reflect these broader social goals. Many in clinical research argue that women, along with ethnic minorities and senior citizens, have been excluded from trials, impacting the validity of the research as well as the safety of these groups.
However, when it comes to the discussion of women in particular, dissenting researchers say studies of clinical trial literature shows the problem is not as dire as their peers suggest.
These fewer voices argue that women are equally included in most trials. Nevertheless, the overarching narrative is that women’s participation in clinical trials has been lacking and efforts are needed to change this — not just for social justice but for scientific validity.
There are several reasons why getting the balance of the sexes correct is important for medical progress, according to the FDA. These include being accurately representative of the broader population, providing better analysis of whether biological sex affects the efficacy and safety of treatment, and helping to shape scientific insight into individual therapy differences.
With this in mind, we look at how bad the problem with women’s participation in clinical trials really is and what it means for the validity of clinical research.
Historically, there has been insufficient knowledge about men and women’s biological differences and what this means for the manifestation of different disease symptoms. Despite increased inclusion of women in clinical trials over the past 25 years, Natalie DiPietro Mager, associate professor of pharmacy practice at Ohio Northern University, says biomedical research is still far from representative.
The prevailing — and incorrect — perspective for many years was that women were just a variation of men and learning about the latter justified assumed knowledge of women, Jill Becker, a senior research scientist at the University of Michigan, tells the New York Times.
The problem is that differences between the biological sexes can affect how effective and safe drugs are in certain cases, DiPietro Mager explains. Often, with women underrepresented in trials, they are more often negatively affected by drugs.
Analyzing 50,000 mice at Britain’s Wellcome Trust Sanger Institute, researchers found that differences in biological sex can impact more than half of their experiments. The differences between sexes include bone mass, metabolism and blood components and, to a lesser degree, qualitative traits such as head shape, coats and paws.
The scientists conclusion was that the same could be true for humans.
“A person’s sex has a significant impact on the course and severity of many common diseases, and the consequential side-effects of treatments—which are being missed,” Natasha Karp, who co-led the study, says.
Many conditions affect men and women differently, and this is especially the case with neuropsychiatric diseases, psychiatrist Florence Thibaut writes. This is in part due to the effects of sexual chromosomes and hormones before puberty and during important periods of brain development.
Thibaut says male-biased conditions often include autistic spectrum disorders, attention deficit hyperactivity disorders, language impairments or schizophrenia. Female-biased conditions, on the other hand, include emotional disorders such as anxiety, depressive or stress and trauma-related disorders or even anorexia nervosa.
While there is clear evidence suggesting biological differences at play, she argues that different sociological factors — such as exposure to violence — also have an impact. The severity of biological or sociological stressors and differences remains unclear. Nevertheless, pharmacokinetic and pharmacodynamic properties of certain compounds may affect men and women differently.
Despite this, only 163 drugs in the US between 1995 and 2000 included sex-based pharmacodynamic analysis. Even with 11 of those showing a difference of 40 percent or more in the effects of pharmacokinetics between males and females, no dosage alterations were listed for men and women.
Women are under threat from drugs in a way men simply are not. Psychologist Durhane Wong-Rieger at Patient Research Exchange refers to a 2001 study which found that female patients have a 1.5-1.7 times higher risk than men of experiencing negative effects from drug treatments. This was attributed to men and women differing in pharmacokinetics, hormones and immunological factors.
Many drugs, such as painkillers, antidepressants and other psychotropic drugs, are known to have gender-specific effects. Wong-Rieger explains that anticonvulsants, for example, might not be as impactful for young women because they have an active liver enzyme that metabolizes the drugs.
The disproportionate representation of men and women differs according to disease areas. For instance, men are overly represented in heart disease studies, whereas women account for almost half of the participants in post-approval studies for medical devices for ear, nose and throat conditions.
Rather worryingly, heart disease is a leading cause of death for women.
Indeed, Elizabeth Pollitzer, Ph.D. says heart disease kills more women in the US than cancer. But it is still considered a man’s disease because the bulk of medical knowledge is based on studies of men.
The problem with this approach, Pollitzer explains, is that the assumption is that women and men show the same symptoms. Like many other diseases, this is not true for cardiovascular disease and the result is that women are less likely to be referred to a cardiologist or be prescribed statin therapy.
In pain research, men alone are included in more than 70 percent of studies. Yet between 1997 and 2000, 10 prescription drugs were deemed a risk to users and pulled from the US market — with eight of these specifically more dangerous to women.
It’s not just heart disease where symptoms, treatments and side effects differ between the sexes. Men and women need to be treated differently when it comes to certain types of cancers, such as oesophagogastric (OG) cancer. A study led by Dr. Michael Davidson, Clinical Research Fellow at The Royal Marsden Hospital NHS Foundation Trust, London, found that men and women differ in terms of incidence and prognosis. Cellular, molecular and metabolic differences between males and females can affect the development and treatment of a cancer.
Davidson analyzed four international trials conducted in the UK and Australasia using first line chemotherapy regimens for patients with advanced OG cancer. Of the 1,654 patients, 80 percent were male and 20 percent female. Even with that disparity, it was found that women experienced more toxicity results and other side effects than men; however, efficacy of treatment was very similar.
These findings do not support alternative dosing strategies for female patients undergoing chemotherapy, Davidson says. It can help healthcare providers to have prevention and support strategies in place.
While the prevailing reportage and opinion covered in the general media suggest women remain underrepresented in clinical trials — especially cancer, vascular surgery and cardiovascular trials — some studies assert that women already enjoy equal access to trials.
This is what researchers at NCBI discovered in their cross‐sectional research of publicly available registration dossiers of drugs approved by the FDA.
They looked at 185,479 patients in 38 drug trials and found that women accounted for 47 percent, with men at 44 percent and 9 percent unclassified.
Interestingly, women’s proportional representation changed as trials moved through phases: Women made up 22 percent of Phase I trials, 48 percent of Phase II and 49 percent of Phase III trials. Based on this data, researchers say “there was no evidence of any systematic under‐representation of women in clinical trials.”
Academic cardiologist Roger Mills agrees that women are not underrepresented in clinical research. Referencing a 2015 study by Eshera et al published in The American Journal of Therapeutics, Mills discusses the demographics of participants in trials for 83 new molecular entity (NME) drugs and biologics approved by FDA between 2010 and 2012.
Women accounted for 45 percent of participants for NMEs and 65 percent for biologics. Additionally, 92 percent of the FDA medical and statistical reviews surveyed considered the effects sex has on safety and efficacy.
More troubling than gender, Mills says, is that 77 percent of patients were white. This was seen again in comparisons by Downing et al in Trials, showing that in more than 200 trials between 2011 and 2013, the gender split was even (men accounted for 50.3 percent and women 49.7 percent). However, a full 79.2 percent of participants were white, 7.4 percent black, 7.4 percent Asians, with patients of other races accounting for the remaining percentage.
The problem, Mills argues, is less about too few women than too few patients of color. The solution is more inclusive trials.
While having women patients in studies is important for clinical validity, including more women researchers is essential too. Not only can they help provide insight into research questions, it is vital our society as well as the medical community is more diverse.
Analysing some 1.5 million medical research papers between 2008 and 2015, sociologist Mathias Nielsen and his team of Danish and American researchers found women to be woefully underrepresented. They sorted the papers according to authorship — and whether a woman was listed as the first author (made major contributions to the study) or the last author (designed the study).
Women account for only 35 percent of all the authors and 27 percent of last authors, Nielsen says. This is despite findings that when women were involved in designing and executing the study, more gender-related and sex-related factors were accounted for in the research.
Debate surrounding the problem of women’s participation in clinical trials is important. While some researchers suggest radical change is needed, others argue there is no problem to resolve.
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