Routinely, drug development studies are conducted using animals and in clinical trials with the participation of human beings. Both of them include two subgroups: the male and female. It is known that there are many differences between the two entities in several aspects including genes, hormones, anatomy, physiology, the interactions between the genes and the whole body, their lifestyle, environment and behavior. That means clinical research which takes into consideration these differences as well as equitable representation by sex (referring to biological traits) and gender (referring to self-identity and sociocultural norms) constitutes an essential step to ensuring true patient-centered, evidence-based care. Nevertheless, there exist several gaps in women’s health research due to problems in conducting sex- and gender-specific research as well as issues regarding the participation of women in clinical trials.
What is the current global status of sex- and gender-based clinical research? Are men and women equally included and represented in clinical trials? Can the promotion of sex- and gender-specific research improve women’s health care? We invite you on a journey through historical and current data to find the answers to these questions.
Why sex and gender matters in clinical trials ?
Sex and gender – each has the potential to influence the effect of the natural history of an illness, our response to therapies and interaction with the healthcare system. According to the Institute of Medicine, every cell in our bodies has a sex (Wizemann 2001). Differences between sexes have been identified at many levels of biological organization, from biochemical to behavioral. They impact myriad physiological functions, disease prevalence, and susceptibility. Notably, sex-based differences in the levels of circulating endogenous hormones, such as testosterone and estradiol as well as weight, muscle mass, body fat, metabolic enzymes, and plasma proteins have an influence on drug pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetics describes the rate and extent of drug movement through the body, including absorption, distribution, metabolism, and excretion. Pharmacodynamics presents a drug’s mechanism of action, including the physiologic and biochemical effects on the body, and the relationship between drug concentration and the rate and extent of pharmacologic response. What are the examples of sex differences in relation to these PK and PD parameters of drugs ? Let’s see:
- women have a higher percentage of fat tissue in their total body weight as compared to men. This may account for greater volumes of drug distribution, depending on a drug’s hydrophilic or hydrophobic properties (Whitley 2009). Lipophilic medications, such as benzodiazepines and neuromuscular blockers, show a longer duration of action in women, which require 22% smaller dosages of these drugs when compared to these used in men;
- women secrete less gastric acid and tend to have slower gastrointestinal transit times than men (Whitley 2009). Because of this, medications that require an acidic environment for absorption (e.g. antifungal drugs) may have lower bioavailability in women. This may reduce the effectiveness of the drug;
- estrogen can influence pain pathways, alter pain perception, and affect response to certain drug classes. Because estrogen is present in substantially higher levels in women than in men, women tend to exhibit lower pain thresholds, increased pain ratings to standardized stimuli, and lower tolerance to pain. Women also demonstrate a greater analgesic response to opioids (Whitley 2009). To achieve equivalent pain relief, men require a 30 to 40% greater dosage of morphine;
- men and women respond differently to antidepressant and antipsychotic agents. Although there appears to be no difference in depression symptom severity, women generally respond better to selective serotonin reuptake inhibitor (SSRI) therapy (Whitley 2009). This may be because women produce more tryptophan and less cortisol when exposed to SSRI therapy.
What’s interesting, women are 50 to 75% more likely than men to experience an adverse drug reaction (ADRs) (Wilson 2022). The reasons for this increased risk are not entirely clear but include sex-related differences in PK, immunological and hormonal factors as well as differences in the use of medications by women compared with men. For example:
- women are at increased risk of experiencing torsades de points, a potentially fatal arrhythmia, after taking drugs which prolong the QT interval (including certain antyarrhythmias, antibiotics, antidepressants and antipsychotics) (Whitley 2009);
- women demonstrate a six- to eightfold increase in drug-induced rash from HIV medications and experience higher rates of drug-induced liver disease from antiepileptic drugs (Short 2006);
- women are more likely to be at risk of excessive daytime sedation and impaired driving proficiency than men following a therapy of insomnia drug – zolpidem (Roehrs 2016);
- when treated with digoxin, women experienced a higher rate of mortality from any cause compared with men treated with digoxin and compared with women taking placebo (Flory 2008).
Gender can shape a patient’s experience in the perioperative period starting from the preoperative period up to patient discharge and can influence outcomes in the perioperative period. Women have a higher incidence of awareness with postoperative recall and connected consciousness during anesthesia than men (Braithwaite 2023).
Transgenders require special consideration because of distinctive health risks, specific healthcare needs and healthcare disparities. For example, female-to-male patients on testosterone therapy may have an increased risk of developing liver disease and breast and endometrial cancers. In trans-males, parenteral testosterone may raise hematocrit to up to 48%, compounding the risk of cerebrovascular accidents and stroke. Thus, their perioperative care requires multidisciplinary involvement including endocrinology, anesthesiology, psychotherapy, psychiatry and social worker.
Participation of women in clinical trials – historical perspective
Have you ever wondered why modern medicine is based on research performed mainly on men ?
In just about every aspect of the world, male bodies have always been the default – from the skeleton in a physician’s office to crash test dummies (Linder 2019). But there is no place for usage of “default” to be more dangerous, than in medical research.
Although, the first randomized control trial was carried out in 1946, the exclusion of women from clinical trials dates back already to the early 1970s when men were still viewed as the ‘dominant’ gender and few women were working in the field of science and medicine (for more information about history of clinical trials, please read our article – The changing face of clinical trials. A long and fascinating journey to effective and safe medicines). The severe birth defects associated with thalidomide in the 1960s led to a conservative approach to testing new drugs in women and in 1977, FDA issued a guideline which stated that “women of childbearing potential should be excluded from the earliest dose-ranging studies”. That exclusion inadvertently led to the underrepresentation or even exclusion of women from clinical trials. Because sex was not recognized as a variable in health research this exclusion was not questioned. Women were underrepresented in all phases of clinical research (Zucker 2020), owing to factors such as concerns about the potential reproductive adverse effects of interventions in pregnant women and the assumed confounding effects of women’s fluctuating reproductive hormone levels.
Since the 1970s the scientific community has been warned that performing clinical trials on a population consisting mostly of young middle-aged men and generalizing the results to whole populations could lead to biased knowledge. Concern increased by the early 1980s, when the proportion of women in medical degrees reached 30% and women physicians began to reach a critical mass in academic medicine.
And then, the pendulum swung. In 1988 the FDA established a mandate to include both men and women as well as sex-based analyses for trials supporting the approval of drugs intended for both sexes. Since this moment many different initiatives began to advocate for the inclusion of women in clinical research. The National Institutes of Health (NIH) established the Office of Research on Women’s Health (ORWH), and the Department of Health and Human Services followed suit with its own Office of Women’s Health. In 1991, Dr. Bernadine Healy became the first female NIH Director and launched the Women’s Health Initiative, a set of clinical trials and an observational study that together enrolled more than 150,000 postmenopausal women over a period of 15 years. In 1993, the FDA issued a new guideline and formally rescinded the 1977 policy that banned most women from participating in studies. To ensure that the policies for inclusion were firmly implemented by NIH, Congress made what had previously been policy into law, through a section in the NIH Revitalization Act of 1993. Moreover, peer-reviewed journals and federal funding agencies began to require justification if studies did not include both males and females.
But have these initiatives changed anything? A very detailed history of analyses covering women’s inclusion in clinical trials has been published. Surprisingly, women seemed to be well represented in the 90s and early 2000s for the most part. But a more recent summary of trials conducted between 1994 and 2013 showed that females accounted for only 37% of participants. At the same time 64% of the studies did neither specify their results by sex nor explain why the influence of sex in their findings was ignored. What’s worse is that trials related to HIV, hypertension, and acute coronary syndrome had lower female enrollment in comparison with the prevalence of those disease states in women. A review from 2015 concluded that “progress has been slow and halting, and we have not achieved sufficient progress in order to truly serve the public health.” (Mazure 2015).
Clinical research in Europe was developed mostly in men until the 1990s. Afterwards, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) promoted the regulatory standards for clinical trials. The ICH guideline E8 requires that the study population should be representative of the target patient population, and also demands phase I pharmacokinetic information in women. Dose‐response data need to be obtained for relevant subpopulations, “according to gender” as in Guideline E4. However, in addition to the provisions regarding gender in above mentioned documents, the European Medicines Agency (EMA) based on internal review and experiences, argues against the need for a separate ICH guideline on women as a special population in clinical trials. This leads to a prevailing underrepresentation of women in clinical research.
Woman’s body, man’s medicine – the sex and gender health gap persists
Today, women make up 49.7% of the world’s population. Across the globe, they access medical care more frequently and actually have a significantly greater health expenditure than men. Nevertheless, women are diagnosed significantly later than men on average across over 700 diseases (Westergaard, 2019), in some cases waiting up to 10 years for the right diagnosis! For many reasons, including sex differences, social inequities and restrictive cultural norms, women are at higher risk and have more severe course of numerous illnesses than men. Which examples of conditions are much more prevalent in females than in males?:
- anxiety – women are twice as likely as men to be diagnosed with an anxiety disorder in their lifetime;
- autoimmune diseases – there are more than 80 autoimmune diseases, and more than 75% of patients who have them are women;
- osteoporosis – of the ten million Americans estimated to have osteoporosis, 80% of them are women;
- HIV/AIDS – more than half of the estimated 38 million cases of adult HIV infection worldwide are in women;
- migraines – they affect more than 30 million Americans, but women are 3 times more likely than men to get migraines;
- depression – women are also twice as likely as men to have depression.
Up to this day, we don’t truly know how women metabolize and react to many medicines, why some ADRs are more common in women, nor how women experience or manifest pain. The efficacy, dosage, and ADRs of many drugs were never tested in women. Despite the significant progress that has been made in promoting gender equality over recent years and the rapid pace of change we are witnessing in the medical field, there is still an imbalance when it comes to providing equal opportunities independent of sex.
Research published in 2020 from UC Berkeley and the University of Chicago analyzed data from several thousands of medical journal articles and found clear evidence of a drug-dose gender gap for 86 different medications approved by the FDA (including antidepressants, cardiovascular and anti-seizure drugs, and painkillers). The study found that 96% of evaluated drugs with female-biased PK values were associated with a higher incidence of ADRs in women than men. The common practice of prescribing equal drug doses to women and men neglects sex differences in PK and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased ADRs (Zucker 2020).
In 2021, over 80% of preclinical studies assessing drug safety and PG effects are still conducted solely in male mice and as few as 22% of phase I clinical trial participants are female. An evaluation of 22 Marketing Authorization Application dossiers submitted to the EMA between 2011 and 2015 for the treatment of various diseases showed that female animals were included in only 9% of the PD studies (Dekker 2021). Moreover, in a systematic review and meta-analysis of 122 US-based COVID-19 clinical trials with 176 654 participants, female participants were underrepresented in treatment trials.
All that means that much of modern medicine is based on trials performed mainly on male bodies and the effects of this research gap are serious. Ignoring the sex and gender differences not only sabotages further research (Lee 2018), but it also means that scientists have often applied findings from male-only research to women as well.
After all, aren’t women just “small men”? (Hint: No, they are not).
Strategies for bridging the sex and gender health gap
There seem to be three main pillars to make possible improvements in the representation of women in clinical trials:
- Funding – closing the sex and gender health gap starts with investing in research on the female body. However, only 4% of healthcare R&D spending in the US goes directly towards women’s health (Lomas 2020). A 2021 study that analyzed federal funding concluded that a disproportionate share of resources is applied to “diseases that affect primarily men, at the expense of those that affect primarily women.” Overall, twice as much funding goes to male-prevalent diseases compared to female-prevalent ones.
- Participation – a recent study of 1.5 million medical papers revealed that even just including women as researchers improved the likelihood of medical research taking sex and gender differences into account. When it comes to patents, including women on inventor teams has similar benefits: all-women teams are 35% more likely than all-male teams to focus on women’s health (Koning 2021). Findings from the study suggest that if male and female inventors had been equally represented in US biomedical patents between 1976 and 2010, there would have been 6 500 more female-focused inventions.
- Technology – an area of healthcare where women are leading innovation, however, is femtech: tech companies addressing female health. In recent years, femtech has evolved from a niche sector of the market into one predicted to exceed $60 billion worldwide by 2027 (Emergen Research 2020). The global femtech industry is made up of over 200 startups (92% of which are founded and led by women), most of them born out of the frustration around a lack of care for women health issues – from menstrual health to menopause.
Last, but not least, we cannot forget about the new EU Clinical Trial Regulation No 536/2014, which aims to create an environment favorable to conducting clinical trials in the EU with the highest standards of ethical and safety protection for participants. In terms of demographics, the new Regulation lists specific population groups to be included in clinical trials, “Unless otherwise justified in the protocol, the subjects participating in a clinical trial should represent the population groups, for example gender and age groups, that are likely to use the medicinal product investigated in the clinical trial” and “non-inclusion has to be justified.” The Regulation contains new legal provisions for including and protecting pregnant and breastfeeding women in clinical trials. Article 33, Chapter V defines the conditions under which pregnant or breastfeeding women can participate in clinical trials, provided the conditions outlined in the legislation are followed. Analysis of results according to Sex and Age Annex IV refers to presenting sex and age differences in the clinical trial results.
Answering the questions posed in the introduction, attention to sex and gender in biomedical, health and clinical research is an important quality and safety issue. Medicinal products become safer and more effective for everyone when clinical research includes diverse population groups. Women and men have different sex- and gender-related risks of developing certain conditions and responses to treatment. These sex and gender differences have important implications for health and healthcare. Thus, it is imperative to target medicines to these patient population sub-groups by utilizing the correlation between sex and the incidence, prevalence, symptoms, age at onset and severity of disease as well as the reaction to medicinal products.
It’s 2024. The female body shouldn’t still be a medical mystery.