Beyond Representation: Legal and Ethical Pathways to Enhance Female Representation in Clinical Trials in Canada
Keywords: clinical research; sex-based representation; health equity
Overview
Clinical research is the epitome of modern medicine, shaping the safety and efficacy of drug use and medical therapies. In today’s clinical research, the integration of sex and gender considerations is growing. Sex and gender influence the status of health and disease interacting with factors such as ethnicity, genetic background, disability, and age (opens in new window) . Sex refers to biological factors including sex hormones, chromosomes, and reproductive anatomy (external link, opens in new window) . Sex is primarily categorized as female or male (external link, opens in new window) . In contrast, gender refers to socially constructed roles, behaviors, and social identities of girls, women, boys, men, and gender-fluid individuals (external link, opens in new window) . Sex is a biological variable that can readily be quantified for research purposes, and gender is a complex social construct requiring multiple factors influencing health for each individual. While gender-based inclusion is equally important as sex-based inclusion in clinical research, this blog post solely focuses on sex-based representation.
In creating healthcare that benefits the larger population, access to clinical resources continues to be an issue. The failure to adequately include diverse populations in clinical studies leads to a critical gap in both treatment and equity. Specifically, the lack of female representation in clinical studies limits achieving positive health outcomes for all patients (external link, opens in new window) , and impedes us from accessing potential for personalized healthcare (external link, opens in new window) for those in need. The inclusion of both male and female sexes in clinical research is not only a scientific necessity, but a moral and legal responsibility (external link, opens in new window) . Achieving equitable sex-based representation in clinical trials is a necessary step to ensure adequate healthcare for the Canadian population.
Sex-bias is created from the exclusion of either sex from studies. This sex bias perpetuates concerns with health equity, which aims to allow equal opportunity for health and quality healthcare for all people. The underrepresentation of either sex from preclinical and/or clinical research fundamentally constrains our understanding of sex-specific biological and physiological pathways that shape the health of the population. This exclusion generates significant health disparities resulting in health equity concerns. The lack of representation highlights the broader issue: clinical research fails to reflect the demographics of the population it aims to serve. This blog post highlights the impacts of excluding females from preclinical and clinical studies, the strategies that Canada has taken to increase the involvement of females in trials, and illustrates the need for further legislative or regulatory reform that may enhance clinical trial efficacy.
Biological and Physiological Sex- and Gender-Based Differences
Pharmacokinetics refers to the different phases of drug transition in the body, including drug absorption, distribution, metabolism, and elimination (external link, opens in new window) . The goal of preclinical research is to define therapeutic parameters for drug use, anticipate appropriate dosages and to discover any harmful and adverse health outcomes in disease models. In certain preclinical studies, animal models are important to mimic the disease for investigating drug and therapeutic efficacy. Males and females differ in anatomical, physiological and hormonal aspects (external link, opens in new window) . These are all important factors when considering pharmacokinetics and therapeutic outcomes.
Optimizing drugs and therapies for one sex limits the relevance and applicability of research findings for the entire population as sex influences disease patterns, pathophysiology, and response to therapeutic treatments. Additionally, this sex-bias hinders our understanding and treatment of diseases, especially in cases in which sex can play a significant role. For example, research on metabolic dysfunction-associated steatotic liver disease (external link, opens in new window) (MASLD) provides evidence on the essential role of sex and its impacts on understanding the disease and treatment. While premenopausal women are typically protected from this condition, research has shown that a specific genetic variant accelerates disease progression in female carriers. These findings (external link, opens in new window) illustrate that through interaction with estrogen receptors, some females experience more aggressive disease progression despite general protection from MASLD. Moreover, due to the higher fat content in females, as well as differences in sex hormone fluctuations (external link, opens in new window) during menstruation, pregnancy, and menopause, medicines and therapeutic treatments may behave differently.
In a survey of literature of preclinical research (external link, opens in new window) , 44% included publications for medications that were created for diseases that mostly affected females, but did not include the sex of the animals used in the methods section. The 88% of publications in the literature that did mention the sex of the animals, included only males. Preclinical studies that only use males may be translated into clinical practice for the availability to the general public, which includes both sexes. This furthers the need for equitable sex-considerations in preclinical research due to the health equity argument pertaining to clinical trial participation.
Historical Context for Exclusion of Females
The mid-1900s drug tragedy involving thalidomide (external link, opens in new window) increased public awareness about protection of fetuses from medical hazards in healthcare. Thalidomide was a drug used by pregnant women in Canada to prevent morning sickness and was later discovered to cause severe birth defects. In 1977, following the thalidomide tragedy, the USA Food and Drug Administration policy excluded females (external link, opens in new window) with childbearing potential from Phase I and early Phase II clinical drug trials. While the intention was to protect females from adverse health effects, the result was systematic exclusion of females from research. In 1993, the policy was lifted (external link, opens in new window) , however, females have been disproportionately excluded from preclinical research due to various reasons, including simplicity, hormone confounding effects, and lower expenditure of grant money (external link, opens in new window) on ordering additional female counterpart species and resources to accommodate the female hormonal cycle, such as caging requirements. The sex-bias in preclinical research has led to a steep disadvantage for understanding the physiological and biochemical pathways in females. This bias represents one of the reasons for the slow translation and reproducibility of preclinical research into the clinical setting.
The historical context (external link, opens in new window) for excluding females from clinical research can be traced back decades ago, where it was assumed that there was nothing fundamentally different between male and female bodies. The result was the male-default bias. In Ontario, female participants were underrepresented in human cardiovascular research funded by a Natural Sciences and Engineering Research Council of Canada Discovery Grant between 2010-2018 (external link, opens in new window) . Females were excluded from 63% of studies and underrepresented in approximately 40% of the sample. The exclusion and underrepresentation of female participants prevents them from gaining benefits from drugs and therapeutic remedies.
Canada’s Approach to Enhance Diversity and Inclusion in Clinical Trials
Inclusion in clinical trials requires representation at the level of preclinical research to enable reproductible results that can be effectively translated to the human population. To achieve this, adequate inclusion of female representation in clinical trials in sufficient numbers is necessary.
Due to the rise in harms and injustices regarding health equity resulting from the underrepresentation of females in clinical trials, the United States and Canada implemented policies and guidelines to promote the inclusion of females in trials. In the USA, the National Institutes of Health (NIH) adopted the NIH Revitalization Act, 1993 (external link, opens in new window) , which formulated guidelines and policies, requiring females to be included in all clinical studies.
In 1997, Canada issued the (PDF file) Guidance Document: Inclusion of Women in Clinical Trials During Drug Development (external link, opens in new window) . This included a policy that encouraged the enrolment of an appropriate number of females into clinical trials for drugs that are to be used specifically by females. Additionally, it encouraged that the composition of clinical trials should represent the society that the manufacturer expects to use the drug in.
More recently, in 2013, Health Canada released the updated version of the Guidance Document: Considerations for Inclusion of Women in Clinical Trials and Analysis of Sex Differences (external link, opens in new window) . The document acknowledged that participation of females in clinical research increased since the 1990s, however, underrepresentation was still evident and gaps still persist (external link, opens in new window) in knowledge and safety. In the Foreword section of the document, it states that the document is meant to “provide assistance to industry and health care professionals on how to comply with governing statutes and regulations.” Although the inclusion of females is promoted through the Guidance document, it is not mandated by law, as it is in some countries like the USA through the NIH Revitalization Act.
A Multi-Faceted Approach to Reforms Addressing Equitable Inclusion in Clinical Trials
Unlike the NIH Revitalization Act, which is a legally binding document mandating the inclusion of females in clinical studies, the Canadian Guidelines were created to encourage the inclusion of females in clinical trials. They are merely guidelines and not law. However, although the USA has mandated such inclusions, both the USA (external link, opens in new window) and Canada (external link, opens in new window) have failed to incorporate the necessary participation of females in clinical trials. The lack of monitoring provisions for such legislation and guidelines prevents effective implementation.
While these efforts may provide guidelines and regulatory assistance in clinical trial participation, there is no provision or policy to enforce such innovation. This represents a gap in healthcare research that demands the need for better institutional and legislative reform to better serve the Canadian population.
In Canada, federal funding agencies for health research, like the Canadian Institutes of Health Research (external link, opens in new window) , promote the Sex and Gender-Based Analysis (external link, opens in new window) in order to assess how groups of girls, women, boys, men, and gender-diverse groups are considered, however, the implementation, monitoring, and reporting is inconsistent. Provincially, there is also room for further reform. For example, Ontario’s Regulated Health Professions Act (external link, opens in new window) and the College of Physicians and Surgeons of Ontario (external link, opens in new window) are two avenues for potential integration of policies that can be mandated in Ontario and guidelines that engage with clinical trial research to include diverse populations and sex inclusion analysis. Likewise, the (PDF file) Canadian Medical Association Code of Ethics (external link, opens in new window) should be expanded to explicitly recognize and mandate the ethical duty of physicians in conducting inclusive research.
While the need for such policies is important, they are not enough. Dedicated bodies that are tasked with overseeing and enforcing the inclusion standards in both preclinical and clinical studies is the forward approach. These bodies could operate through either provincial ministries of health, national ethics agencies, or through independent review panels. The ministry should be tasked with monitoring recruitment practices, ensuring sex- and gender-disaggregated data is reported in publications and regulatory submissions to enhance transparency to the public, and to evaluate adherence to inclusivity and diversity standards. Research Ethics Boards, guided by the (PDF file) Tri-Council Policy Statement (external link, opens in new window) , should be required to demand and mandate clear reporting of sex- and gender-based methodologies and any justifications for excluding either sex or gender from research.
Only through concerted efforts of funding agencies, institutional bodies, provincial governments, and ethics boards, can we ensure that drugs and medical treatments are safe, effective, and equitable for all Canadians. By addressing this ethical dilemma, Canada can lead the way in fostering a healthcare system that serves the diverse needs of its population, setting a global standard for inclusive and ethical medical research. This in turn will allow researchers and medical professionals to safely tailor therapeutic treatments with decreased adverse health consequences. Inclusion of all sexes and genders in clinical research will allow for equal opportunity for health and quality healthcare, to help us achieve health equity.