Increasing Diverse Clinical Populations: Sex

Lacking Representation & Diversity in Medical Research

The lack of representation and diversity in medical research reveals a lack of access to trial participation for many segments of the greater human population. As a result, it can limit the validity and generalizability of conclusions drawn from study data. Attracting a diverse population of patients for a clinical trial is critical to develop effective, safe therapies and long-term population health. Drugs and therapeutics may impact different persons —— in vastly different ways depending on age, race, sex, and other factors. Therefore, trials need to draw on diverse groups of patients to ensure reliable and representative data is collected. This three part series will examine the varied challenges and solutions to increasing diverse clinical populations. In Part I, we’ll look at how research can better address often overlooked gender based differences as an underappreciated variable in the evidence generated in the clinical development lifecycle and why extrapolation of results from one gender to another is objectionable.

Differences in Treatment Outcomes Based on Biological Sex

The safety and efficacy of drugs or biologics can vary based on biological sex. Many physiological and pathological functions as well as patterns in gene expression differ by gender and have also manifested in the outcomes of treatments. Despite this, even in pre-clinical research, 80% of animal studies use only male animals.(1) Irving Zucker, PhD, a professor of psychology and integrative biology at Berkeley and his co-author Brian Prendergast, PhD, a professor at the University of Chicago, analyzed studies in which cisgender men and cisgender women received the same drug dosage. They found that in more than 90% of cases, cisgender women experienced stronger side effects and adverse drug reactions at almost twice the rate that cisgender men experienced.(2) Moreover, differences in pharmacokinetics and the body of evidence around pharmacodynamic variation by gender(3) explains why these differences in treatment outcomes are observed.

Throughout history, clinical trials have mostly focused on cisgender men. For a long time, cisgender women couldn’t even participate in clinical research trials. This was because of the prevailing misconception that fluctuations in female hormones could make it difficult to study cisgender women. There were also concerns about women of childbearing age and the harmful effect of unproven drugs on fetuses(4) and developing babies of breastfeeding mothers. Although cisgender women actively participate in clinical research today, they aren’t represented equally to cisgender men or overall demographics (women make up more than half of the U.S. population).(5) An analysis of data from one of the largest trial registries in the world found that less than 40% of the people enrolled in stroke and heart disease clinical research are cisgender women. This is especially concerning because cardiovascular disease is the leading cause of death for cisgender women worldwide(6) and gender bias in the data of dose tolerability, appropriate dosing, metabolic, and clinical pharmacology of approved medicines is well accepted.

Representation for Transgender People

Transgender individuals, both Assigned Female at Birth (AFAB) and Assigned Male at Birth (AMAB), are also underrepresented in clinical trials. Transgender people are often excluded from the very clinical research that could stand to benefit them. For example, transgender men and cisgender women were omitted from HIV research studies supporting marketing authorizations for emtricitabine/tenofovir alafenamide (Descovy - the second drug approved for pre-exposure prophylaxis or PrEP) . The only way to know if they’ll work is if transgender people are included in studies given the potential impact of gender and exogenous hormone therapies on efficacy and safety endpoints.

Even if the ratio of genders is appropriate, pooling data of gender data may still yield inexact results and problems of reproducibility. Several theoretical models and clinical trials have demonstrated that pooling data across genders can mask important differences in baseline data, treatment response and also in sex treatment interactions and leads to biased results that are not rigorously adapted to any gender.(7)

How Decentralized Clinical Trials Can Help

It is estimated that more than 300,000 clinical trials start every year. With great opportunity of therapeutic exploration also comes potential harm for subgroups that are not well represented in clinical trials. To be reliable, clinical trials need to be both internally and externally valid. Lack of external validity calls for more pragmatic “real world data” and the production of data that are drawn from all categories of patients. Decentralized clinical trials (DCTs) and digital approaches can help bring research opportunities to a broader range of candidates. The remote aspect of DCTs enables people with different lifestyles, functional capabilities, geographic locations and availability to commit to participate.

Diversity should be prized and is one reason a decentralized trial approach can result in better research and outcomes. Meeting research diversity goals will require contributions from across the life sciences industry. Sponsors and CRO’s can help lead the way through the use of DCT models and proactive outreach to diverse populations of all types. Read our report How DCTs Make Research More Accessible and Inclusive for Participants and Sites to learn:

• How DCT elements can help address the barriers to effective enrollment
• Key ways DCT approaches can reduce the need to exclude patients based on geography
• Strategies for improving access to research for both participants and sites

References:

(1) Beery AK, Zucker I. “Sex bias in neuroscience and biomedical research.” Neurosci Biobehavrev. 2011; 35(3):565-72.

(2)Healthline

(3) Gandhi M., Aweeka F., « Sex Differences in Pharmacokinetics and Pharmacodynamics” AnnualReview of Pharmacology and Toxicology 2004;44(1), 499-523.

(4) Healthline

(5) US Census

(6)Newsroom

(7) Tannenbaum C., Ellis R. “Sex and gender analysis improves science and engineering.” Nature. 2019;575: 137–146.

Sinead Callinan

Executive Director of DeliveryEMEA

Sinead is a Digital Healthcare and Clinical Research Executive with a career spanning clinical care, academic research and digital health across multiple therapeutic areas including oncology, internal medicine and vaccines development. She joins THREAD with over 18 years of experience in clinical service delivery, sponsor research governance, CRO and eHealth.