Why Sex Bias Occurs in Clinical Trials and How We Can Change It

Editor’s note: This is the second part of a two-article series investigating gender bias in otolaryngology. Part one, which focused on gender bias in research funding, was published in the May 2019 issue of ENTtoday.

Sex bias favoring males in clinical trials has been pervasive for decades. The many reasons include concerns that women’s estrogen hormonal variation may create biologic and physiologic inconsistencies, creating unknown variables in studies. In addition, unknown hazards of drugs tested in clinical trials could impact women’s childbearing potential. Furthermore, studies performed on men or male animals were presumed to translate directly to women.

However, it’s now known that men and women have different disease prevalence and risks, said Brent Senior, MD, the Nathaniel and Sheila Harris Distinguished Professor of otolaryngology–head and neck surgery at the University of North Carolina at Chapel Hill.

In 1986, The National Institutes of Health (NIH) changed its policy to include women of childbearing age in research. Then, the NIH Revitalization Act of 1993 mandated the inclusion of women and minorities in clinical research. However, in the 1990s and 2000s, data continued to reveal that inclusion of women didn’t increase significantly in clinical trials despite this legislation, said Zainab Farzal, MD, resident physician and researcher in the department of otolaryngology/head and neck surgery at the University of North Carolina at Chapel Hill. Furthermore, there was evidence that drugs were not being tested on both male and female animals before moving to the human testing phase. The scientific community continued to pressure the NIH to investigate and, in 2016, the NIH issued a policy requiring all funding proposals to consider sex as a biological variable in all human and animal research.

This didn’t solve everything, however, said Dr. Farzal. “This policy didn’t mandate that a certain percentage of women be included in every study and had no jurisdiction over research not funded by the NIH,” she said. “Consequently, sex bias continues to be a major force in our field.”

Studies that don’t take into account women’s metabolism and concerns don’t honor the differences between women and men and may result in incorrect or harmful care for female patients. —Sujana Chandrasekhar, MD

The Status Quo

Based on her work with Dr. Senior and other colleagues, Dr. Farzal hasn’t seen a corresponding increase in sex-inclusive research in otolaryngology despite mandates and policies for sex-inclusive research (Laryngoscope. 2019;129:858–864; Laryngoscope. 2019;129:613–618).

In reviewing otolaryngology clinical literature, Drs. Farzal and Senior and their colleagues found that only 46.7% of studies analyzed data by sex. Additionally, only 330 studies included at least half as many participants of one sex in a study as they had the other. When the researchers specifically analyzed randomized controlled trials, they noted that 40% of otolaryngology trials analyzed data by sex, which was even lower than clinical otolaryngology literature.

Dr. Senior added that, when comparing today’s trials with those from past decades, he and his colleagues found that inclusion of sex-based analyses and under-inclusion of one sex has marginally improved. For example, in the 40 years between 1949 and 1989, a study found that 32% to 45% of publications in human research journals studied both sexes (Neurosci Biobehav Rev. 2011;35:565–572). That number climbed to greater than 60% for articles published between 1999 and 2009. In addition, the researchers reported that sex-unspecified publications decreased from greater than 20% in the earlier time period to 7% in the latter. However, significant disparities still exist today; a 2011 study concluded that 75% of 86 human research articles that were federally funded lacked sex-based analysis (J Womens Health (Larchmt)). 2011;20:315–320).

Impacts of Disparity

When women are left out of clinical research, there are gaps in our knowledge of disease processes and how they might affect men and women differentially, Dr. Farzal said. Differences in treatment efficacy can also occur.

In otolaryngology, Dr. Senior noted differences in disease states and prevalence depending on sex. For example, benign thyroid nodules are much more common in women, as are thyroid cancers. While otosclerosis is histologically present in both men and women, the clinical diagnosis is much more common in women. “Not recognizing these sex differences and not studying them will result in large segments of the population being improperly treated,” he said.

Gender disparities can also impact patient care. If women don’t comprise a significant percentage of the researchers in a given field, important questions may be missed and gender bias can occur in terms of subjects, said Sujana S. Chandrasekhar, MD, a partner at ENT & Allergy Associates, LLP, in New York City. “Studies that don’t take into account women’s metabolism and concerns don’t honor the differences between women and men and may result in incorrect or harmful care for female patients,” she added.

Erynne A. Faucett, MD, pediatric otolaryngologist with the department of surgery in the division of otolaryngology at Phoenix Children’s Hospital in Arizona, said it’s important to be able to predict any sex-specific outcomes for better personalization of treatment and prevention strategies because there are sex-based differences in diseases of the head and neck. “Knowing how to manage and treat these disease processes in men and women is important,” she said.

Comparing Otolaryngology with Other Research

The bottom line is that sex bias in clinical trials remains prevalent in all medical disciplines. In general surgery, a review of 1,303 studies published in 2011 and 2012 from five general surgery journals revealed that 17.3% did not report participant sex and only 33% analyzed data by sex (JAMA Surg. 2016;151:1022–1030). In orthopedics, a slight improvement in sex-based analysis has been demonstrated, from 19% in 2000 to 30% in 2010 (Clin Orthop Relat Res. 2015;473:3700–3704).

In otolaryngology, deficiency in sex reporting and sex-based statistical analysis similarly exists but appears to be slightly better than those two disciplines. “Our work has shown that 91% of studies reported on participant sex, and only 2.1% had single-sex participants,” Dr. Senior said. Furthermore, slightly fewer than half of studies analyzed outcomes by sex (47%), and nearly two- thirds of studies had more than 50% or greater sex matching. In rhinology specifically, Dr. Senior found that participant sex was reported in 93% of studies, and only 0.5% included participants of a single sex. Sex-based statistical analysis was performed on 52% of studies.

Areas to Focus On

Given that sex bias in clinical trials still exists, Dr. Farzal said researchers need to ensure that they strive for equal representation of both sexes in all trials. “We also need to report the sex of the subjects in all studies and analyze data by sex so that any sex-based differences are evident,” she added.

For basic science studies, Dr. Farzal recommends making sure that new treatments or tests are performed in both male and female animals or cells prior to going live in a human testing trial phase.

Additionally, otolaryngology journals need to follow other periodicals, such as the Journal of the American Medical Association network journals, in setting requirements for sex reporting and statistical analysis by sex, Dr. Farzal added.

In his work, Dr. Senior saw that the best rates of sex-based analysis were found in database studies. Randomized controlled trials (RCT), however, were found to perform sex-based analysis in only 40% of cases. “Given the fact that much of our evidence-based medicine dogma and treatment algorithms are derived from RCTs, this problem area seems particularly important to tackle,” he said. “Researchers need to take care to perform sex-based matching when appropriate and to perform sex-based analysis of their results.”

Action Steps

By making the otolaryngology research community aware of sex bias in clinical research, Dr. Senior hopes that researchers will address these issues. Furthermore, journal editors can help by mandating that only studies following current recommendations on reporting and data analysis by sex be published. Single-sex studies should provide a
rationale for exclusion.

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Karen Appold is a freelance medical writer based in New Jersey.