Echoing historical trends, researchers have found that a significant level of sex bias exists in human surgical studies. Though women and men are being included in roughly equal numbers in some papers, only about one-third of the articles reviewed for a new study1 reported the data by sex, and even less than that analyzed the data independently for men and women.

“Sex bias exists in human surgical clinical research,” concluded researchers led by Melina R. Kibbe, MD, a clinician in the department of surgery at the University of North Carolina at Chapel Hill. “Few studies included men and women equally, less than one-third performed data analysis by sex, and there was wide variation in inclusion and matching of the sexes among the specialties and the journals reviewed. Because clinical research is the foundation for evidence-based medicine, it is imperative that this disparity be addressed so that therapies benefit both sexes.”

Furthermore, the sex of the participants included in the research was not stated at all in 17.3% of the studies, the researchers found.

“If research is conducted on both sexes, but the results or outcomes of the drug are reported in aggregate with the response in both sexes lumped together, how will we know if a drug has a different effect in one sex over the other?” Kibbe tells IRB Advisor. “If we are ever to achieve true precision medicine, we must address the basic variable of sex first.”

For example, the human papillomavirus vaccine is much more effective in women than men, she says. However, if sex-based reporting of the data was not done, the poor efficacy in men may have diluted the overall results to the degree that vaccine development may have been abandoned.

“We need to have bigger studies so the results in men or women are not diluted,” says Julie A. Freischlag, MD, a clinician at the University of California-Davis Health System, who co-wrote an accompanying commentary2 on the study. “If gender is specified, investigators may see results skew higher or lower for a specific sex, which could help create targeted therapies for one sex or, conversely, offer caution around certain therapies.”

The roots of the problem go back to 1977, when the FDA cited a lack of safety data in recommending that women of childbearing age be excluded from clinical trials. Even as the safety of including women in trials became more established, other issues contributed to a continuing historical bias in clinical trials.

“For many years, some diseases, such as heart disease and lung cancer, were thought to only be male diseases, so women were largely left out of studies,” Freischlag says. “Now, of course, we recognize that coronary heart disease is the number-one killer of both men and women, and that about a quarter of women in the United States will die from heart disease. In addition, the female menstrual cycle has been perceived by some to be a complicating factor for studies, making it ‘easier’ to enroll men.”

As a result, the National Institutes of Health “Revitalization Act” in 1993 called for inclusion of women in clinical research funded by the NIH. However, Kibbe and colleagues found that the problem persists.

“The FDA has no mandates or requirements for sex-based reporting of the data with new drug applications,” says Kibbe. “Given the lack of policy, focus, or requirements by any funding or government agency, these data did not surprise me.”

The research blind spot could mean drugs much more effective in men may be ultimately recommended for women as well, creating the disturbing possibility of more side effects and adverse outcomes in women because they were underrepresented in research populations.

“For example, the odds of an adverse drug reaction in women is 50% greater than in men, women are more likely to be hospitalized because of an adverse drug reaction, and 80% of the drugs removed from the market by the FDA are because of undesirable adverse effects in women,”3-5 the researchers report.

Collecting data on both male and female participants and conducting an independent analysis by sex could reduce this problem and lead to better treatment for men and women.

“Unless a study is focusing on a disease specific to only women, such as uterine or ovarian cancer, we should include both genders,” Freischlag says. “One of the bigger points here is around harm prevention. Some therapies that work well in men may actually be harmful to women, causing unnecessary suffering and possibly death. By identifying both men and women in studies, potential harmful effects could be mitigated. I don’t recommend a 50-50 mandate, but I do recommend enrolling all who sign up, regardless of gender, and reporting both sexes in studies.”

The researchers gleaned data from five surgery journals, analyzing studies published from Jan. 1, 2011, through Dec. 31, 2012. Of 1,303 articles reviewed, 17 (1.3%) included males only; 41 (3.1%) included females only, and 1,020 (78.3%) included males and females. However, 225 studies did not report the sex of the participants.

“Regardless of good overall inclusion of females in human surgical clinical research, we were surprised at the low rate of matching of participants regarding sex,” Kibbe and colleagues noted in the paper. “Furthermore, we were amazed that the sex of the participants included was still not reported in more than 17.3% of peer-reviewed studies.”

Overall, only 23% of the articles included a discussion of sex-based results.

“Sex matching of the included participants in the research overall was poor, with 45.2% (589 of 1,303) of the studies matching the inclusion of both sexes by 50%,” the researchers reported. “During analysis of the different surgical specialties, a wide variation in sex-based inclusion, matching, and data reporting existed, with colorectal surgery having the best matching of male and female participants and cardiac surgery having the worst.”

The authors note that to their knowledge, the study is the largest and most comprehensive paper to examine sex bias in human surgical clinical research.

Kibbe and colleagues recommended that FDA mandate that drugs and devices be tested equally in male and female participants before approval. In addition, they called for journal editors to require authors to report the sex of all participants studied and perform sex-based analysis of the data.

“This is a simple thing to do — it just takes doing it,” Kibbe says. “The FDA is a bigger issue. To require testing in both sexes, have it powered appropriately, and require sex-based reporting of the data can be done. I am not sure why the FDA has not done this, but the more we raise awareness of this important issue, I am hopeful for change.”

REFERENCES

  1. Mansukhani NA, Yoon DY, Teter KA, et al. Determining If Sex Bias Exists in Human Surgical Clinical Research. JAMA Surg 2016;151(4): doi:10.1001/jamasurg .2016.2032.
  2. Freischlag JA, Silva MM. Commentary: Precision Health Outcomes Require Precise Patient Identification: JAMA Surg. Published online August 17, 2016: doi:10.1001/jamasurg.2016.2078.
  3. Heinrich J. GAO-01-286R Drugs Withdrawn From Market. Washington, DC: United States General Accounting Office; 2001.
  4. Zopf Y, Rabe C, Neubert A, et al. Women encounter ADRs more often than do men. Eur J Clin Pharmacol. 2008;64(10):999-1004.
  5. Tharpe N. Adverse drug reactions in women’s health care. J Midwifery Womens Health. 2011;56 (3):205-213.