Efforts are underway to consider sex differences in drug development by increasing woman’s participation in clinical trials, but the lack of regulatory guidelines remains a barrier to taking gender diversity into account, experts say.

The COVID-19 pandemic and South Korea’s vaccination programs have shed light on how a disease and its treatment can affect men and women differently.

According to the Korea Disease Control and Prevention Agency’s data, the percentage of female patients who reported side effects due to the COVID-19 vaccine came to 3.56 per 1,000 cases, 1.7 times higher than the percentage of male patients who did, 2.59 per 1,000 cases.

Due to physiological differences, vaccines can have different impacts on women and men, according to experts. To minimize the side effects from inoculation of new vaccines, more details should be considered during clinical studies, they said.

The following are key excerpts from interviews with Dr. Tarun Saluja, head of clinical development at the International Vaccine Institute, and Dr. Shin Dong-seung, vice director of the Clinical Trials Center at Gachon University Gil Medical Center, regarding the underrepresentation of women in clinical trials.

Q: Does sex have a crucial influence on human vaccine response?

A: “Historically, it was assumed that there were no fundamental differences between men and women’s bodies other than size, weight and reproductive organs. Modern science has documented well that male and female bodies are genetically different and they experience differences in the prevalence, course and severity of many common human diseases and metabolize foreign substances like medicines and vaccines differently,” according to Saluja, the IVI clinical development head.

Saluja also mentioned that several peer-reviewed journals have reported that higher magnitudes of immune responses in adult women have been found for many vaccine candidates for yellow fever, measles, mumps, rubella, influenza and hepatitis A and B.

Q: Do clinical trials for vaccines take physiological sex differences into consideration these days?

A: “Increasingly current vaccine and drug clinical trials do consider sex as a fundamental variable and disaggregate data to explain differences in intervention outcomes, especially in the later stages of clinical development,” Saluja said.

But, Saluja also noted, “progress on including women has been encouraging but there's still a long way to go.” Particularly in the early phases of clinical trials, “women are still largely underrepresented or even excluded, fostering a gender bias in the data on dose tolerability, appropriate dosing, metabolic and clinical pharmacology.”

“Fifteen to twenty years back, when I started my research career, whenever we thought about baselines to enter clinical trials, it was always just basically males, there wasn’t even a discussion of how diseases affect women differently. But the paradigm is changing, the dynamic is changing, and people are thinking more about how we ensure the drugs we are creating actually serve the broader population and take gender into account,” Saluja added.

Q: Can you tell us about the current state of women's participation in clinical trials in Korea?

A: According to Shin, the vice director of clinical trials at Gachon University Gil Medical Center, women’s participation in clinical trials here has increased over the last decade, although male participants still comprise more than the majority.

The sex ratio for the country’s clinical trial participants is usually seven men to three women here, Shin added.

But improvements are being made, according to Shin.

“Until 10 years ago, there were no guidelines from the country’s health authorities with regards to women’s participation in clinical trials. But then the government started to suggest pharmaceutical firms include more female participants,” Shin said.

Q: Why is women’s participation in clinical trials low in Korea?

A: Shin said women tend to become more cautious when joining clinical trials compared to men, due to the possible negative effects of vaccines or drugs on individuals capable of pregnancy and those who are pregnant.

“Especially in first-in-human clinical trials, doctors also may decide to limit the number of female participants since there is no existing data regarding a drug candidate’s safety,” Shin said.

Shin, however, noted that “it is always better if clinical trials can secure participants with diverse demographic backgrounds."

Q: How should clinical trials be designed to avoid gender bias?

“Each clinical trial should include males and females in numbers appropriate to allow the detection of clinically significant gender differences in drug responses, and the same should come from regulatory agencies to ensure adherence,” Saluja said.

He added, “Well controlled clinical studies taking into account (participants') sexual activity, their use of contraceptives, their sexual orientation, the possible sterility of their partners, or even their desire to have a child should be considered carefully.”

Q: Should the sex ratio become 50:50?

A: Saluja said that gender bias is a complex problem, and it cannot be solved by simply achieving a 50:50 distribution of male and female participants. Considering female participation in proportion to disease prevalence may be a better path leading to equity.

“To achieve equity, many operational factors should be considered by sponsors and researchers to encourage female participation,” Saluja said.

Q: Are many pharmaceutical companies taking gender differences into their clinical trials?

A: “Increasingly, firms are realizing that at the end of the day, it can be even more costly to withdraw a drug from the market if it has increased adverse events or a lack of effectiveness in women,” Saluja said.

He added that designing clinical trials with more female participants is very feasible. “Many recent but limited studies are already doing so," he said, noting however there is still a "long way to go.”

Q: What other measures have there been to address the underrepresentation of women in clinical trials and reduce potential side effects in women?

“Whenever research lacks or excludes female subjects, the guidelines should clearly state that the evidence has been obtained mainly from men. Once a drug is marketed, the scientific or patient leaflet should mention the ratio and total number of women and men that participated in the clinical trials,” Saluja said.

Saluja suggested a multipronged approach is needed. The regulatory, ethical and funding framework should be also strengthened to encourage firms to take into account gender diversity and specific data analysis with regards to safety, drug immunogenicity and efficacy in their study reports.

Saluja and Shin both said having a pharmacovigilance system to monitor and prevent gender-specific side effects actively is a good option to assess the risks of commercialized drugs.