Leaving women out of study populations can cause ‘great harm’
In October 2019, the FDA approved emtricitabine/tenofovir alafenamide as a second option for HIV PrEP in at-risk adults and adolescents but excluded cisgender women from the approval because of a lack of efficacy data.
In a perspective written at the time, Infectious Diseases News Editorial Board Member Jeanne M. Marrazzo, MD, MPH, FACP, FIDSA, said the decision “intensifies concern for the landscape of HIV prevention options in women” and noted that other studies assessing PrEP candidates also were not fully enrolling women.
“Don’t women deserve their own strategic vision for HIV prevention?” Marrazzo wondered.
A Gilead spokesperson told Infectious Disease News that a planned study of emtricitabine/tenofovir alafenamide (FTC/TAF) in cisgender adolescent girls and women with sites in sub-Saharan Africa has experienced delays in site selection because of the COVID-19 pandemic but is still slated to start enrolling participants in mid-2021.
The spokesperson said the company “is committed to generating data informing the use of all our medications in women to ensure that all individuals seeking HIV prevention and treatment medicines have access to options that are most suitable for them.”
We spoke with experts about why women are left out of research populations and what is being done to address the issue.
“The percentage of women in HIV treatment clinical trials is almost always less than the global proportion of women living with HIV — approximately 51% of all those living with HIV — given that in the geographic regions in which we conduct most of our trials, North America and Europe, the majority of those living with and at risk for HIV are men,” Gilead said.
The FTC/TAF decision underscored existing concerns over leaving women out of clinical research.
“Women are not simply smaller men but differ from men in many ways biologically,” explained Infectious Disease News Editorial Board Member Elizabeth Connick, MD, professor of medicine and chief of the division of infectious diseases at the University of Arizona College of Medicine. “There are sex differences in immune responses, drug metabolism and disease states. Some differences are mediated by hormonal differences and others by other biological factors.”
Connick said extrapolating studies in men to women “has the potential to cause great harm” and is not allowed by the FDA.
“It is essential to include women in research studies so that they can benefit from the results of research in the same way as men,” Connick said in an interview.
“The worst outcome might be that an intervention that is found to be of benefit in a population that didn’t include women is then not approved for use in women,” Marrazzo said.
A global issue
The issue is not unique to the United States. A recently published large-scale analysis found that sex bias in clinical studies endures globally.
Sergey Feldman, PhD, a research scientist at the Allen Institute for Artificial Intelligence in Seattle, and colleagues assessed studies from 1966 to 2018 on PubMed and records from 1999 to 2018 on ClinicalTrials.gov. In total, they included 43,135 articles with more than 792 million participants and 13,165 records with more than 12 million participants in the analysis.
The study found substantial female underrepresentation in seven of 11 disease categories but especially in HIV/AIDS, chronic kidney diseases and cardiovascular diseases.
It demonstrated that sex bias in articles for all categories combined was unchanged over time when using the proportion of studies as a measurement unit but improved from before or during 1993 when using participants as the measurement unit.
“Despite legal and policy initiatives to increase female representation, sex bias against female participants in clinical studies persists,” the authors concluded.
There are multiple reasons why women are left out of clinical trials, and those reasons can vary depending on the diseases or drugs that are being studied, experts said.
According to Connick, one of the primary reasons is that researchers often have concerns about women becoming pregnant and the potential teratogenic effects of drugs. Connick said historically, it was “easier and cheaper for researchers to exclude women than to address these concerns.”
Some reasons for excluding women are valid, “but it’s mostly fear and risk aversion,” Marrazzo said.
“It is understandable in some instances not to want to recruit participants who will become pregnant, to avoid possible harm to a fetus,” Connick said. “Nevertheless, there are ways to include women that overcome this hurdle, for example, by requiring use of contraception.”
Connick said it is “reasonable” to exclude pregnant women from clinical trials of new drugs if there is an existing safe treatment for them to use. However, for some illnesses — such as multidrug-resistant tuberculosis or COVID-19 — there are no existing treatment options available.
“It is essential to find ways to include pregnant women in clinical trials in those instances,” Connick said.
Another concern is that the women using hormonal contraception in clinical trials may have an adverse experience, because hormonal contraceptives interact with and can be affected by multiple medications.
“It is essential to understand the impact of medications on hormonal contraception effectiveness, and vice versa. These studies should be required but unfortunately are not,” Connick said.
She cited the discovery by Kimberly Scarsi, PharmD, and colleagues that efavirenz-based ART undermined the contraceptive effectiveness of levonorgestrel implants, resulting in unwanted pregnancies, as “one of the most egregious examples” of the failure to study the impact of a medication on the effectiveness of hormonal contraception.
“Efavirenz had been first-line antiviral therapy for many years before this unfortunate discovery was made,” Connick added. “If evaluation of drug effectiveness in combination with hormonal contraception was a requirement, this discovery would have been made much sooner and could have prevented many unwanted pregnancies.”
Marrazzo said researchers should cautiously consider women of childbearing age — with or without a requirement for contraception — for their studies if the product has a good, safe animal model profile and looks good in phase 1 and possibly phase 2 studies.
“The problem is that these women are excluded from the trials evaluating the initial safety and efficacy of these products, but then almost never do the companies go back and readdress or redo the studies in the next step — for example, in women who are of childbearing age who want to conceive, who are pregnant or who are breastfeeding,” Marrazzo said.
There are other reasons women are not included in medical research, including that some conditions are more prevalent in men than women — such as HIV in the U.S. — making it easier to identify male participants than female participants, Connick said.
Additionally, “women in general have more family responsibilities than men, which makes it more difficult for them to participate in research,” Connick said.
Women also may have fewer resources, making it more difficult for them to take time for research appointments, she said. Moreover, women are underrepresented among researchers, meaning that research is often conducted by white men in the U.S. Women, particularly women who are not white, may not trust these researchers, according to Connick.
“It may be more difficult or take a longer period of time to recruit women to some studies,” she added. “This translates into greater costs for the study, which I think is a major reason why women are not included in adequate numbers in many HIV studies in the U.S.”
However, she said this is not an acceptable reason to exclude women.
“It is very clear that if adequate recruitment of women and minorities is established as an expectation, researchers will accomplish it,” Connick said.
‘Credibility of evidence’
The consequences of leaving women out of research populations can be serious, experts agreed.
“Progress toward personalized medicine and, in turn, women’s well-being will be hindered — for example, women’s symptoms for heart attack can be similar to heartburn,” said Infectious Disease News Editorial Board Member Gitanjali Pai, MD, AAHIVS, an infectious disease physician at Memorial Hospital and Physicians’ Clinic in Stilwell, Oklahoma. “Coupled with the apathy and tendency to minimize women’s suffering, the impact on the patient and the family can only be imagined.”
Pai said the inadequacy of research to include women was reflected in the FDA withdrawing the approval of 10 drugs between 1997 and 2000 — eight of which had harmful side effects on women.
She said excluding women from research has precluded sufficient exploration of many ailments that affect women differently than men — such as organ transplant rejection, concussions and anxiety and depression — translating to “a big gap in providing health care to people.”
This “information deficit” affects policies and guidelines that are intended to benefit everyone equally, Pai said.
“It is a challenge which must be met to enhance the credibility of evidence,” she added.
Researchers are at least cognizant of the underrepresentation of women in clinical research, Pai said.
“Over the last few decades, recommendations by national research centers and federal agencies as well as regulatory interventions have addressed this issue progressively,” she said.
In the U.S., the NIH has asserted that applicants for funding should include plans to consider sex as a biological variable in their research proposals. However, Connick said this is not uniformly enforced.
For example, the National Heart, Lung, and Blood Institute “has been pretty strong in enforcing this,” whereas the National Institute of Allergy and Infectious Diseases “has been weak,” Connick said.
“Many journals have also begun to insist upon reporting sex and gender, and to encourage analysis of data by sex. Nevertheless, it is still largely insufficient,” Connick said. “In my experience, the preclinical researchers are often the most egregious offenders in terms of ignoring sex as a biological variable.”
Marrazzo noted that a 7-year, NIH-funded project called the Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) was created to provide “immediately actionable” documentation and guidance to help provide more evidence regarding pregnant women and HIV.
The guidance, compiled by a working group, was the culmination of extensive research, including consultations with more than 150 experts from around the world, two international workshops, commissioned legal briefings and a qualitative study that includes 140 pregnant and recently pregnant women in the U.S. and Malawi.
Among 12 recommendations, the group suggested creating and funding a formal global network dedicated to advancing research that is needed among pregnant women and providing more training in the research community on the ethical and legal issues related to such research.
Pai noted additional strides, including that Congress in 1994 mandated the adequate inclusion of women in NIH-sponsored clinical trials, and the FDA in 2000 got the authority to place a trial on hold if sponsors exclude men or women only because of reproductive potential.
“Protectionist policies of the last century are slowly being modified or changed to ensure sex and gender integration as standard practice,” Pai said.
However, there also is an urgent need to monitor provisions in these regulations, Pai said.
“We have seen time and again that mere mandates do not work,” she said. “The challenge is to institutionalize desirable changes envisaged down the decades to meet standards of health equity for women.”
- FDA. FDA approves second drug to prevent HIV infection as part of ongoing efforts to end the HIV epidemic. https://www.fda.gov/news-events/press-announcements/fda-approves-second-drug-prevent-hiv-infection-part-ongoing-efforts-end-hiv-epidemic. Accessed Sept. 16, 2020.
- Feldman S, et al. JAMA Netw Open. 2019;doi: 10.1001/jamanetworkopen.2019.6700.
- PHASES. New guidance: Ending the evidence gap for pregnant women around HIV & co-infections. http://www.hivpregnancyethics.org/. Accessed Sept. 16, 2020.
- Scarsi KS, et al. Clin Infect Dis. 2015;doi:10.1093/cid/civ1001.
- For more information:
- Elizabeth Connick, MD, can be reached at email@example.com.
- Jeanne M. Marrazzo, MD, MPH, FACP, FIDSA, can be reached at firstname.lastname@example.org.
- Gitanjali Pai, MD, AAHIVS, can be reached at email@example.com.
Click here to read the At Issue, “Who is being left out of COVID-19 research?”