The U.S. population is becoming more diverse, but clinical trials don't reflect that, experts say. Some are focusing on recruiting minorities to participate in research.
Nestled in a predominately Hispanic neighborhood, a new mural outside Guadalupe Centers Middle School in Kansas City, Missouri imparts a powerful message: “Clinical Research Needs Representation.” The colorful portraits painted above those words feature four cancer survivors of different racial and ethnic backgrounds. Two individuals identify as Hispanic, one as African American and another as Native American.
One of the patients depicted in the mural is Kim Jones, a 51-year-old African American breast cancer survivor since 2012. She advocated for an African American friend who participated in several clinical trials for ovarian cancer. Her friend was diagnosed in an advanced stage at age 26 but lived nine more years, thanks to the trials testing new therapeutics. “They are definitely giving people a longer, extended life and a better quality of life,” said Jones, who owns a nail salon. And that’s the message the mural aims to send to the community: Clinical trials need diverse participants.
While racial and ethnic minority groups represent almost half of the U.S. population, the lack of diversity in clinical trials poses serious challenges. Limited awareness and access impede equitable representation, which is necessary to prove the safety and effectiveness of medical interventions across different groups.
A Yale University study on clinical trial diversity published last year in BMJ Medicine found that while 81 percent of trials testing the new cancer drugs approved by the U.S. Food and Drug Administration between 2012 and 2017 included women, only 23 percent included older adults and 5 percent fairly included racial and ethnic minorities. “It’s both a public health and social justice issue,” said Jennifer E. Miller, an associate professor of medicine at Yale School of Medicine. “We need to know how medicines and vaccines work for all clinically distinct groups, not just healthy young White males.” A recent JAMA Oncology editorial stresses out the need for legislation that would require diversity action plans for certain types of trials.
Ensuring meaningful representation of racial and ethnic minorities in clinical trials for regulated medical products is fundamental to public health.--FDA Commissioner Robert M. Califf.
But change is on the horizon. Last April, the FDA issued a new draft guidance encouraging industry to find ways to revamp recruitment into clinical trials. The announcement, which expanded on previous efforts, called for including more participants from underrepresented racial and ethnic segments of the population.
“The U.S. population has become increasingly diverse, and ensuring meaningful representation of racial and ethnic minorities in clinical trials for regulated medical products is fundamental to public health,” FDA commissioner Robert M. Califf, a physician, said in a statement. “Going forward, achieving greater diversity will be a key focus throughout the FDA to facilitate the development of better treatments and better ways to fight diseases that often disproportionately impact diverse communities. This guidance also further demonstrates how we support the Administration’s Cancer Moonshot goal of addressing inequities in cancer care, helping to ensure that every community in America has access to cutting-edge cancer diagnostics, therapeutics and clinical trials.”
Lola Fashoyin-Aje, associate director for Science and Policy to Address Disparities in the Oncology Center of Excellence at the FDA, said that the agency “has long held the view that clinical trial participants should reflect the clinical and demographic characteristics of the patients who will ultimately receive the drug once approved.” However, “numerous studies over many decades” have measured the extent of underrepresentation. One FDA analysis found that the proportion of White patients enrolled in U.S. clinical trials (88 percent) is much higher than their numbers in country's population. Meanwhile, the enrollment of African American and Native Hawaiian/American Indian and Alaskan Native patients is below their national numbers.
The FDA’s guidance is accelerating researchers’ efforts to be more inclusive of diverse groups in clinical trials, said Joyce Sackey, a clinical professor of medicine and associate dean at Stanford School of Medicine. Underrepresentation is “a huge issue,” she noted. Sackey is focusing on this in her role as the inaugural chief equity, diversity and inclusion officer at Stanford Medicine, which encompasses the medical school and two hospitals.
Until the early 1990s, Sackey pointed out, clinical trials were based on research that mainly included men, as investigators were concerned that women could become pregnant, which would affect the results. This has led to some unfortunate consequences, such as indications and dosages for drugs that cause more side effects in women due to biological differences. “We’ve made some progress in including women, but we have a long way to go in including people of different ethnic and racial groups,” she said.
A new mural outside Guadalupe Centers Middle School in Kansas City, Missouri, advocates for increasing diversity in clinical trials. Kim Jones, 51-year-old African American breast cancer survivor, is second on the left.
Artwork by Vania Soto. Photo by Megan Peters.
Among racial and ethnic minorities, distrust of clinical trials is deeply rooted in a history of medical racism. A prime example is the Tuskegee Study, a syphilis research experiment that started in 1932 and spanned 40 years, involving hundreds of Black men with low incomes without their informed consent. They were lured with inducements of free meals, health care and burial stipends to participate in the study undertaken by the U.S. Public Health Service and the Tuskegee Institute in Alabama.
By 1947, scientists had figured out that they could provide penicillin to help patients with syphilis, but leaders of the Tuskegee research failed to offer penicillin to their participants throughout the rest of the study, which lasted until 1972.
Opeyemi Olabisi, an assistant professor of medicine at Duke University Medical Center, aims to increase the participation of African Americans in clinical research. As a nephrologist and researcher, he is the principal investigator of a clinical trial focusing on the high rate of kidney disease fueled by two genetic variants of the apolipoprotein L1 (APOL1) gene in people of recent African ancestry. Individuals of this background are four times more likely to develop kidney failure than European Americans, with these two variants accounting for much of the excess risk, Olabisi noted.
The trial is part of an initiative, CARE and JUSTICE for APOL1-Mediated Kidney Disease, through which Olabisi hopes to diversify study participants. “We seek ways to engage African Americans by meeting folks in the community, providing accessible information and addressing structural hindrances that prevent them from participating in clinical trials,” Olabisi said. The researchers go to churches and community organizations to enroll people who do not visit academic medical centers, which typically lead clinical trials. Since last fall, the initiative has screened more than 250 African Americans in North Carolina for the genetic variants, he said.
Other key efforts are underway. “Breaking down barriers, including addressing access, awareness, discrimination and racism, and workforce diversity, are pivotal to increasing clinical trial participation in racial and ethnic minority groups,” said Joshua J. Joseph, assistant professor of medicine at the Ohio State University Wexner Medical Center. Along with the university’s colleges of medicine and nursing, researchers at the medical center partnered with the African American Male Wellness Agency, Genentech and Pfizer to host webinars soliciting solutions from almost 450 community members, civic representatives, health care providers, government organizations and biotechnology professionals in 25 states and five countries.
Their findings, published in February in the journal PLOS One, suggested that including incentives or compensation as part of the research budget at the institutional level may help resolve some issues that hinder racial and ethnic minorities from participating in clinical trials. Compared to other groups, more Blacks and Hispanics have jobs in service, production and transportation, the authors note. It can be difficult to get paid leave in these sectors, so employees often can’t join clinical trials during regular business hours. If more leaders of trials offer money for participating, that could make a difference.
Obstacles include geographic access, language and other communications issues, limited awareness of research options, cost and lack of trust.
Christopher Corsico, senior vice president of development at GSK, formerly GlaxoSmithKline, said the pharmaceutical company conducted a 17-year retrospective study on U.S. clinical trial diversity. “We are using epidemiology and patients most impacted by a particular disease as the foundation for all our enrollment guidance, including study diversity plans,” Corsico said. “We are also sharing our results and ideas across the pharmaceutical industry.”
Judy Sewards, vice president and head of clinical trial experience at Pfizer’s headquarters in New York, said the company has committed to achieving racially and ethnically diverse participation at or above U.S. census or disease prevalence levels (as appropriate) in all trials. “Today, barriers to clinical trial participation persist,” Sewards said. She noted that these obstacles include geographic access, language and other communications issues, limited awareness of research options, cost and lack of trust. “Addressing these challenges takes a village. All stakeholders must come together and work collaboratively to increase diversity in clinical trials.”
It takes a village indeed. Hope Krebill, executive director of the Masonic Cancer Alliance, the outreach network of the University of Kansas Cancer Center in Kansas City, which commissioned the mural, understood that well. So her team actively worked with their metaphorical “village.” “We partnered with the community to understand their concerns, knowledge and attitudes toward clinical trials and research,” said Krebill. “With that information, we created a clinical trials video and a social media campaign, and finally, the mural to encourage people to consider clinical trials as an option for care.”
Besides its encouraging imagery, the mural will also be informational. It will include a QR code that viewers can scan to find relevant clinical trials in their location, said Vania Soto, a Mexican artist who completed the rendition in late February. “I’m so honored to paint people that are survivors and are living proof that clinical trials worked for them,” she said.
Jones, the cancer survivor depicted in the mural, hopes the image will prompt people to feel more open to partaking in clinical trials. “Hopefully, it will encourage people to inquire about what they can do — how they can participate,” she said.
Many women want non-hormonal birth control. A 22-year-old's findings were used to launch a company that could, within the decade, bring a new kind of contraceptive to the marketplace.
Now a scientist with NextVivo, Shrestha is not directly involved in the development of the contraceptive that is based on her research. But, back in 2016 when she was going through her own problems with hormonal contraceptives, she “was very personally invested” in her research project, Shrestha says. She was coping with a long list of negative effects from an implanted hormonal IUD. According to the Mayo Clinic, those can include severe pelvic pain, headaches, acute acne, breast tenderness, irregular bleeding and mood swings. After a year, she had the IUD removed, but it took another full year before all the side effects finally subsided; she also watched her sister suffer the “same tribulations” after trying a hormonal IUD, she says.
For contraceptive use either daily or monthly, Shrestha says, “You want the antibody to be very potent and also cheap.” That was her goal when she launched her study.
Shrestha unshelved antibody research that had been sitting idle for decades. It was in the late 80s that scientists in Japan first tried to develop anti-sperm antibodies for contraceptive use. But, 35 years ago, “Antibody production had not been streamlined as it is now, so antibodies were very expensive,” Shrestha explains. So, they shifted away from birth control, opting to focus on developing antibodies for vaccines.
Over the course of the last three decades, different teams of researchers have been working to make the antibody more effective, bringing the cost down, though it’s still expensive, according to Shrestha. For contraceptive use either daily or monthly, she says, “You want the antibody to be very potent and also cheap.” That was her goal when she launched her study.
The problem
The problem with contraceptives for women, Shrestha says, is that all but a few of them are hormone-based or have other negative side effects. In fact, some studies and reports show that millions of women risk unintended pregnancy because of medical contraindications with hormone-based contraceptives or to avoid the risks and side effects. While there are about a dozen contraceptive choices for women, there are two for men: the condom, considered 98% effective if used correctly, and vasectomy, 99% effective. Neither of these choices are hormone-based.
On the non-hormonal side for women, there is the diaphragm which is considered only 87 percent effective. It works better with the addition of spermicides — Nonoxynol-9, or N-9 — however, they are detergents; they not only kill the sperm, they also erode the vaginal epithelium. And, there’s the non-hormonal IUD which is 99% effective. However, the IUD needs to be inserted by a medical professional, and it has a number of negative side effects, including painful cramping at a higher frequency and extremely heavy or “abnormal” and unpredictable menstrual flows.
The hormonal version of the IUD, also considered 99% effective, is the one Shrestha used which caused her two years of pain. Of course, there’s the pill, which needs to be taken daily, and the birth control ring which is worn 24/7. Both cause side effects similar to the other hormonal contraceptives on the market. The ring is considered 93% effective mostly because of user error; the pill is considered 99% effective if taken correctly.
“That’s where we saw this opening or gap for women. We want a safe, non-hormonal contraceptive,” Shrestha says. Compounding the lack of good choices, is poor access to quality sex education and family planning information, according to the non-profit Urban Institute. A focus group survey suggested that the sex education women received “often lacked substance, leaving them feeling unprepared to make smart decisions about their sexual health and safety,” wrote the authors of the Urban Institute report. In fact, nearly half (45%, or 2.8 million) of the pregnancies that occur each year in the US are unintended, reports the Guttmacher Institute. Globally the numbers are similar. According to a new report by the United Nations, each year there are 121 million unintended pregnancies, worldwide.
The science
The early work on antibodies as a contraceptive had been inspired by women with infertility. It turns out that 9 to 12 percent of women who are treated for infertility have antibodies that develop naturally and work against sperm. Shrestha was encouraged that the antibodies were specific to the target — sperm — and therefore “very safe to use in women.” She aimed to make the antibodies more stable, more effective and less expensive so they could be more easily manufactured.
Since antibodies tend to stick to things that you tell them to stick to, the idea was, basically, to engineer antibodies to stick to sperm so they would stop swimming. Shrestha and her colleagues took the binding arm of an antibody that they’d isolated from an infertile woman. Then, targeting a unique surface antigen present on human sperm, they engineered a panel of antibodies with as many as six to 10 binding arms — “almost like tongs with prongs on the tongs, that bind the sperm,” explains Shrestha. “We decided to add those grabbers on top of it, behind it. So it went from having two prongs to almost 10. And the whole goal was to have so many arms binding the sperm that it clumps it” into a “dollop,” explains Shrestha, who earned a patent on her research.
Suruchi Shrestha works in the lab with a colleague. In 2016, her research on antibodies for birth control was inspired by her own experience with side effects from an implanted hormonal IUD.
UNC - Chapel Hill
The sperm stays right where it met the antibody, never reaching the egg for fertilization. Eventually, and naturally, “Our vaginal system will just flush it out,” Shrestha explains.
“She showed in her early studies that [she] definitely got the sperm immotile, so they didn't move. And that was a really promising start,” says Jasmine Edelstein, a scientist with an expertise in antibody engineering who was not involved in this research. Shrestha’s team at UNC reproduced the effect in the sheep, notes Edelstein, who works at the startup Be Biopharma. In fact, Shrestha’s anti-sperm antibodies that caused the sperm to agglutinate, or clump together, were 99.9% effective when delivered topically to the sheep’s reproductive tracts.
The future
Going forward, Shrestha thinks the ideal approach would be delivering the antibodies through a vaginal ring. “We want to use it at the source of the spark,” Shrestha says, as opposed to less direct methods, such as taking a pill. The ring would dissolve after one month, she explains, “and then you get another one.”
Engineered to have a long shelf life, the anti-sperm antibody ring could be purchased without a prescription, and women could insert it themselves, without a doctor. “That's our hope, so that it is accessible,” Shrestha says. “Anybody can just go and grab it and not worry about pregnancy or unintended pregnancy.”
Her patented research has been licensed by several biotech companies for clinical trials. A number of Shrestha’s co-authors, including her lab advisor, Sam Lai, have launched a company, Mucommune, to continue developing the contraceptives based on these antibodies.
And, results from a small clinical trial run by researchers at Boston University Chobanian & Avedisian School of Medicine show that a dissolvable vaginal film with antibodies was safe when tested on healthy women of reproductive age. That same group of researchers earlier this year received a $7.2 million grant from the National Institute of Health for further research on monoclonal antibody-based contraceptives, which have also been shown to block transmission of viruses, like HIV.
“As the costs come down, this becomes a more realistic option potentially for women,” says Edelstein. “The impact could be tremendous.”