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 Last April, the FDA issued a new draft guidance encouraging industry to find ways to revamp recruitment into clinical trials.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.
Hyperbaric oxygen therapy has been used in the past to help people with traumatic brain injury, stroke and other conditions involving wounds to the brain. Now, researchers at Shamir Medical Center in Tel Aviv are studying how it could treat Long Covid.
Efrati came to HBOT almost by accident. The physician had seen how it had helped heal diabetic ulcers and improved the lives of other patients, but he was busy with his own research. Then the director of his Tel Aviv hospital threatened to shut down the small HBOT chamber unless Efrati took on administrative responsibility for it. He reluctantly agreed, a decision that shifted the entire focus of his research.
“The main difference between wounds in the leg and wounds in the brain is that one is something we can see, it's tangible, and the wound in the brain is hidden,” says Efrati. With fMRIs, he can measure how a limited supply of oxygen in blood is shuttled around to fuel activity in various parts of the brain. Years of research have mapped how specific areas of the brain control activity ranging from thinking to moving. An fMRI captures the brain area as it’s activated by supplies of oxygen; lack of activity after the same stimuli suggests damage has occurred in that tissue. Suddenly, what was hidden became visible to researchers using fMRI. It helped to make a diagnosis and measure response to treatment.
HBOT is not a single thing but rather a tool, a process or approach with variations depending on the condition being treated. It aims to increase the amount of oxygen that gets to damaged tissue and speed up healing. Regular air is about 21 percent oxygen. But inside the HBOT chamber the atmospheric pressure can be increased to up to three times normal pressure at sea level and the patient breathes pure oxygen through a mask; blood becomes saturated with much higher levels of oxygen. This can defuse through the damaged capillaries of a wound and promote healing.
The trial
Efrati’s clinical trials started in December 2020, barely a year after SARS-CoV-2 had first appeared in Israel. Patients who’d experienced cognitive issues after having COVID received 40 sessions in the chamber over a period of 60 days. In each session, they spent 90 minutes breathing through a mask at two atmospheres of pressure. While inside, they performed mental exercises to train the brain. The only difference between the two groups of patients was that one breathed pure oxygen while the other group breathed normal air. No one knew who was receiving which level of oxygen.
The results were striking. Before and after fMRIs showed significant repair of damaged tissue in the brain and functional cognition tests improved substantially among those who received pure oxygen. Importantly, 80 percent of patients said they felt back to “normal,” but Efrati says they didn't include patient evaluation in the paper because there was no baseline data to show how they functioned before COVID. After the study was completed, the placebo group was offered a new round of treatments using 100 percent oxygen, and the team saw similar results.
Scans show improved blood flow in a patient suffering from Long Covid.
Sagol Center for Hyperbaric Medicine
Efrati's use of HBOT is part of an emerging geroscience approach to diseases associated with aging. These researchers see systems dysfunctions that are common to several diseases, such as inflammation, which has been shown to play a role in micro infarcts, heart disease and Alzheimer’s disease. Preliminary research suggests that HBOT can retard some underlying mechanisms of aging, which might address several medical conditions. However, the drug approval process is set up to regulate individual disease, not conditions as broad as aging, and so they concentrate on treating the low hanging fruit: disorders where effective treatments currently are limited and success might be demonstrated.
The key to HBOT's effectiveness is something called the hyperoxic-hypoxic paradox where a body does not react to an increase in available oxygen, only to a decrease, regardless of the starting point. That danger signal has a powerful effect on gene expression, resulting in changes in metabolism, and the proliferation of stem cells. That occurs with each cycle of 20 minutes of pure oxygen followed by 5 minutes of regular air circulating through the masks, while the chamber remains pressurized. The high levels of oxygen in the blood provide the fuel necessary for tissue regeneration.
The hyperbaric chamber that Efrati has built can hold a dozen patients and attending medical staff. Think of it as a pressurized airplane cabin, only with much more space than even in first class. In the U.S., people think of HBOT as “a sack of air or some tube that you can buy on Amazon” or find at a health spa. “That is total bullshit,” Efrati says. “It has to be a medical class center where a physician can lose their license if they are not operating it properly.”
Shai Efrati
Alexander Charney, a research psychiatrist at the Icahn School of Medicine at Mount Sinai in New York City, calls Efrati’s study thoughtful and well designed. But it demands a lot from patients with its intense number of sessions. Those types of regimens have proven difficult to roll out to large numbers of patients. Still, the results are intriguing enough to merit additional trials.
John J. Miller, a physician and editor in chief of Psychiatric Times, has seen “many physicians that use hyperbaric oxygen for various brain disorders such as TBI.” He is intrigued by Efrati's work and believes the approach “has great potential to help patients with long COVID whose symptoms are related to brain tissue changes.”
Efrati believes so much in the power of the hyperoxic-hypoxic paradox to heal a variety of tissue injuries that he is leading the medical advisory board at Aviv Clinic, an international network of clinics that are delivering HBOT treatments based on research conducted in Israel. His goal is to silence doubters by quickly opening about 50 such clinics worldwide, based on the model of standalone dialysis clinics in the United States. Sagol Center is treating 300 patients per day, and clinics have opened in Florida and Dubai. There are plans to open another in Manhattan.
A scientist works on a blood test in the Ajay Goel Lab, one of many labs that are developing blood tests to screen for different types of cancer.
In recent years, this type of cancer has been on the upswing in adults under age 50 and in those without a family history. In 2021, the American Cancer Society's revised guidelines began recommending that colorectal cancer screenings with colonoscopy begin at age 45. But that still wouldn’t catch many early-onset cases among people in their 20s and 30s, says Ajay Goel, professor and chair of molecular diagnostics and experimental therapeutics at City of Hope, a Los Angeles-based nonprofit cancer research and treatment center that developed the new blood test.
“These people will mostly be missed because they will never be screened for it,” Goel says. Overall, colorectal cancer is the fourth most common malignancy, according to the U.S. Centers for Disease Control and Prevention.
Goel is far from the only one working on this. Dozens of companies are in the process of developing blood tests to screen for different types of malignancies.
Some estimates indicate that between one-fourth and one-third of all newly diagnosed colorectal cancers are early-onset. These patients generally present with more aggressive and advanced disease at diagnosis compared to late-onset colorectal cancer detected in people 50 years or older.
To develop his test, Goel examined publicly available datasets and figured out that changes in novel microRNAs, or miRNAs, which regulate the expression of genes, occurred in people with early-onset colorectal cancer. He confirmed these biomarkers by looking for them in the blood of 149 patients who had the early-onset form of the disease. In particular, Goel and his team of researchers were able to pick out four miRNAs that serve as a telltale sign of this cancer when they’re found in combination with each other.
The blood test is being validated by following another group of patients with early-onset colorectal cancer. “We have filed for intellectual property on this invention and are currently seeking biotech/pharma partners to license and commercialize this invention,” Goel says.
He’s far from the only one working on this. Dozens of companies are in the process of developing blood tests to screen for different types of malignancies, says Timothy Rebbeck, a professor of cancer prevention at the Harvard T.H. Chan School of Public Health and the Dana-Farber Cancer Institute. But, he adds, “It’s still very early, and the technology still needs a lot of work before it will revolutionize early detection.”
The accuracy of the early detection blood tests for cancer isn’t yet where researchers would like it to be. To use these tests widely in people without cancer, a very high degree of precision is needed, says David VanderWeele, interim director of the OncoSET Molecular Tumor Board at Northwestern University’s Lurie Cancer Center in Chicago.
Otherwise, “you’re going to cause a lot of anxiety unnecessarily if people have false-positive tests,” VanderWeele says. So far, “these tests are better at finding cancer when there’s a higher burden of cancer present,” although the goal is to detect cancer at the earliest stages. Even so, “we are making progress,” he adds.
While early detection is known to improve outcomes, most cancers are detected too late, often after they metastasize and people develop symptoms. Only five cancer types have recommended standard screenings, none of which involve blood tests—breast, cervical, colorectal, lung (smokers considered at risk) and prostate cancers, says Trish Rowland, vice president of corporate communications at GRAIL, a biotechnology company in Menlo Park, Calif., which developed a multi-cancer early detection blood test.
These recommended screenings check for individual cancers rather than looking for any form of cancer someone may have. The devil lies in the fact that cancers without widespread screening recommendations represent the vast majority of cancer diagnoses and most cancer deaths.
GRAIL’s Galleri multi-cancer early detection test is designed to find more cancers at earlier stages by analyzing DNA shed into the bloodstream by cells—with as few false positives as possible, she says. The test is currently available by prescription only for those with an elevated risk of cancer. Consumers can request it from their healthcare or telemedicine provider. “Galleri can detect a shared cancer signal across more than 50 types of cancers through a simple blood draw,” Rowland says, adding that it can be integrated into annual health checks and routine blood work.
Cancer patients—even those with early and curable disease—often have tumor cells circulating in their blood. “These tumor cells act as a biomarker and can be used for cancer detection and diagnosis,” says Andrew Wang, a radiation oncologist and professor at the University of Texas Southwestern Medical Center in Dallas. “Our research goal is to be able to detect these tumor cells to help with cancer management.” Collaborating with Seungpyo Hong, the Milton J. Henrichs Chair and Professor at the University of Wisconsin-Madison School of Pharmacy, “we have developed a highly sensitive assay to capture these circulating tumor cells.”
Even if the quality of a blood test is superior, finding cancer early doesn’t always mean it’s absolutely best to treat it. For example, prostate cancer treatment’s potential side effects—the inability to control urine or have sex—may be worse than living with a slow-growing tumor that is unlikely to be fatal. “[The test] needs to tell me, am I going to die of that cancer? And, if I intervene, will I live longer?” says John Marshall, chief of hematology and oncology at Medstar Georgetown University Hospital in Washington, D.C.
Ajay Goel Lab
A blood test developed at the University of Texas MD Anderson Cancer Center in Houston helps predict who may benefit from lung cancer screening when it is combined with a risk model based on an individual’s smoking history, according to a study published in January in the Journal of Clinical Oncology. The personalized lung cancer risk assessment was more sensitive and specific than the 2021 and 2013 U.S. Preventive Services Task Force criteria.
The study involved participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial with a minimum of a 10 pack-year smoking history, meaning they smoked 20 cigarettes per day for ten years. If implemented, the blood test plus model would have found 9.2 percent more lung cancer cases for screening and decreased referral to screening among non-cases by 13.7 percent compared to the 2021 task force criteria, according to Oncology Times.
The conventional type of screening for lung cancer is an annual low-dose CT scan, but only a small percentage of people who are eligible will actually get these scans, says Sam Hanash, professor of clinical cancer prevention and director of MD Anderson’s Center for Global Cancer Early Detection. Such screening is not readily available in most countries.
In methodically searching for blood-based biomarkers for lung cancer screening, MD Anderson researchers developed a simple test consisting of four proteins. These proteins circulating in the blood were at high levels in individuals who had lung cancer or later developed it, Hanash says.
“The interest in blood tests for cancer early detection has skyrocketed in the past few years,” he notes, “due in part to advances in technology and a better understanding of cancer causation, cancer drivers and molecular changes that occur with cancer development.”
However, at the present time, none of the blood tests being considered eliminate the need for screening of eligible subjects using established methods, such as colonoscopy for colorectal cancer. Yet, Hanash says, “they have the potential to complement these modalities.”