Racial disparities in cancer clinical trials: ‘An old problem with new implications’
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Racial disparities in cancer clinical trial enrollment have existed for decades, with Black, Hispanic and other underserved populations prevented from accessing the same cutting-edge treatments as their white counterparts.
The need to close these care gaps has taken on greater significance with the advent of targeted immunotherapies. As clinical trials are conducted with the aim of securing FDA approval for these novel treatments, it is important to understand the unique biology and pharmacokinetics of these drugs in diverse patient populations, according to experts with whom HemOnc Today spoke.
Source: Brian Strickland.
The lack of racial and ethnic minority representation in clinical trials of these and other cancer treatments threatens not only to compromise data, but also to perpetuate existing disparities in cancer outcomes.
“Lack of enrollment and diversity in trials is an old problem with new implications,” Leah L. Zullig, PhD, MPH, associate professor in the department of population health sciences at Duke University Medical Center, said in an interview with HemOnc Today. “When we have immunotherapies that we know work on specific inhibitors that are poorly represented among minority people and then we don’t even enroll those folks in clinical trials, we are knowingly developing therapies without fully understanding how they work.”
A multifaceted problem
Racial disparities in clinical trial enrollment are driven by various factors at the clinician, patient and institutional levels. According to Zullig, one key issue is that cancer clinical trials often do not recruit patients from within the communities they serve.
“Trials tend to recruit still in academic medical centers,” Zullig said. “When we continue to enroll at academic medical centers, we’re going to continue to get more affluent people who tend to be white, younger and healthier and have fewer comorbidities. We really have to push these out into the community setting, where a more diverse range of patients receive care.”
She said in her state of North Carolina, approximately 80% of patients receive care in the community setting, yet this is not reflected in cancer clinical trial populations.
“Most patients are not coming to Duke or to academic medical centers,” she said. “So, I think right from the start with our recruitment site choices, we are missing huge opportunities.”
Eligibility criteria also can serve as a barrier to enrollment of Black and Hispanic patients, according to Andrea M. Denicoff, RN, MS, ANP, nurse consultant in the division of cancer treatment and diagnosis at NCI and head of clinical trials operations for NCI’s National Clinical Trials Network.
“Our team worked on a tool that looks at why patients don’t enroll in NCI trials when they’re offered them,” Denicoff said in an interview with HemOnc Today. “One of the big factors is that they just don’t meet the eligibility criteria, that it can be too strict. Patients who have other comorbidities may not be eligible.”
She said NCI is seeking to broaden eligibility criteria, where appropriate, to ensure access to clinical trials for a more diverse group of patients.
“We have to balance safety with casting the widest net possible,” she said. “That is something we are actively working on.”
The troubled history of minority clinical trial participation has engendered medical mistrust, which experts said will need to be overcome at the community level. The exploitation of Black study participants in unethical research such as the Tuskegee syphilis experiments has left a lingering wariness of trial participation in many Black patients and may dissuade them from enrolling in trials that could benefit them.
“There is mistrust of research in some diverse communities that is very well-founded and needs to be overcome,” Zullig said. “That is tough to do if you have only 7 minutes in a visit and you need to get through other critical matters. It’s also a bit of a double whammy, with folks also having mistrust of the academic medical centers. So, even if we have a targeted, eligible population with the ability to come to places where we have trials open, that potential mistrust of the health care system continues to present a barrier.”
Geographic location is another significant obstacle for some patients, especially those without insurance or with financial challenges that make it difficult to take time off from work.
“If you don’t have health insurance or live a long distance from a health care setting, you might be slower to seek health care,” Denicoff said. “Financial concerns and other factors in their lives might cause people to delay getting help. These issues present obstacles to consider enrolling in a clinical trial.”
The need to ‘disaggregate’
Although racial and ethnic disparities in clinical trial enrollment have been acknowledged as an area in need of improvement, experts cautioned against viewing different minority groups collectively.
“I think it’s important to disaggregate minorities,” Worta McCaskill-Stevens, MD, MS, chief of the Community Oncology and Prevention Trials Research Group at NCI, said in an interview with HemOnc Today. “Are we talking about Hispanics? If so, how are we disaggregating them?
“There are many differences,” she said. “For example, we have a site that has been funded as a network for providing clinical trials in Puerto Rico for nearly 2 decades now. I think that’s an interesting example, because their ability to enroll reflects organizational barriers, which sometimes they can overcome and sometimes they can’t.”
Language barriers also can be a problem at trial sites such as the one in Puerto Rico, according to McCaskill-Stevens.
“Nuances in the language particular to Puerto Rico have led to changes in the way we think, and this has resulted in several initiatives that are ongoing,” she said. “Through these, we are translating some of our very important initiatives — such as patient-reported outcomes and quality-of-life tools — into different languages so that we can enhance enrollment.”
In addition, enrollment issues can vary widely by cancer type, making accrual of minorities more challenging in some cases than others, Denicoff said.
“For example, a prostate cancer trial for a hormonal therapy — a pill — might mostly involve brief outpatient visits and not be very demanding on people’s time. That might enroll easily. But a breast cancer trial that includes frequent visits and intensive chemotherapy, with potentially severe side effects, could have some patients concerned it may be hard to take that much time off from work or impact other factors in their lives. So, even if everyone is offered a trial, they might choose not to participate.”
Racial and ethnic disparities in clinical trial enrollment also tend to vary based on whether the trials are funded by the NCI or by pharmaceutical companies. A 2020 study conducted by Unger and colleagues evaluated the representation of Black patients in 85 pharmaceutical company-sponsored cancer clinical trials with that of 273 National Cancer Trials Network trials included in the SWOG Cancer Research Network. The study also compared representation in these trials — results of which were used to support FDA drug approvals between 2008 and 2018 — with the U.S. cancer population.
Results showed the overall proportion of Black patients was 2.9% for pharmaceutical company-sponsored trials, 9% for SWOG trials and 12.1% for the U.S. cancer population (P < .001 for each pairwise comparison), with similar findings across the 15 individual cancer types analyzed.
“The study mentions that Black enrollment in NCI trials is three times higher compared with pharmaceutical trials of multiple myeloma,” Denicoff said. “Part of the reason NCI trials are doing better is because we fund sites in areas with diverse populations, like the one in Puerto Rico. When we fund our sites to essentially enroll from their communities, it’s going to result in more diversity.”
Addressing implicit bias
In a partnership designed to increase clinical trial participation among underserved racial and ethnic groups, ASCO and the Association of Community Cancer Centers plan to test a research site-evaluation tool and training program designed to address implicit bias.
Both projects aim to identify major institutional- and provider-level barriers to trial participation facing eligible patients from historically underrepresented groups, according to an ASCO press release.
“This is a problem that we all need to be concerned about,” steering committee co-chair Randall A. Oyer, MD, immediate past president of Association of Community Cancer Centers (ACCC), told HemOnc Today in an interview about the program earlier this year. “There are areas of the country that have high levels of socioeconomic deprivation, and these areas have lower cancer survival. And that is linked to biases within our health care system, specifically in terms of poor access to clinical trials.”
The pilot project was introduced in July 2020 with a request for ideas from the oncology community. To date, ASCO and ACCC have recruited more than 75 oncology research sites to participate in the site assessment and implicit bias training program. The assessment tool will consider structural and procedural factors that may impact patient screening and participation. The implicit bias training will be curriculum-based and will include interventional exercises and educational vignettes.
According to Lori J. Pierce, MD, FASTRO, FASCO, steering group co-chair and chair of ASCO’s board of directors, the goal of the program is to teach clinicians to recognize and transcend these biases.
“Implicit bias training is not a one-and-done thing,” she told HemOnc Today earlier this year. “We have to be constantly improving ourselves, so that we continue to take what we’ve learned and implement it in our daily lives.”
Pierce, past president of ASCO, emphasized that diversity in clinical trials is important not only in terms of health care equity, but also in advancing scientific knowledge.
“If we don’t include a broad population, if we don’t include all the people who have the condition we’re trying to study, you can’t extrapolate to a diverse population of patients,” Pierce said. “The population that you’ve studied isn’t the same as the population that will be treated or will need to be treated. So, there’s an imbalance.”
In addition, ACCC has established its Community Oncology Research Institute, which seeks to make clinical trial participation a standard of care in cancer treatment plans by using ACCC’s network of partnerships to provide community oncology programs with access to educational resources, best practices and mentorships.
“Communities belong in cancer research and cancer research belongs in the community,” Oyer said in an association press release. “Connecting community cancer centers through partnerships will help overcome persistent barriers that exist to conducting research in the community.”
‘We must engage differently’
Pharmaceutical companies also have implemented programs to help increase racial and ethnic diversity in clinical trial enrollment.
Genentech has initiated its Advancing Inclusive Research Site Alliance, a collaboration of clinical research sites that will work with the company to promote inclusion of diverse patient populations in its oncology clinical trials. The initiative also will test recruitment and retention efforts, as well as establish best practices that can be used across the industry to reduce health disparities among people with cancer, according to a Genentech press release.
The research site alliance consists of founding partners within the oncology field, including City of Hope Comprehensive Cancer Center, Mays Cancer Center, O’Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, and West Cancer Center in Memphis. Each site will prioritize enrolling historically underrepresented patient groups in Genentech’s oncology studies. The sites will work together to share information and assess new ways of increasing access to clinical trials for any patient who may benefit.
“We must engage differently with disenfranchised patient communities if we want to ensure the most representative and effective clinical research and achieve optimal treatment outcomes for all,” Quita Highsmith, MBA, chief diversity officer at Genentech, said in a press release. “Through the Advancing Inclusive Research Site Alliance, we’re partnering with highly experienced and trusted research centers located in areas with higher Black and Hispanic/Latinx populations to meet patients where they are and take practical and meaningful strides toward eliminating the systemic inequities of our health care system.”
The Bristol Myers Squibb Foundation Diversity in Clinical Trials Career Development Program has targeted these inequities by supporting the career development of new investigator physicians who are underrepresented in medicine or who have shown a desire to increase diversity in clinical trials.
The program seeks to train 250 community-oriented clinical trial investigators over the course of 5 years, offering sponsorship, support and tools to prepare them for research and mentoring that will promote health equity.
A virtual workshop offered Nov. 6-11 by American Association for Cancer Research will mark the beginning of the program, according to an association press release. The workshop will emphasize the principles of quality clinical research and highlight the need to include historically underrepresented populations, as well as investigate the disconnect between communities and clinical trialists. At the conclusion of the workshop, each participant will be assigned a mentor, with whom they will work for the next 2 years.
‘Hub-and-spoke’ models
Other efforts to reduce disparities have focused on removing geographic barriers through “hub-and-spoke models,” with academic medical centers serving as “hubs” that provide resources and support to clinics conducting trials in outlying communities, or “spokes.”
One program that uses such a model is The Leukemia & Lymphoma Society’s IMPACT (Influential Medicine Providing Access to Clinical Trials), a $3.75 million research grant program that will provide funding to major academic medical centers such as Weill Cornell Medicine, Mayo Clinic in Rochester, Minnesota, and Vanderbilt University Medical Center, according to a society press release.
“We’re going to use the expertise of the major medical centers to design the trials and set them up, but they are going to be looking for patients outside those major medical centers,” Lee Greenberger, PhD, chief scientific officer of The Leukemia & Lymphoma Society, said in an interview with HemOnc Today when the program was launched earlier this year.
The society piloted the program with Dana-Farber Cancer Institute, which achieved an approximately 15% enrollment rate from community centers in clinical trials.
“So, we knew the system could work,” Greenberger said. “We decided a few years ago that we wanted to adapt this to have major medical centers going out into their community settings.”
Establishing a road map
As institutions and companies pursue their various approaches to improving diversity in cancer clinical trial enrollment, it may be helpful to look to programs that already achieved success in this area.
One example is a community outreach and engagement program launched by University of Pennsylvania’s Abramson Cancer Center. Through the 5-year intervention, the center has more than doubled the percentage of Black patients enrolled onto its cancer clinical trials, from 12.2% to 23.9%, according to study results presented at this year’s virtual ASCO Annual Meeting.
The outreach program included culturally targeted marketing approaches, plans to improve Black participant enrollment for each study protocol, partnerships with faith-based organizations to provide education in Black communities, pilot programs for enabling access to transportation and interpreter services, patient navigation and an augmented informed-consent process. Implementation of these strategies led to a 41.5% increase in total cancer clinical trial accrual, from 9,308 patients in 2014 to 13,170 patients in 2018.
“In 2014, we found a major gap in care — specifically, that 16.5% of patients with cancer in our catchment area were Black, but only 11.1% of patients seen at Abramson Cancer Center were Black,” Robert H. Vonderheide, MD, DPhil, director of Abramson Cancer Center, said in an interview with HemOnc Today. “We found that change is possible. We didn’t solve the problem, but now we have a road map, and we know that change is possible with concerted effort.”
‘A two-pronged approach’
With so many initiatives being prioritized at the institutional, corporate and community levels, it may seem inevitable that cancer clinical trials will begin to reflect improvements in diversity. However, Zullig said ongoing, multifaceted efforts will be needed to bring about lasting change.
“I think that we need a two-pronged approach. We need the boots-on-the ground relationship-building and education with providers and patients — that one-on-one communication,” she said. “But I also think we need the institutional and organizational commitment. It’s where we see that connection between institutions, individuals and populations that we will be successful.”
She cited interagency collaborations such as the NCI and Department of Veterans’ Affairs’ NAVIGATE program, through which the two agencies work together to increase enrollment of veterans with cancer onto NCI-funded trials.
“Examples like the VA/NCI connection for NAVIGATE are really valuable,” Zullig said. “I think we need more institutional agreements that are going to push trials out into the community where regular folks get care. In doing that, I think some of the other issues may sort themselves out.”
- References:
- AACR to partner with the Bristol Myers Squibb Foundation on its Diversity in Clinical Trials Career Development Program. Available at: www.aacr.org/about-the-aacr/newsroom/news-releases/aacr-to-partner-with-the-bristol-myers-squibb-foundation-on-its-diversity-in-clinical-trials-career-development-program/. Published May 19. 2021. Accessed Sept. 27, 2021.
- ASCO-ACCC piloting test tools to diversify cancer clinical trials. Available at: www.asco.org/about-asco/press-center/news-releases/asco-accc-piloting-test-tools-diversify-cancer-clinical-trials. Published May 3, 2021. Accessed Sept. 27, 2021.
- Association of Community Cancer Centers launches institute to diversify cancer clinical trials. Available at: www.accc-cancer.org/home/news-media/press-releases/news-template/2021/06/04/association-of-community-cancer-centers-launches-institute-to-diversify-cancer-clinical-trials. Published June 3, 2021. Accessed Sept. 27, 2021.
- Genentech launches oncology clinical trial diversity alliance. Available at: www.gene.com/media/statements/ps_062321. Published June 23, 2021. Accessed Sept. 15, 2021.
- Guerra C, et al. Abstract 100. Presented at: ASCO Annual Meeting; June 4-8, 2021.
- Niranjan SJ, et al. Cancer. 2020;doi:10.1002/cncr.32755.
- Oncology practices nationwide show high interest in diversifying cancer clinical trials. Available at: www.asco.org/about-asco/press-center/news-releases/oncology-practices-nationwide-show-high-interest-diversifying. Published July 15, 2021. Accessed Sept. 27, 2021.
- The Leukemia & Lymphoma Society launches IMPACT research grants to help underserved patients access clinical trials. Available at: www.prnewswire.com/news-releases/the-leukemia--lymphoma-society-launches-impact-research-grants-to-help-underserved-patients-access-clinical-trials-301285367.html. Published May 6, 2021. Accessed Sept. 15, 2021.
- Unger J, et al. JNCI Cancer Spectr. 2020;doi:10.1093/jncics/pkaa034.
- For more information:
- Andrea M. Denicoff, RN, MS, ANP, can be reached at the Division of Cancer Treatment and Diagnosis, National Cancer Institute, Building 31, 9609 Medical Center Drive, 5W428, Bethesda, MD 20892; email: denicofa@dctod.nci.nih.gov.
- Worta McCaskill-Stevens, MD, MS, can be reached at the Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Drive, 5E346, Bethesda, MD 20892; email: mccaskiw@mail.nih.gov.
- Leah L. Zullig, PhD, MPH, can be reached at Duke University Medical Center, 411 W. Chapel Hill St., Suite 600, Durham, NC 27701; email: leah.zullig@duke.edu.
Perspective
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Beverly Moy, MD, MPH
Broadening eligibility criteria and study design will allow diverse patient populations to enter clinical trials. Multiple studies, including one by Minasian and Unger, showed underrepresented minority patients are very happy to join clinical trials, but once they are screened, they are often found to be ineligible. Its one of the major reasons why patients from diverse populations do not enroll in clinical trials.
Why are the eligibility criteria so narrow? Why are patients with certain comorbidities, such as active cardiovascular disease, HIV or psychiatric illnesses, excluded from clinical trials? Its a complicated issue, because many of these trials are, by definition, looking at therapeutic drugs that either have not yet received FDA approval or are being studied for a new indication. Study sponsors would prefer to have healthy patients enrolled in the trial. So, from a safety perspective, there is less risk. One can see why study designers or sponsors would want narrower eligibility criteria. However, the way we do things now, entire patient populations are excluded. Further, when these drugs eventually receive FDA approval, we dont know the real-world effects of these treatments. This is because the population of patients who enroll in clinical trials does not reflect many real-world patients with cancer.
Certainly, these companies take a great deal of financial risk in getting these drugs further along in development, and its clear why they would want a healthier patient population to enter trials. However, in terms of safety, we need to remember the end goal is to determine whether the drug is safe and effective in a broad patient population, not just the healthiest patients.
Reference:
Minasian LM and Unger JM. JCO Oncol Pract. 2020;doi:10.1200/
JOP.19.00735.
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