Effort to recruit more minorities for clinical trials becoming ‘national priority’

Only one in 30 patients with cancer enroll in clinical trials.

Participation rates among ethnic and racial minorities are particularly bleak, even though incidence of certain cancers is higher and outcomes traditionally are poorer for these groups.

Non-Hispanic white patients accounted for 82.9% of phase 3 study populations between 2001 and 2010, or seven times the combined percentage of black (6.2%), Asian (3.3%), Hispanic (2.2%) and Native American (0.1%) patients.

“With this low participation rate, we are really missing opportunities to engage patients in cutting-edge treatment,” Leah L. Zullig, PhD, MPH, assistant professor of medicine at Duke University Medical Center, told HemOnc Today.

Photo by Evan Feldman.

This disparity prompted former FDA Commissioner Robert M. Califf, MD, to declare 2016 “the year of diversity in clinical trials.” The agency’s effort included strategies to increase public awareness of and access to clinical trials, as well as to refine trial analyses to provide better estimates of treatment effects for diverse populations.

Other groups — including the NCI Community Oncology Research Program — took similar steps to improve diversity in clinical trials.

Still, formidable barriers to enrollment remain at the institutional and system levels. A lack of communication about trial participation between some minority groups and their physicians compounds the challenge.

HemOnc Today spoke with clinicians and researchers about how the lack of minorities in cancer studies impedes research; the socioeconomic, genomic and cultural factors associated with disparities in outcomes and access to care; and the need for greater awareness efforts to encourage minority patients to participate in clinical trials.

Incidence and mortality

Cancer incidence and mortality differ considerably based on many factors, such as sex, age and race/ethnicity.

“Blacks have higher rates than whites, who have higher rates than Native Americans, who have higher rates than Hispanics, who have higher rates than Asians,” Otis W. Brawley, MD, MACP, chief medical officer at the American Cancer Society and a HemOnc Today Editorial Board member, said in an interview.

Black men and women are “the hardest hit group” for certain cancers, Zullig said.

“Black men have higher incidence and cancer-related deaths than other races for prostate, colorectal and lung cancers,” Zullig said. “Black women are less likely than white women to be diagnosed with many cancers; however, black women are more likely to die from cancer-related causes. It is very disheartening.”

ACS’s 2017 cancer statistics report — prepared by Siegel and colleagues and published in CA: A Cancer Journal for Clinicians — showed cancer-related deaths remained 15% higher among blacks than whites in 2014, even though the percentage of uninsured black individuals in the United States declined from 21% in 2010 to 11% in 2015.

Between 2009 and 2013, breast cancer incidence rate was highest among non-Hispanic white women (128.3 per 100,000 population), followed by black women (125.1) and Hispanic women (91.7). However, the mortality rate among black women (30) was more than double that among Hispanics (14.4) and whites (11.1).

Black men have the highest lung cancer incidence (90.8) and mortality (69.8) rates, followed by white men (incidence, 77.7; mortality, 58.3) and American Indians/Alaska natives (incidence, 71.3; mortality, 46.2).

Prostate cancer incidence (198.4) and mortality (42.8) rates also are highest among black men, followed by white men (incidence, 114.8; mortality, 18.7) and Hispanic men (incidence, 104.9; mortality, 16.5).

“The death rates overall are significantly higher in black men, which really highlights the disparities,” Daniel Sullivan, MD, associate center director of clinical science at Moffitt Cancer Center, told HemOnc Today. “Black people are more likely than white people to be diagnosed at a later stage of disease. This is closely aligned with health insurance coverage, which is lower among minorities than among non-Hispanic whites.”

Differences in biology and lifestyle could partially explain the disparities. Data suggest some cancers may be more biologically aggressive in black individuals, Zullig said.

A study by Huo and colleagues — published this year in JAMA Oncology — suggested 40% of the differences in breast cancer subtype frequency between blacks and whites could be explained by germline genetic variants. Analyses of 930 patients in The Cancer Genome Atlas revealed 9,232 genes (49.1%) differentially expressed between black and white patients after adjustment for age and batch effects.

Black patients had a higher likelihood of basal-like (OR = 3.8; 95% CI, 2.46-5.87) and HER-2–enriched (OR = 2.22; 95% CI, 1.1-4.47) breast cancer subtypes, as well as shorter breast cancer–free interval (HR = 1.67; 95% CI, 1.02-2.74).

“Beyond different races, people have different cultures that have different genetic and other risk factors that will impact their cancer risk and outcomes,” Zullig said.

For instance, a study by Schabath and colleagues, published last year in Cancer Control, showed American Indians/Alaska Natives (29.2%) and multiracial adults (27.9%) had the highest smoking prevalence rates in 2014, whereas Asians (9.5%) had the lowest.

“Today, black men are the highest demographic of smokers,” Zullig said. “This and other lifestyle factors, such as diabetes and obesity, may also have an impact.”

More diversity in clinical trials “will help develop more generalized data that will give us appropriate ammunition to develop the best evidence to make treatment decisions,” Zullig added.

Individual mistrust

Data from Kwiatkowski and colleagues showed black patients accounted for 6.2% of participants in phase 3 cancer treatment trials conducted between 2001 and 2010, down from 10.5% between 1990 and 2000.

However, during those same periods, the proportion of black participants in cancer prevention trials increased from 5.5% to 11.6%.

Researchers in the United Kingdom established the National Cancer Research Network (NCRN) in 2001 to broaden cancer clinical research and improve patient care.

A study by Stead and colleagues — published in 2011 in British Journal of Cancer — showed NCRN increased recruitment of patients across ethnicities from less than 3.5% in 2001 to 12% in 2008. In addition, 74% of studies met their recruitment target, compared with 39% prior to NCRN.

However, minority populations remain underrepresented in clinical trials, according to R. Paul Symonds, MD, FRCP, FRCR, professor of clinical oncology in the department of cancer studies at University of Leicester in the United Kingdom.

“We have noticed the difficulty in getting [minority] patients into clinical trials,” Symonds told HemOnc Today. “There is a problem, no doubt, and it isn’t exclusive to the United States.”

The pervasiveness of these disparities suggests barriers beyond those within individual health systems.

In a study published last year in Cancer Control, Hamel and colleagues cited awareness of clinical trials, perception of hospital/infrastructure, attitude/experience, access and mistrust as some barriers experienced on an individual level.

Physicians may be hesitant to recommend black patients for clinical trials due to their potential perception that blacks have been used or mistreated by medical institutions, the researchers wrote.

This “mistrust” between physicians and their minority patients — particularly blacks — does exist, Brawley said.

“Blacks tend to feel they are being exploited or taken advantage of, mostly due to past happenings,” Brawley said.

He cited the Tuskegee Study of Untreated Syphilis in the Negro Male, initiated in 1932.

Researchers enrolled black men in this study to treat them for “bad blood.” However, they did so without informed consent.

In exchange for study participation, the men received free medical exams, meals and burial insurance, but they did not receive proper treatment, according to the CDC. Patients did not receive penicillin when it became standard for syphilis in 1947, and they were not given the choice to quit the study.

“This study was and is still talked about,” Brawley said. “The result is that blacks are suspicious they will be used.”

Prostate screening guidelines are another example, Brawley said.

“If you look at the history of screening in the United States, we told black people they needed to be screened because they would get prostate cancer if they didn’t,” he said. “We forgot to tell them there was no science available that showed screening saved lives, and that screening generates a lot of revenue. This has translated to black people being suspicious that we are only in the business to make money. We in medicine work very hard to ensure distrust exists.”

A senior or more experienced physician may alleviate some trust issues.

Symonds and colleagues conducted a study — published in 2012 in British Journal of Cancer — that showed more South Asian patients in Britain entered a clinical trial when approached by a senior doctor compared with someone perceived as having a “lesser hierarchical status.”

“There is a hierarchal element there and certainly considered by patients from a British context,” Symonds said.

Results also showed that, in the United States, trial recruitment improved with greater prevalence of Hispanic staff. Consent forms also can improve recruitment if they are directed toward specific groups.

Still, distrust dissuades some racial or ethnic minorities — particularly black men — from seeing a doctor altogether, Zullig said.

She cited a series of studies conducted by researchers at UNC Chapel Hill that looked at perceptions of clinical trials among black men and women. Results showed patients expressed concern about the language used in clinical trials and about the role of the trials in their personal treatment.

“The idea of mistrust in the health care system should not be underestimated,” Zullig said.

‘Poverty is the carcinogen’

Lifestyle and cultural differences, including poverty level and geographical demographics, also may affect a patient’s ability or willingness to participate in a trial.

Most minorities visit local community centers and hospitals for treatment, and patients may have to travel far — sometimes 2 to 3 hours — to participate in trials, Sullivan said.

“Bigger academic hospitals and centers enroll 15% to 17% of their patients on clinical trials, whereas community hospitals enroll between 1% and 2%,” he said. “Generally, community hospitals do not conduct a lot of clinical research. This is a big barrier, because community hospitals see the majority of patients with cancer, and if they don’t have clinical trials, then the overall accrual remains low.”

Physicians at community hospitals — who see more minority patients and work longer hours — may not have the time to talk about clinical trials, Brawley said.

“A minority patient will most likely go to a community hospital where a doctor sees between 35 and 40 patients a day,” he said. “It’s not that they do not want to talk about trials or don’t have the skills, they are just unable to do so because of scheduling and being overwhelmed.”

“There are huge disparities in the United States based on socioeconomic status,” Brawley added. “I believe poverty is the carcinogen, as opposed to race.”

He noted how whites who live in the Appalachian region have some of the worst cancer mortality rates in the United States.

“People who live there are more likely to smoke, less likely to be educated, more likely to be obese and more likely to live in a polluted environment,” Brawley said.

A patient’s family also may play a role.

“Patients agree to take part in the study, go home and try to get consent from family members, and then not actually do it,” Symonds said. “In Asian culture, it is impolite to say no, so often times — from [my] experience — an Asian patient will say they will participate and then never do.”

Local community leaders may be influential and could help encourage enrollment, Symonds added.

“We need to involve community leaders in raising awareness and education, because a patient may in fact go to a faith leader to ask advice,” he said. “Our experience is that it is important to see doctors, but doctors also have to be really careful about their relationship not becoming coercive. It needs to be genuine.”

Health care and system-wide barriers

Health care system–wide barriers also prevent minorities from enrolling in clinical trials.

“Many of the barriers to enrollment in clinical trials are the same challenges to health care access that are seen across our health care system, especially economic factors and health insurance status,” 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 the NCI’s National Clinical Trials Network, told HemOnc Today.

Hamel and colleagues cited the availability of clinical trials, supporting infrastructure, costs and insurance coverage, eligibility criteria and lack of community engagement as system-level barriers that limit minority participation in cancer clinical trials.

Moffitt Cancer Center tries to foster community engagement and ensure that staff exists to recruit minority patients, Sullivan said.

“We do well in terms of putting minorities on clinical trials at Moffitt, but it does not just happen,” he said. “We have a minority clinical research committee that meets at least monthly to address issues. We have a task force to educate people at Moffitt and in the community about clinical research in general and putting minorities on specifically.”

However, not every hospital or clinical center has the means or money to conduct clinical trials.

“The thing to do is improve health care to where clinical trials are offered in as many places as possible,” Brawley said. “This involves decompressing some of the places where blacks and minorities get their health care, decompressing the crowdedness in centers, and allowing doctors the time to actually study the clinical trials and participate.”

Perceptions and misunderstandings further impede access.

A study by Eggly and colleagues — published in 2013 in Health Expectations — analyzed recorded oncology visits between clinicians and patients potentially eligible for clinical trials.

Researchers found that black patients had shorter visits than white patients — measured via mean word count (4,877.73 vs. 7,247.18) — and visits among black patients included less discussion about the topic of clinical trials (mean word count, 2.73 vs. 4.27). When patients and physicians discussed clinical trials, mean word count about trials also was less for black patients (1,089.64 vs. 1,867.09).

Thus, black patients may be making decisions about clinical trial participation based on little knowledge of the process, researchers wrote.

“Researchers and clinicians are already developing tools to overcome some of these barriers, particularly differences in language skills and health literacy,” Zullig said. “There is a push for a more culturally sensitive informed-consent process, as well as efforts to develop materials for patients who have lower literacy levels and to involve community groups to help.”

Specialized programs

The National Institutes of Health Revitalization Act of 1993 required women and minority groups to be included in all NIH–funded research, including NCI cooperative group trials.

“This federal law — written by a bunch of politicians who had no idea about science — required inclusion by race and ethnicity. It requires there be a valid subset analysis, meaning a researcher needs to look at blacks in the trial to see if the investigational drug or method works the same in blacks vs. whites vs. Asians,” Brawley said. “If you are a clinical trialist, you are taught that subset analysis is often invalid and will not reveal very much.

“I don’t want to see minorities participating [because of this law], I want to see more minorities participating in clinical trials as a sign that their doctors are practicing a better quality of medicine,” Brawley added. “It is more of a social justice reason to me than the law.”

The NIH Revitalization Act had the most impact on enrollment for women through 2012. However, enrollment of other minority groups in cancer clinical trials remains low, so new programs and partnerships have been implemented by the FDA, NCI and other organizations to close this gap.

The FDA’s year of diversity for clinical trials followed the agency’s 2014 action plan to enhance the collection and availability of demographic subgroup data.

“The [plan] identified three key priorities: addressing data quality, raising awareness and increased transparency,” FDA spokeswoman Lauren Smith Dyer told HemOnc Today.

Almost all of these action items have been addressed, Smith Dyer said.

“This work to diversify trials includes raising patients’ awareness about the value of participating in clinical research, ensuring that researchers include clinical scientists who are trusted by minority participants, and ensuring that oversight is proactive in addressing enrollment of diverse participants at the earliest stages,” she said.

The 2016 campaign featured a video of black woman sharing her story about participating in clinical trials. The video reached more than 6,000 people via YouTube and 7.3 million people via Twitter within the first week of its launch, according to Smith Dyer.

“Ensuring meaningful representation of minorities in clinical trials for FDA–regulated medical products is fundamental to the FDA’s regulatory mission and public health,” Smith Dyer said. “Minority participation helps researchers find better treatments and better ways to fight such diseases as cancer, diabetes, heart disease and HIV/AIDS, which all disproportionately affect minorities. In addition, it uncovers differences by [sex], race and ethnicity that may be important for safe and effective use of therapies.”

Last fall, the FDA released a document titled “Collection of Race and Ethnicity Data in Clinical Trials: Guidance for industry and Food and Drug Administration Staff,” which provides information and toolkits to stakeholders and patient advocates to encourage participation in clinical trials.

The NCI Community Oncology Research Program (NCORP) — a cancer-focused practice-based research network established in 1983 — is “very active” in ensuring clinical trials are available to diverse populations, Denicoff said.

NCORP is designed to bring cancer clinical trials and cancer care delivery research directly to individuals in their communities, with the hope of fostering direct patient evidence that helps improve outcomes and reduce cancer disparities.

“Many NCI–designated cancer centers have developed partnerships within their own communities to do outreach and education,” Denicoff said.

A lot of the early success of minority recruitment can be attributed to NCORP, Zullig said.

“The program brings opportunities for minority patients to enroll in trials into diverse communities where they are seeking care,” she said.

Other NCI–designated cancer centers have developed partnerships within their own communities to foster outreach to increase awareness and education, Denicoff said. For example, University of Oklahoma implemented a Native American patient navigator program, and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins hired an assistant director for clinical trial accrual.

“We have seen minority enrollment improving, and at least some of that is due to the increased awareness and support for clinical trials that is provided by a number of programs,” Denicoff said. “These [show how] many centers have increased their efforts and collaborations to remove barriers to minority participation in trials, and we think focused efforts like these are leading to improvements.”

In 2009, five institutions — University of Minnesota, University of Alabama at Birmingham, Johns Hopkins University, The University of Texas MD Anderson Cancer Center and University of California, Davis — established the Enhancing Minority Participation in Clinical Trials (EMPaCT) consortium.

Durant and colleagues detailed how the consortium systematically addressed perceptions of limited recruitment and enrollment of minorities in cancer clinical trials within the cancer centers.

Researchers found that lack of insurance and language discordance most discouraged providers from asking patients to participate in trials. Non–English-speaking patients may not be recruited onto trials due to the expense of making consent forms and materials available in multiple languages.

Moffitt Cancer Center has implemented various practices to try to overcome language barriers, Sullivan said.

“There are several Spanish-speaking doctors on staff, and I think patients feel more comfortable when they can speak to them,” he said. “We’ve translated a lot of signage to Spanish and advertise on TV in Spanish, as well.”

Pharmaceutical companies and other stakeholders also have made attempts to eliminate barriers for minorities. Zullig cited the partnership of Eli Lilly and the National Center for Bioethics in Research and Health Care at Tuskegee University that “focuses on increasing trial diversity with programs involving research and education,” she said.

In addition, the National Minority Quality Forum partnered with the Pharmaceutical Research and Manufacturers of America to increase diversity. The collaboration includes the National Clinical Trial Network, which will provide a permanent IT infrastructure to researchers to quickly identify minority populations in medical need.

“This is the good news,” Zullig said. “Increasing diversity is a national priority, and there are a lot of stakeholders who now have a seat at the table.”

Disparities persist

Although minority enrollment has improved, disparities persist.

Duma and colleagues presented a study at this year’s ASCO Annual Meeting that evaluated enrollment data from all completed therapeutic trials conducted from 2003 to 2016.

Among 1,012 clinical trials, only 310 (31%) of them — comprising 55,689 enrollees — reported ethnicity. Non-Hispanic whites accounted for significantly greater clinical trial enrollment (enrollment fraction [EF], 1.2%) than blacks (EF, 0.7%; P < .001) and Hispanics (EF, 0.4%; P < .001).

When researchers compared data from 2003 to 2016 with historical data from 1996 to 2002, they observed decreased enrollment for black patients (6% vs. 9.2%) and Hispanic patients (2.6% vs. 3%). Hispanics only accounted for 3% of breast cancer trial populations and 1.5% of prostate cancer clinical trial populations. Blacks accounted for 5.4% of lung cancer trial populations and 3% of renal cell carcinoma trial populations.

Conversely, Asian recruitment doubled over 14 years (2% vs. 5.3%).

Further, FDA research also presented at ASCO showed the populations of trials that support drug approval is not representative of the U.S. population for whom the drugs will be prescribed. For instance, whites accounted for 88% of trial enrollees in 2016 but 77.1% of the population, whereas blacks represented 6% of trial enrollees and 13.3% of the population.

Patient navigation stands to reverse these trends.

A study by Fouad and colleagues, published last year in Journal of Oncology Practice, showed patient navigators increased by nearly fivefold (OR = 4.88; 95% CI, 2.56-9.31) the likelihood that a black patient would complete a trial. The participation rate of blacks in therapeutic cancer clinical trials increased from 9% to 16% throughout the study period.

Another study by Ghebre and colleagues demonstrated a low rate of clinical trial refusal (range, 4% to 6%) with use of patient navigation training and implementation.

However, few studies have reported on the ability of patient navigation to increase enrollment.

Although the patient navigation model has focused on improving medical care, it has potential to become a part of increasing enrollment in clinical trials, Zullig said.

“It is a fantastic opportunity,” she said. “We see patient navigators have a huge role because they are well connected with the health care system, can speak the regular language of patients, be available as a first point of contact for questions and really become a trusted source of information for patients.”

Regardless of the programs, awareness is lacking and is the key to change, Symonds said.

“The bottom line is, the best way of getting patients into trials is having them see a doctor of their ethnicity, talking to them and explaining the trial,” Symonds said. “It needs to be someone they trust.”

Improving health care as a whole ultimately will increase minority enrollment, Brawley said.

“There are huge numbers of blacks in the United States who get less than good health care, yet we fixate very frequently on blacks going into clinical trials,” Brawley said. “Maybe we should focus on blacks getting adequate health care.” – by Melinda Stevens

Click here to read the , “Are subset analyses an effective way to overcome the lack of data from minorities in clinical trials?”

References:

Califf RM. 2016: The year of diversity in clinical trials. Available at: blogs.fda.gov/fdavoice/index.php/2016/01/2016-the-year-of-diversity-in-clinical-trials. Accessed on May 15, 2017.

Duma M, et al. Abstract 2533. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Durant RW, et al. Cancer. 2014;doi:10.1002/cncr.28574.

Eggly S, et al. Health Expect. 2013;doi:10.1111/hex.12108.

Fashoyin-Aje LA, et al. Abstract 6518. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

FDA. Collection of race and ethnicity data in clinical trials: Guidance for industry and Food and Drug Administration staff. Available at: https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126396.pdf. Accessed on May 16, 2017.

Fouad MN, et al. J Oncol Pract. 2016;doi:10.1200/JOP.2015.008946.

Ghebre RG, et al. Cancer. 2013;doi:10.1002/cncr.28570.

Hamel LM, et al. Cancer Control. 2016;23(4):327–337.

Haynes-Maslow L, et al. Cancer Med. 2014;doi:10.1002/cam4.284.

Huo D, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2017.0595.

Kwiatkowski K, et al. Cancer. 2013;doi:10.1002/cncr.28168.

Schabath MB, et al. Cancer Control. 2016;23(4):338–346.

Siegel RL, et al. Cancer. 2017;10.3322/caac.21387.

Stead M, et al. Br J Cancer. 2011;doi:10.1038/bjc.2011.69.

Symonds RP, et al. Br J Cancer. 2012;doi:10.1038/bjc.2012.240.

Trantham LC, et al. J Natl Med Assoc. 2015;doi:10.1016/S0027-9684(15)30007-9.

For more information:

Otis W. Brawley, MD, MACP, can be reached at otis.brawley@cancer.org.

Andrea M. Denicoff, RN, MS, ANP, can be reached at denicofa@dctod.nci.nih.gov.

Daniel Sullivan, MD, can be reached at dan.sullivan@moffitt.org.

R. Paul Symonds, MD, FRCP, FRCR, can be reached at rps8@leicester.ac.uk.

Leah L. Zullig, PhD, MPH, can be reached at leah.zullig@duke.edu.

Disclosure: Brawley, Denicoff, Sullivan, Symonds and Zullig report no relevant financial disclosures.