Diversity Is Paramount for Progress in Clinical Trials

Clinical cancer trials that fail to successfully enroll a racially and ethnically diverse patient population run the risk of leaving critical gaps in understanding regarding the effectiveness of new approaches. The importance of inclusion in such efforts is underscored even further as more studies demonstrate race-based differences in relation to immune status, incidences of tumor mutation, and even mortality rate in patients with cancer.

As some cancer types demonstrate clear racial disparities, with higher incidences for some diseases observed in certain minority groups, more research efforts must be dedicated to gaining a better understanding why more diverse patients aren’t included or willing to participate in clinical cancer trials and what is needed to create an institutional infrastructure that could effectively address this issue.

“One of the highest mortality rates in lung cancer, for example, is seen in black men,” Narjust Duma, MD, is an assistant professor of medicine and a thoracic oncologist at the University of Wisconsin Carbone Cancer Center, told OncLive. “If we aren’t offering the optimal treatment, which would be a clinical trial, to black men, we’re just prolonging the disparity. It [widens] the gap in the care that black men receive compared with white [patients].”

Several studies have examined the need for more diversity in cancer immunotherapy trials and have outlined strategies that several institutions and cancer centers can implement to encourage racial and ethnic minority patients to participate in ongoing research efforts that possess the potential to move the needle across malignancies.

A Dearth of Diverse Enrollment in Cancer Immunotherapy Trials

Although several pivotal trials have led to the US regulatory approval of immune checkpoint inhibitors in lung cancer in recent years, results from a review published in the American Society of Clinical Oncology Educational Book have indicated a severe lack of racial diversity with regard to the patient populations included in these efforts. Specifically, investigators have found that black patients accounted for only 4% of all patients who were enrolled across multiple trials.¹ Similar disparities were also observed in immunotherapy trials that were focused done in patients with other diseases, such as renal cell carcinoma.

In the review, study authors shared that an analysis of 1 million patients with cancer in the United States revealed that African American patients have a 28% higher cancer-specific mortality rate compared with white patients. The survival gap was determined to be independent of sociodemographic factors, disease stage, and access to treatment.

“Discrepancies between clinical trial populations and real-world patients who will ultimately receive the treatments present a major challenge that has been well described,” authors of the review wrote. “This discrepancy extends across all phases of clinical trials and impacts elderly patients, females, racial/ethnic minorities, and patients with unique comorbid conditions that render them ineligible for clinical studies.”

Moreover, the authors added that the underrepresentation of racial minorities in the early phases of drug evaluation could potentially further perpetuate disparities in outcomes if the established doses of the agent are suboptimal or not tolerable. Underrepresentation in trials that have led to approvals could also limit the generalizability of trial findings to all patients.

It is important to adequately represent racial and ethnic minorities on immunotherapy clinical trials, as responses to this approach has been considered to be dependent on the interplay between a patient's immune system, the tumor microenvironment, and tumor characteristics, according to the study authors. As such, race-based differences in immune status must be taken into consideration when these trials are designed.

“The contribution of race-based differences in the innate and adaptive immune systems to outcome differences is well-recognized and such variability has been shown to impact disease severity and outcomes in infectious diseases…” the authors write. “A similar impact of racial variations in host immunity and immune biology is expected on the efficacy and outcomes of cancer immunotherapy.”

For example, a multiple linear regression analysis that aimed to determine the association between gene expression and race considering variation in percent tumor and stroma tissue collected prostate cancer samples from both white and black patients.2 Investigators were able to demonstrate a difference in the immune composition of the tumor and surrounding stroma between the patient subgroups. Notably, the genes that were found to be the most differentially expressed were reported in the stroma; this indicated that host immune factors are likely to affect outcomes as compared with tumor factors, according to the study authors.

Another analysis indicated a higher degree of infiltrates of tumor-associated macrophages in black patients versus white patients; the infiltrates are associated with the poorer prognosis and also could result in poorer outcomes for black patients who receive treatment with immunotherapy.

Regulatory Actions to Boost Inclusion Fall Short

Although federal initiatives have been made to enroll more diverse clinical trial populations, the majority continue to miss the mark, according to the study authors. Contemporary oncology trials still enroll patient populations that are comprised primarily of white men (80% and 59.8%, respectively). Moreover, access to cancer trials continues to be limited to just a minority of patients with cancer in the United States, just 27% of all cases, according to the study authors.

To address this issue, the US Congress took legislative action by passing the National Institutes of Health (NIH) Revitalization Act of 1993, which mandated that all NIH-sponsored clinical trials had to included women and minorities as well as a plan for outreach and recruitment of these subgroups; however, this did not have a lasting impact on the inclusion of minority patients.

In fact, an analysis looking at racial enrollment on National Cancer Institute—funded trials 2 decades following the legislative act showed that only 2% of the 10,000 trials had acceptable representation of minority patients. Additionally, another analysis which examined a total of 782 randomized clinical trials published in prominent medical journals and included 142 reports from NIH-funded trials, showed that only 13.4% reported outcomes by race or ethnicity. “[This suggests] that NIH policies and congressional mandate has failed to notably increase enrollment or reporting of outcome by race,” the study authors write.

Although the extent to which disparities exist with regard to access to clinical cancer trials is unknown, several reports have illustrated a significant imbalance. Once such report, the 2018 Drug Trials Snapshots issued by the FDA, indicated that of 5157 patients who participated in cancer trials that year, only 38% of participants were women, 15% were Asian, 4% were African American, and 4% were Hispanic. The majority, or 68%, of the participants were found to be white. According to the study authors, these percentages distinctly differ from the racial distribution that is seen in the general US population. As of July 2019, 76.3% white, 18.5% Hispanic or Latino, 13.4% black or African American, and 5.9% Asian.³

Being part of a community that has a majority Hispanic and Latino population is a big driving factor that helps to inform how investigators at The University of Texas MD Anderson Cancer Center inform the design of their clinical trials. “Our region is San Antonio and South Texas, which is around 69% Hispanic or Latino,” Ruben Mesa, MD, director of UT Health San Antonio MD Anderson Cancer Center, told OncLive. “We accrue well over 50% Hispanic [patients] onto our cancer clinical trials, as well as an overrepresentation in terms of other minority groups, such as African Americans. We’re close to representing our population, but it isn’t 100%. This is something we focus on and consider for every clinical trial that we open—from the consent process to the design of the study, to the barriers that we are hoping to overcome.”

More efforts are needed to ensure that patients of all races are represented on clinical trials. In order to do that, it is important to understand some of the barriers that limit access to these research efforts, according to the study authors, who theorize that the reason this issue is not being adequately addressed is because the scope of the problem is not clearly understood.

Many barriers to inclusion of minority populations on cancer trials have been well described, according to the study authors. Some barriers can include a lack of outreach programs or a staff dedicated to assisting underserved populations. Restrictive enrollment requirements are an additional factor that needs to be taken into consideration, as certain comorbidities such as poor renal function and cardiac function are prevalent in minority communities. For example, type II diabetes mellitus is likely to result in impaired kidney function; this is prevalent in black and Native American populations, and this possesses the potential to result in exclusion from ongoing trials. Moreover, patient-level factors can include concerns regarding additional costs that are associated with more frequent visits required for trial assessment.

Strategies Pave the Way for Increased Inclusion of Minorities in Future Trials

Authors of another study set out to identify practices used by leading cancer centers across the United States that have been employed to increase the participation of racial and ethnic minority groups on cancer trials^.₄

“Many papers have been published on the barriers of [enrolling minority] patient populations. [Some myths have indicated] that [reaching out] takes too long or it’s too hard to engage [patients of color],” Jeanne M. Regnante, first author of the study and chief health equity and diversity officer of LUNGevity Foundation, told OncLive. “Probably about 60 papers focus on barriers to clinical research inclusion. But really, [when it comes to] cancer centers that are able to recruit racial and ethnic minority populations with success, [nobody asks], ‘What are they doing to drive that success?’”

The National Minority Quality Form and Sustainable Healthy Communities Diverse Cancer Communities Working Group (CWG) applied criteria developed by a group of 14 diversity thought leaders in the United States to identify potential cancer centers of excellence. Centers that met that eligibility criteria shared their practices for inclusion.

The CWG conducted a literature review to inform data collection research methodology and interview surveys were conducted and an interview guide was created to standardize data collection. Surveys were issued to participating centers within 2 weeks of the interview date and the discussion guide was used to collect notable practices.

The discussion guide focused on 6 specific themes that informed diversity and inclusion best practices for cancer trial enrollment: leadership and commitment, operational capabilities, community engagement, patient engagement, investigator training and hiring/mentoring, and recommended sponsor practices for enhanced racial and ethnic minority recruitment.

Through the use of these surveys and guides, investigators were able to uncover several institutions that are leading the way for increased diversity and inclusion of minority populations in cancer trials. Such institutions include Fox Chase Cancer Center, Temple Health, Harold C. Simmons Comprehensive Cancer Center of the University of Texas Southwestern Medical Center, Henry Ford Cancer Institute, Hollings Cancer Center and Medical University of South Carolina (MUSC), John T. Vucurevich Cancer Institute (JVCI) and Rapid City Regional Hospital, The University of Texas MD Anderson Cancer Center, the University of California Davis (UC Davis) Comprehensive Cancer Center, and Winship Cancer Institute of Emory University.

All of the previously mentioned institutions were found to meet the criteria for inclusion and represented every major ethnic minority group, according to the Health and Human Services, Office of Management and Budget race and ethnicity designations. In a 12-month reporting period ranging from 2016 to 2018, these centers reported a specific 10% range of accrual and had created programs that were dedicated specifically to enrolling racial and ethnic minorities to cancer clinical trials. All centers targeted patient populations that were within their catchment or service area.

For example, Fox Chase targeted 10% to 20% (African Americans, Hispanic Americans, and Asian Americans); University of Texas Southwestern targeted 30% to 40% (African Americans and Hispanic Americans); Henri Ford Cancer Institute targeted 30% to 40% (African Americans); MUSC targeted 20% to 30% (African Americans and Hispanic Americans); JVCI targeted 10% to 20% (American Indians/Alaskan Natives); MD Anderson targeted 10% to 20% (African Americans, Hispanic Americans, and Asian Americans); UC Davis targeted 30% to 40% (Asian Americans); and Winship Cancer Institute targeted 20% to 30% (African Americans and Hispanic Americans).

“These cancer centers don’t do anything without engaging the community. One center that serves a large Native American population, JVCI, has established a relationship with local tribes through a tribal lay navigator who works with cancer center leaders to help educate and provide research for the populations that they serve,” said Regnante. “Several centers additionally ask for patient insights or establish patient advisory boards by cancer type to help inform clinical cancer trials.”

Overall the reported percentage of racial and ethnic minority patient populations accrued in cancer trials for all 8 centers ranged from 10% to 40% within this time period, noted the study authors.

“All centers reported that the proportion of racial and ethnic minority populations included in cancer research and the engagement of healthcare professionals in the community as partners had increased over time,” study authors wrote. “Centers also reported the establishment of a process for obtaining ethnically diverse patients’ and/or caregivers’ input on research projects, as well as engagement of community groups to drive participation.”

Cancer centers that had leadership that placed their institutional focus on diversity and stronger physician and patient engagement reported greater inclusion of diverse populations in clinical research. Strategies to enhance community outreach included cultural competence training, community advisory boards, lay community representatives, and transparency in research findings.

The University of Wisconsin Carbone Cancer Center has implemented some of the strategies dedicated to enhancing community relations to accrue a more racially diverse patient population to their clinical trials. “[We have] community educators in the oncology suite waiting areas that share information about clinical trials,” said Duma. “We are going to our patients instead of asking the patients to come to the University of Wisconsin, which includes more expenses and is more challenging for rural populations and minorities. We are taking those community educators to the clinics to ensure that patients are educated about their options. Education is power for a patient.”

Several leaders additionally noted that a simple recommendation from a healthcare provider is 1 of the most important efforts that can contribute toward a patient's willingness to participate in clinical cancer trials. Providers should also engage patients in trial participation decision-making and provide materials that are culturally appropriate, according to the study authors.

“Notable practices in clinical trial inclusion for centers of excellence have a lot of overlap and the majority of practices all centers do regardless of the population they serve,” added Regnante. “These cancer centers aren’t doing anything remarkably different from each other and several of the themes and practices they reported on with [regard to] sustainability were all the same, just with different examples of how they do it. It takes leadership, coordination, and commitment from multiple stakeholders to ensure appropriate inclusion in clinical trials.”

In order to help ethnic and racial minority patients make informed decisions regarding participation in clinical cancer trials, it's important for clinical research and education materials to be culturally and linguistically accessible and user friendly, noted the study authors. Additionally, informed consent processes must be easily understandable to patients and their families; this is an essential component of building trust.

“We should not offer patients suboptimal care,” concludes Duma. “Excluding minority patients from clinical trials is doing [exactly that]. It shouldn’t be seen as a recruitment effort to increase numbers in a clinical trial; it should be seen as a way to improve patients’ clinical outcomes. Everything that we do in oncology is to help our patients live better and live longer; [participating] in a clinical trial is proven to do just that.”

References

1. Nazah B, Mishra M, Pentz R, et al. Enrollment of racial minorities in clinical trials: old problem assumes new urgency in the age of immunotherapy. Am Soc Clin Oncol Educ Book. Published online May 17, 2019. doi:10.1200/EDBK_100021

2. Kinseth MA, Jia Z, Rahmatpanah F, et al. Expression differences between African American and Caucasian prostate cancer tissue reveals that stroma is the site of aggressive changes. Int J Cancer. 2014;134(1):81-91. doi:10.1002/ijc.28326.

3. United States Census Bureau. QuickFacts. Updated July 1, 2019. Accessed August 25, 2020. https://bit.ly/3lhRknA

4. Regnante JM, Richie NA, Fashoyin-Aje L, et al. US Cancer Centers of Excellence strategies for increased inclusion of racial and ethnic minorities in clinical trials. J Oncol Pract. 2019;15(4):e289-e299. doi:10.1200/JOP.18.00638

This article originally appeared on OncLive as, "Understanding the Impact of Racial Representation on Clinical Cancer Trials."