Diversity and Inclusion in Pancreatic Cancer Clinical Trials

Abstract

Pancreatic cancer is defined by the lethality of the disease. With an estimated 5-year survival rate of 9% and increasing incidence, it is projected to soon become the second leading cause of cancer deaths in the United States.1Rahib L. Smith B.D. Aizenberg R. et al.Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.Cancer Res. 2014; 74: 2913-2921Crossref PubMed Scopus (3359) Google Scholar Pancreatic cancer does not affect all populations equally, as significant health disparities exist between race, ethnicity, and gender. Over the last 2 decades black individuals have persistently had a 19% higher incidence of pancreatic cancer when compared with other racial groups.2SEER∗Explorer: an interactive website for SEER cancer statistics. Surveillance Research Program, National Cancer Institute.https://seer.cancer.gov/explorer/Google Scholar They present at younger ages with more advanced disease. Moreover, black patients with pancreatic cancer experience a higher age-adjusted mortality rate compared with all other racial groups (13.3 vs 11.0 per 100,000 population of all other racial/ethnic groups combined). Native American patients also have higher rates of death from pancreatic cancer, with an estimated 5-year survival rate of 6.7%.2SEER∗Explorer: an interactive website for SEER cancer statistics. Surveillance Research Program, National Cancer Institute.https://seer.cancer.gov/explorer/Google Scholar In contrast, Hispanic patients diagnosed with pancreatic cancer have the longest median and overall survival when compared with other ethnic groups.3Riner A.N. Underwood P.W. Yang K. et al.Disparities in pancreatic ductal adenocarcinoma—the significance of Hispanic ethnicity, subgroup analysis, and treatment facility on clinical outcomes.Cancer Med. 2020; 9: 4069-4082Crossref PubMed Scopus (3) Google Scholar These disparities are not entirely accounted for by comorbidities, socioeconomic status, and access to high-quality health care alone, suggesting that biologic processes may be partially responsible.4Arnold L.D. Patel A.V. Yan Y. et al.Are racial disparities in pancreatic cancer explained by smoking and overweight/obesity?.Cancer Epidemiol Biomarkers Prev. 2009; 18: 2397-2405Crossref PubMed Scopus (77) Google Scholar Although it is critical to address the systemic injustices, institutional racism, and disadvantages faced by minority populations, ancestral differences in tumor biology cannot be overlooked. Recently, increased focus has been applied to exploring racial and ethnic differences in patient and tumor biology through a multiomics approach. Oncologic disparities have been identified based on differences in germline and somatic mutations, molecular subtypes, tumor immune response, epigenetics, and microbiota.5Vick A.D. Hery D.N. Markowiak S.F. et al.Closing the disparity in pancreatic cancer outcomes: a closer look at nonmodifiable factors and their potential use in treatment.Pancreas. 2019; 48: 242-249Crossref PubMed Scopus (0) Google Scholar Black patients with pancreatic cancer are more likely to have KRAS somatic mutations and HER2 protein overexpression when compared with white patients.6Pernick N.L. Sarkar F.H. Philip P.A. et al.Clinicopathologic analysis of pancreatic adenocarcinoma in African Americans and Caucasians.Pancreas. 2003; 26: 28-32Crossref PubMed Scopus (41) Google Scholar Germline loss-of-function mutations in BRCA 1/2 genes and CDKN2A tumor suppressor genes are also more common in patients with African ancestry. Patients with germline BRCA and CDKN2A mutations are at an increased risk for pancreatic cancer and may exhibit different treatment responses to targeted therapies.7Golan T. Kindler H.L. Park J.O. et al.Geographic and ethnic heterogeneity of germline.J Clin Oncol. 2020; 38: 1442-1454Crossref PubMed Scopus (21) Google Scholar,8McWilliams R.R. Wieben E.D. Chaffee K.G. et al.Germline rare coding variants and risk of pancreatic cancer in minority populations.Cancer Epidemiol Biomarkers Prev. 2018; 27: 1364-1370Crossref PubMed Scopus (9) Google Scholar Given these and other racial and ethnic differences in pancreatic cancer tumor biology, it is unlikely that all patients will exhibit similar outcomes to trialed therapeutics. To address these inequities, Congress issued the Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11) requiring race and ethnicity reporting in ClinicalTrials.gov for clinical trial participants.9ClinicalTrials.gov. ClinicalTrials.gov background.https://clinicaltrials.gov/ct2/about-site/backgroundGoogle Scholar Given the implementation of these requirements, we sought to assess the current state of diversity and inclusion by investigating trends in demographic data reporting and assessing its impact on the diversity of pancreatic cancer clinical trials. We hypothesized that racial and ethnic minority patients with pancreatic cancer continue to be under-represented, despite the federal requirement for more transparent trial demographic reporting. As a consequence, participation under-representation in clinical trials likely perpetuates the health disparities found in pancreatic cancer treatment and outcomes. To evaluate trends in diversity and inclusion, a comprehensive review of pancreatic cancer clinical trials was performed using the US National Library of Medicine’s ClinicalTrials.gov database. Search criteria included “pancreatic cancer” and “pancreatic carcinoma.” Subtopics included “pancreatic neoplasm,” “pancreas cancer,” “cancer of the pancreas,” “cancer of pancreas,” “pancreatic tumors,” “carcinoma of the pancreas,” and “neoplasm of pancreas.” The search was filtered to include adult study participants (>18 years of age) and interventional (clinical trial) studies. Trials were limited to “with results,” which comprises those with study results information included in the study record under the Study Results tab. All study phases were included. The study phase labeled not applicable, or N/A, describes device or behavioral interventions that are not defined by the US Food and Drug Administration (FDA). The database was queried on December 21, 2020, and this initial search yielded 337 clinical trial results. One hundred thirty clinical trials were excluded because they were conducted outside of the United States (n = 44) and included other cancer types (n = 83) or other pancreatic pathologies (n = 3). These exclusion criteria were selected to cleanly analyze pancreatic cancer clinical trials within the United States. Descriptive statistics were recorded from provided study results. Results were cross-referenced with formally linked publications on ClinicalTrials.gov as well as PubMed.gov using trial registry numbers in the secondary source identification field. Results were reported on ClinicalTrials.gov by gender (female, male), ethnicity (Hispanic or Latinx, not Hispanic or Latinx, unknown or not reported) and race (American Indian or Alaska Native, Asian, Native Hawaiian or other Pacific Islander, black or African American, white, more than 1 race, and unknown or not reported). Because of the lack of racial and ethnic demographic reporting from 2005 to 2007, these data were excluded from longitudinal analysis (n = 1). Clinical trial sponsors were categorized by primary sponsor type into university/cancer center, National Cancer Institute (NCI), pharmaceuticals/biotech, and private hospitals. The enrollment fraction (EF) was calculated for each trial and subgroup population. The term EF was initially described by Murthy et al10Murthy V.H. Krumholz H.M. Gross C.P. Participation in cancer clinical trials: race-, sex-, and age-based disparities.JAMA. 2004; 291: 2720-2726Crossref PubMed Scopus (1315) Google Scholar and is defined as the number of clinical trial participants divided by the US incidence of cancer in each race, ethnicity, and gender subgroup. Wilcoxon rank sum tests were used to determine whether the center of the distribution of EF ratios among all trials differed from 1. Incident cases of pancreatic cancer were collected through the North American Association of Central Cancer Registries from 2013 to 2017 and age-adjusted to the 2000 US Standard Population.11Goldberg D.W. Kohler B. Kosary C. The Texas A&M, NAACCR, NCI Geocoding Service (2021).https://geo.naaccr.orgGoogle Scholar Pancreatic cancer incidence was unavailable for “multiracial” and “unknown” racial and ethnic subgroups so EF analysis could not be calculated. All analyses were performed using the R statistical software package (V4.0.2; The R Foundation for Statistical Computing). Two-hundred seven pancreatic cancer clinical trials comprising 8429 pooled participants were included with results reported between 2005 and 2020. In this timespan race and ethnicity were reported in only 49.3% and 34.7% of studies respectively, whereas 99% of studies reported participants’ gender (Supplementary Table 1). Reporting of participant race and ethnicity data, however, has improved substantially over time (P < .0001) (Figure 1A). In 2019, 100% of trials reported data on race and 73.3% of trials reported data on ethnicity. In 2020, 100% of race and ethnicity data were reported, although only 2 trials meeting inclusion criteria had publicly reported results at the time of data analysis. These data represent an encouraging trend toward improved sponsor reporting of race and ethnicity data over the last decade. Despite a positive trajectory in the reporting of race and ethnicity data, nonwhite and Hispanic patients remain markedly under-represented in pancreatic cancer clinical trials. White patients made up the majority (84.7%; EF = 1.05, P = .002) of pancreatic cancer clinical trial participants, whereas black (8.2%; EF = 0.43, P = .002), Asian/Pacific Islander (2.4%; EF = 0, P < .0001), American Indian or Alaskan Native (0.3%; EF = 0, P < .0001), and Hispanic (6%; EF = 0.47, P < .0001) patients were disproportionately missing (Table 1). Trial participants were also more likely to be male (54.8%; EF = 1.07, P = .0006) than female (45.2%; EF = 0.93, P = .001). Indicated by a significantly low median EF, under-representation of nonwhite and Hispanic patients was not the result of a few trials but rather systemic under-representation across pancreatic cancer clinical trials.Table 1Diversity of Pancreatic Cancer Clinical Trial ParticipantsParticipant demographicsNo. of cases (%)Proportion of incident casesaIncident cases 2013–2017, age-adjusted to the 2000 US Standard Population. (%)Median EFbMedian EF of each individual trial with demographic data reported.P valuecWilcoxon rank sum tests determined distribution of EF ratios were different from 1.Race (102 trials with race data, 4374 participants) White3704 (84.7)82.31.05.002 Black360 (8.2)12.40.43<.0001 Asian/Pacific Islander105 (2.4)3.30<.0001 American Indian/Alaska native11 (0.3)0.40<.0001 MultiracialdIncident cases were not reported in North American Association of Central Cancer Registries for multiracial and unknown subgroups.32 (0.7)NANANA UnknowndIncident cases were not reported in North American Association of Central Cancer Registries for multiracial and unknown subgroups.162 (3.7)NANANAEthnicity (73 trials with ethnicity data, 2981 participants) Non-Hispanic2711 (90.9)91.51.02.271 Hispanic180 (6.0)8.50.47<.0001 UnknowndIncident cases were not reported in North American Association of Central Cancer Registries for multiracial and unknown subgroups.90 (3.0)NANANAGender (204 trials with gender data, 8278 participants) Female3744 (45.2)48.40.93.001 Male4534 (54.8)51.41.07.0006NOTE. NA describes device or behavioral interventions that are not defined by the U.S. Food & Drug Administration.a Incident cases 2013–2017, age-adjusted to the 2000 US Standard Population.b Median EF of each individual trial with demographic data reported.c Wilcoxon rank sum tests determined distribution of EF ratios were different from 1.d Incident cases were not reported in North American Association of Central Cancer Registries for multiracial and unknown subgroups. Open table in a new tab NOTE. NA describes device or behavioral interventions that are not defined by the U.S. Food & Drug Administration. Additionally, nonwhite, Hispanic, and female patients with pancreatic cancer were under-represented across nearly all phases of clinical trials (Supplementary Table 2). In fact, when studies were limited to pancreatic cancer clinical trials in the United States, no black or American Indian/Alaskan Native patients were documented in phase III clinical trials and no Asian/Pacific Islander and American Indian/Alaskan Native patients were reported in phase IV clinical trials. Based on EF, nonwhite and Hispanic patients with pancreatic cancer were under-represented in clinical trials sponsored by universities and cancer centers, pharmaceutical and biotech companies, and the NCI (Supplementary Table 3). Female patients were also under-represented by all sponsor types except the NCI. Although progress was made in demographic reporting (Figure 1A), trends in participant racial and ethnic diversity remained relatively unchanged from 2008 to 2020 (Figure 1B and C). These data indicate that nonwhite, Hispanic, and female patients with pancreatic cancer continue to be disproportionately represented across pancreatic cancer clinical trials relative to the disease burden. This under-representation spans clinical phases and sponsors, and there has been no meaningful improvement in participant diversification in the last decade. The lack of diversity found in pancreatic cancer clinical trials is a salient example of broader disparities in diversity and inclusion found across clinical trials. Enrollment disparities in cancer clinical trials was first noted by Murthy et al10Murthy V.H. Krumholz H.M. Gross C.P. Participation in cancer clinical trials: race-, sex-, and age-based disparities.JAMA. 2004; 291: 2720-2726Crossref PubMed Scopus (1315) Google Scholar as they evaluated racial and ethnic representation in breast, colorectal, lung, and prostate cancer clinical trials from 2000 to 2002 within the NCI clinical trial cooperative group. They noted that racial and ethnic minorities, women, and the elderly were less likely to enroll in cancer clinical trials. Subsequently, Duma et al12Duma N. Vera Aguilera J. Paludo J. et al.Representation of minorities and women in oncology clinical trials: review of the past 14 years.J Oncol Pract. 2018; 14: e1-e10Crossref PubMed Scopus (83) Google Scholar explored racial, ethnic, and gender disparities in common cancer clinical trials and found a decrease in recruitment of minority patients from 2003 to 2016 as well as low recruitment of black, Hispanic, and female patients in cancer clinical trials. Further supporting these findings in a study focused on prostate cancer clinical trials, Rencsok et al13Rencsok E.M. Bazzi L.A. McKay R.R. et al.Diversity of enrollment in prostate cancer clinical trials: current status and future directions.Cancer Epidemiol Biomarkers Prev. 2020; 29: 1374-1380Crossref PubMed Scopus (15) Google Scholar found that most participants were white men. Moreover, African and Caribbean countries with predominantly black populations represented only 3% of prostate cancer clinical trials from 1987 to 2016.13Rencsok E.M. Bazzi L.A. McKay R.R. et al.Diversity of enrollment in prostate cancer clinical trials: current status and future directions.Cancer Epidemiol Biomarkers Prev. 2020; 29: 1374-1380Crossref PubMed Scopus (15) Google Scholar Under-representation of racial and ethnic minority populations has also been found in surgical oncology trials and clinical trials leading to FDA approval of oncology drugs.14Stewart J.H. Bertoni A.G. Staten J.L. et al.Participation in surgical oncology clinical trials: gender, race/ethnicity, and age-based disparities.Ann Surg Oncol. 2007; 14: 3328-3334Crossref PubMed Scopus (170) Google Scholar,15Loree J.M. Anand S. Dasari A. et al.Disparity of race reporting and representation in clinical trials leading to cancer drug approvals from 2008 to 2018.JAMA Oncol. 2019; 5e191870Crossref PubMed Scopus (88) Google Scholar Over the last 3 decades, federal initiatives have aimed to increase the accrual of racial/ethnic minority patients in clinical trials. In 1990 the Minority-Based Community Clinical Oncology Program was founded with the goal to increase the NCI’s clinical trial network to minority populations and to decrease racial/ethnic disparities.16McCaskill-Stevens W. McKinney M.M. Whitman C.G. et al.Increasing minority participation in cancer clinical trials: the minority-based community clinical oncology program experience.J Clin Oncol. 2005; 23: 5247-5254Crossref PubMed Scopus (61) Google Scholar Coupled with the National Institutes of Health Revitalization Act of 1993 and FDA Modernization Act of 1997, initial progress was made to improve the heterogeneity of clinical trial participants. Unfortunately, despite this early progress, national accrual of minority patients in clinical trials has remained poor over the last 2 decades.17Chen M.S. Lara P.N. Dang J.H. et al.Twenty years post-NIH Revitalization Act: enhancing minority participation in clinical trials (EMPaCT): laying the groundwork for improving minority clinical trial accrual: renewing the case for enhancing minority participation in cancer clinical trials.Cancer. 2014; 120: 1091-1096Crossref PubMed Scopus (180) Google Scholar Spurred by Section 907 of the FDA Safety and Innovation Act of 2012, the FDA has recently instituted multiple initiatives to improve the representation of racial and ethnic minorities in clinical trials. This includes the FDA’s Action Plan to enhance the collection and availability of demographic subgroup data.18U.S. Food & Drug AdministrationEnhancing the diversity of clinical trial populations—eligibility criteria, enrollment practices, and trial designs. Guidance for industry.https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enhancing-diversity-clinical-trial-populations-eligibility-criteria-enrollment-practices-and-trialGoogle Scholar Although the implementation of these initiatives has improved data collection and availability, the evidence provided in this study indicates that we are not only falling short of achieving representation, but that participant diversity has not improved. The challenges associated with improving clinical trial diversity are multifaceted and complex, although they may be simplified by categorization based on patients, providers, and systemic challenges. Historically, distrust has been quoted as a key challenge in the recruitment of minority patients in clinical trials. This distrust has been attributed to the historic atrocities and exploitation of minority populations, particularly the Tuskegee Syphilis Study in which black men were unknowingly given syphilis and treatment was withheld.19Hamel L.M. Penner L.A. Albrecht T.L. et al.Barriers to clinical trial enrollment in racial and ethnic minority patients with cancer.Cancer Control. 2016; 23: 327-337Crossref PubMed Scopus (125) Google Scholar Despite this rightful distrust of the medical system, black and Hispanic patients are in actuality equally as willing as white patients to participate in clinical trials.20Wendler D. Kington R. Madans J. et al.Are racial and ethnic minorities less willing to participate in health research?.PLoS Med. 2006; 3: e19Crossref PubMed Scopus (518) Google Scholar Factors that disproportionally impact minority populations such as poor health literacy, low socioeconomic status, and access to care also largely affect willingness or ability to enroll in a clinical trial.21Clark L.T. Watkins L. Piña I.L. et al.Increasing diversity in clinical trials: overcoming critical barriers.Curr Probl Cardiol. 2019; 44: 148-172Crossref PubMed Scopus (89) Google Scholar Although much emphasis has been placed on overcoming patient factors, the literature suggests that physician bias, false perceptions, and prejudices may influence participation in clinical trials. In a study by van Ryn and Burke,22van Ryn M. Burke J. The effect of patient race and socio-economic status on physicians' perceptions of patients.Soc Sci Med. 2000; 50: 813-828Crossref PubMed Scopus (938) Google Scholar physicians were more likely to believe that black patients are less intelligent and less likely to comply with medical treatment. As a result, physicians do not recommend clinical trials to minority patients because of concerns for compliance with trial protocols. Notably, racial/ethnic disparities are negated when patients are given equal opportunity or explicitly offered participation in a clinical trial.23Kehl K.L. Arora N.K. Schrag D. et al.Discussions about clinical trials among patients with newly diagnosed lung and colorectal cancer.J Natl Cancer Inst. 2014; 106: dju216Crossref Scopus (6) Google Scholar Moreover, only 2.3% of practicing oncologists are black or African American and only 5.8% of practicing oncologists are Hispanic, likely largely impacting trial referral practices and patient trust.24American Society of Clinical OncologyFacts & figures: diversity in oncology.https://www.asco.org/news-initiatives/current-initiatives/diversity-oncology-initiative/facts-figuresGoogle Scholar Systemic barriers in clinical trial design and infrastructure also may limit minority patient participation. These include limited number of trials and resources, poor community engagement, and strict trial eligibility criteria. Patients of racial and ethnic minority backgrounds are also more likely to receive care at institutions with insufficient resources.21Clark L.T. Watkins L. Piña I.L. et al.Increasing diversity in clinical trials: overcoming critical barriers.Curr Probl Cardiol. 2019; 44: 148-172Crossref PubMed Scopus (89) Google Scholar Additionally, strict eligibility criteria often exclude many minority patients interested in participating in clinical trials. In a study by Adams-Campbell et al,25Adams-Campbell L.L. Ahaghotu C. Gaskins M. et al.Enrollment of African Americans onto clinical treatment trials: study design barriers.J Clin Oncol. 2004; 22: 730-734Crossref PubMed Scopus (139) Google Scholar most black patients were rendered ineligible for clinical trials secondary to medical morbidities. In the face of these challenges, it is imperative to equitably include racial and ethnic minorities in clinical trials. Emphasis on improved communication, trust, and education between both patients and providers is critical. If clinical trials do not reflect the patient population they serve, disparities in treatment and outcomes will be perpetuated. The inclusion of racial and ethnic minority populations in pancreatic cancer clinical trials will take concerted and intentional efforts toward diversification. This study has several limitations that warrant further discussion. The exclusion of trials including other cancer types and pancreatic pathologies may underestimate the number of patients with pancreatic cancer who participated in disease-agnostic phase I and II clinical trials. Additionally, including only studies within the United States may limit the number of phase III and phase IV clinical trials captured as well as global generalizability. These latter limitations allow for us to offer a more focused assessment relative to US minority patient participation in US-based pancreatic cancer clinical trials. Within the North American Association of Central Cancer Registries database, race is characterized as white, black, Asian/Pacific Islander, and American Indian/Alaska Native. The assumption that participants are siloed neatly into each demographic category may be an overgeneralization of the true diversity of the US population. Despite these limitations, these data suggest that although demographic reporting has improved over time, the diversity of clinical trial participants is disproportionate to the disease burden of pancreatic cancer. These findings emphasize the persistent trend of under-representation of racial and ethnic minority patients in pancreatic cancer clinical trials. Representation of minority patients in pancreatic cancer clinical trials is a critical link between oncologic innovation and patient outcomes. Although prior initiatives have experienced varying levels of success, we propose that future interventions will need to be implemented on multiple levels to effectively include minority populations in pancreatic cancer clinical trials. To improve the diversity of pancreatic cancer clinical trials, we propose the following potential next steps:•Promotion of inclusivity through the re-evaluation of strict eligibility criteria, particularly those that disproportionally exclude patients from racial and ethnic minority backgrounds.•Clinical trial accountability from sponsor organizations to support the inclusion of a diverse patient population.•Improved diversity of both providers and coordinators conducting pancreatic cancer clinical trials.•Creation of pancreatic cancer clinical trial environments that are free of both explicit and implicit bias through dedicated workforce training.•Conduction of pancreatic cancer clinical trials in locations that are accessible to racially and ethnically diverse patient populations.•Continued efforts toward patient advocacy and public policy to promote future change in the diversity and inclusion of pancreatic cancer clinical trials.