In this article, we discuss why participation in clinical trials in the community oncology setting is often inadequate, how this affects cancer research, and the ways to close this gap.
Click here to read an expert perspective from Stephanie L. Graff, MD.
Participation in cancer clinical trials provides patients access to the latest, most promising investigational interventions, as well as close monitoring of care. However, only 3% to 5% of eligible adult cancer patients are enrolled in clinical trials. This results in delays in the progress of cancer research, as well as increased costs for improving and disseminating effective cancer treatments. The reasons for low rates of clinical trial participation are numerous. Trials may not be available to those willing to participate; when they are available, patients are often excluded because they do not meet trial eligibility criteria.[2-4] In the United States, available data on the demographics of oncology patients participating in clinical trials show that those who do enroll are more likely to be younger, male, and Caucasian, and to have later-stage cancer, compared with those not enrolled in trials.[5-8] These trends are also true of clinical trials conducted in other countries.
Cancer-related clinical research and clinical trials have traditionally been conducted at well-established academic medical centers, while 85% of cancer patients are diagnosed and treated at local, community-based clinical practices. Therefore, community-based cancer research is critical in advancing cancer care for the large, diverse patient population that receives treatment in a variety of local healthcare delivery settings. In addition, participation of community oncologists and primary care physicians in cancer prevention, control, and treatment trials significantly helps facilitate the translation of research advances into practice.
For the last 4 decades, the National Cancer Institute (NCI) has acknowledged the importance of community-based oncology research through several initiatives and programs for community practices. Historically, the significance of community-based research was solidified in 1982, when the NCI initiated the CCOP. This collaborative partnership between research institutions and community-based physicians helped to facilitate phase III cancer prevention, control, and treatment trials in the community-based practice setting. The CCOP was designed to disseminate and implement advances in cancer care by linking cancer investigators and academic centers to community-based practices, thus expanding access to clinical trials and promoting cancer treatment innovations within the community populations that otherwise might not have had access.
Despite these efforts, community-based cancer research continued to face challenges as a result of the era of emerging science, technology, genomics, and molecular-targeted therapy, as well as a rapidly changing healthcare environment. In 2007, the NCI further expanded its community-targeted efforts by launching the NCCCP, a public–private partnership with 21 community hospitals in 16 states. The goals of the NCCCP were to enhance access to and improve the quality of cancer care by expanding the infrastructure to support a platform for basic, clinical, and population-based research, as well as informatics, biospecimen collection, and cancer care disparities in community hospitals. Self-reported data collected at NCCCP sites between 2007 and 2010, supplemented with data from the NCI Cancer Therapy Evaluation Program, showed that the availability of phase III trials and patient accrual increased by 16% and 133%, respectively, at NCCCP sites, compared with 8% and 30% nationally. In addition, enrollment of racial and ethnic minorities in oncology trials increased by 82%, from 83 to 151 patients; the accrual of patients aged 65 years or older in oncology trials also rose by 221%, from 200 to 641 patients. The exact changes in trial portfolios and accrual differed by sophistication of the site and by prior experience conducting clinical trials at the site.
In 2014, the NCI initiated a new community-based program, the NCORP, to align with and replace the CCOP and NCCCP programs. The goals of the NCORP are to support clinical trials on cancer control, prevention, treatment, and screening in the community setting, as well as to expand the scope of research to include cancer care delivery. The NCORP initiative emerged around the same time as two other significant changes: 1) the transformation and condensing of nine longstanding NCI Cooperative Group programs into four new groups under the National Clinical Trials Network, and 2) the implementation of the NCI Central Institutional Review Board. Both of these changes helped to provide easier access to all NCI Cooperative Group clinical trials with some reduced regulatory burden. In a study conducted at St. Francis Cancer Treatment Center in Grand Island, Nebraska, we found that participation in both NCI programs, NCCCP and NCORP, positively impacted clinical trial–related activities and expanded research, with enhanced access to quality cancer care. In addition, NCORP provided a robust Cooperative Group trial linkage, resulting in a record-high clinical trial portfolio.
Funding is one of the largest challenges facing Cooperative Group clinical trials. Namely, there has been a growing discrepancy between the actual cost of Cooperative Group trials compared with the amount of funding received from the NCI. In addition, the routine per-case reimbursement for Cooperative Group trials has remained stagnant at around $2,000, despite an increase seen in the actual cost over time to approximately $6,000. In a 2010 American Society of Clinical Oncology (ASCO) survey of 500 clinical trial sites, 33% indicated that they planned to limit their involvement in Cooperative Group trials, and 75% cited inadequate funding as a reason for doing so. To address these concerns, the NCORP intends to award $74.5 million of funding in fiscal year 2019 to be used for up to seven 6-year research projects. While application budgets are unlimited, the focus should reflect the needs of diverse patients in a variety of community oncology settings, including rigorous studies on cancer prevention, control, screening, care delivery, and quality of life.
As strong and, to some extent, as successful as these NCI programs have been, the national clinical trial participation rate of 3% to 5% remains unchanged, with mounting barriers to enrollment. In addition to regulatory and bureaucratic requirements, administrative, financial, and organizational challenges beyond the control of participating hospitals and clinicians impede clinical trial participation nationally. Barriers to clinical trial participation have also been classified as structural, clinical, and attitudinal, with some differentiation according to demographic and socioeconomic factors.
In an era of increasing emphasis on shared decision making, the opportunity for patients to choose to participate in a clinical trial would be of great significance.[18,19] However, several disparities exist between trials in oncology vs other medical specialties. Hirsch et al reported on the 40,970 studies registered with ClinicalTrials.gov and found that oncology trials comprise 21.8% of all trials, followed by trials focusing on mental health (9.0%), infectious disease (8.3%), diabetes mellitus (6.1%), and cardiology (5.7%). Oncology studies were significantly more likely to be single-arm, open-label, and non-randomized. In addition, oncology trials were smaller compared with other specialties, with a median patient accrual of 51 vs 72 in other disease states. Early-phase trials were also more common in oncology. Further comparisons between trials in oncology vs other medical specialties have found that oncology trials are more likely to have ongoing recruitment and are less likely to report completion of trials.
Among all stakeholders-including healthcare providers, patients, advocacy groups, institutions, and third-party payers-there exists a lack of awareness about and accurate understanding of clinical trials, including the critical need for them in the community setting. Prior research focusing on efforts to diffuse and implement innovations in health services has consistently shown that three inter-
related, critical factors promote behavioral change: awareness, commitment, and champions. While awareness among community-based healthcare providers, patients, and institutions is critical in increasing clinical trial enrollment, it is largely lacking. A study evaluating the challenges and facilitators of CCOP participation found that awareness is potentially linked to the other two facilitators of change, commitment and champions. Specifically, emphasizing and building awareness can help create new champions, while enhancing commitment to clinical trial participation.
For healthcare providers, clinical trial awareness should start in the curricula of medical schools, nursing schools, and other healthcare provider training schools, and it should extend into postgraduate schools, fellowship trainings, specialty board certifications, and maintenance of certification processes. In community settings with an active clinical trials program, good infrastructure, and widespread access to clinical trials for providers and patients, considerable variability in clinical trial enrollment rates exists between oncology providers at the same practice. Values, attitudes, beliefs, training, and awareness strongly influence clinicians’ willingness to take advantage of available resources and to enroll large numbers of patients. It is possible that poor patient accrual stems from a lack of provider motivation to utilize existing resources, as well as a lack of genuine awareness of the significance of clinical trials. This may also be the case for some investigators in the academic setting. Fenton et al surveyed oncologists about their awareness of and attitudes toward clinical trials; 50% indicated that they are aware of all (7%) or most (43%) clinical trials of new agents in their geographic area. However, many oncologists noted that they are unable to closely follow the existence and findings of ongoing clinical trials due to time constraints.
Awareness should also extend to patients, institutions, advocacy groups, third-party payers, and professional societies. Fifty-eight percent of Americans believe clinical trials are of great value, and an additional 38% believe they are of some value. Recently, many well-established medical centers and pharmaceutical industry stakeholders have adopted a direct-to-consumer advertising approach to clinical trials, mostly for those promoting a particular drug. At the same time, the lack of awareness about and promotion of the many high-quality, wide-spectrum NCI Cooperative Group clinical trials still remains. The NCI Cooperative Group and professional society websites do offer some useful information about these clinical trials. However, this web-based approach and other indirect approaches to raising awareness about clinical trials do not match the high impact of direct-to-consumer advertisements of clinical trials by industry and established medical centers.
Finally, the collaborative engagement of relevant professional medical societies in promoting community-based research may be very productive. The best example of this is ASCO’s Research Community Forum (RCF), a solution-oriented venue for research sites to overcome barriers to conducting clinical trials. ASCO-RCF’s key objective is to convene researchers to identify challenges in conducting research, with the intention of developing solutions and facilitating clinical trial participation, particularly in community research settings.
The expansion of cancer research via high-quality NCI Cooperative Group clinical trials in communities in which the majority of cancer patients live remains elusive. However, the continued efforts from the NCI, ASCO, and other stakeholders are encouraging, as is the progress made by a number of high-performing community clinical trial sites that have found ways to improve the incredibly low rate of clinical trial participation in the community setting.[24,25] Actualizing such an investment in community-based research will help to advance cancer research and ensure that the majority of patients with cancer have access to important advances in cancer care.
Note:This article is the first in a series of discussions in which thought leaders from various industries will share perspectives on barriers to participation in cancer clinical trials.
Financial Disclosure:Dr. Copur has no financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Cost Barriers and Beyond
Stephanie L. Graff, MD
It is time we move away from the barriers to clinical trials in the community setting. There is a large disconnect between the 85% of cancer patients treated in the community and the 3% to 5% of patients enrolled in clinical trials. Fortunately, the American Society of Clinical Oncology, Friends of Cancer Research, and the US Food and Drug Administration have been working to broaden eligibility criteria, which represent one of the most significant limitations in clinical trial accruals. Other broader issues will require collaborative solutions for increased participation and improved awareness. Outside the scope of this perspective is the unanswered question of what percentage of patients need to be treated on trial to optimize patient care and scientific advancement, without redundancy or wasted resources.
While Dr. Copur highlights the financial burden community cancer centers must endure to have a robust clinical research program, patients, too, are asked to carry a heavy financial burden. At my own Midwestern community practice, patients often drive 2 to 3 hours to receive care. The time off work, resultant job insecurity, and reduction in pay, paired with the extra gasoline expense for simple services like routine bloodwork, are no small burden. Over half of cancer patients accrue more than $10,000 in debt, and 3% file for bankruptcy. We need to be finding ways to incorporate telehealth, decentralized labs, and mail delivery for oral drugs to help improve access for all patients, regardless of geography.
Raising awareness of clinical trials is also crucial. It is all too common for patients to believe that clinical trials are no more than a last resort. I would love to see television and movies portray cancer patients participating in clinical trials as commonplace, or ads celebrating the patient volunteers whose clinical trial participation brought a new drug to market. Given the brisk pace of clinical research in oncology and the ability of social media to bring together physicians and patients, every trial should come paired with social media–friendly promotional materials for physicians, health systems, cooperative groups, and advocacy organizations to broadly share. This low-cost solution could increase reach and raise awareness across patients and physicians. Patient-centered language could make social media campaigns more useable than national clinical trial databases like ClinicalTrials.gov, which can be overwhelming even to experienced clinicians and advocates.
Given the adage “the best care for any patient is within a trial,” we need to broadly incorporate that message to normalize clinical trial participation. The oncology community should continue to utilize emerging technology to broadly identify patients for treatment on trial, while tearing down common barriers. I hope robust national discussion fostered in part by the Beau Biden Cancer Moonshot Initiative continues and includes the voice of valued community oncology partners in bringing the best care directly to patients.
Financial Disclosure:Dr. Graff receives research funding from Boehringer Ingelheim, Celldex Therapeutics, Dana-Farber Cancer Institute, Genentech, GRAIL, Immunomedics, Innocrin Pharmaceuticals, Lilly, Merus NV, Novartis, Odonate Therapeutics, and TapImmune.
Dr. Graff is Director of the Breast Program at the Sarah Cannon Cancer Institute HCA Midwest Health, and Associate Director of the Breast Cancer Research Program at Sarah Cannon Research Institute, Kansas City, Missouri.
1. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA. 2004;291:2720-6.
2. Ford JG, Howerton MW, Lai GY, et al. Barriers to recruiting underrepresented populations to cancer clinical trials: a systematic review. Cancer. 2008;112:228-42.
3. Ross S, Grant A, Counsell C, et al. Barriers to participation in randomised controlled trials: a systematic review. J Clin Epidemiol. 1999;52:1143-56.
4. Unger JM, Green S, Albain KS. Under-representation of elderly patients in cancer clinical trials: causes and remedial strategies. In: Balducci L, Lyman GH, Ershler WB, Extermann M, editors. Comprehensive Geriatric Oncology. 2nd ed. New York and London: Taylor & Francis; 2004. p. 464-91.
5. Hunter CP, Frelick RW, Feldman AR, et al. Selection factors in clinical trials: results from the Community Clinical Oncology Program Physician’s Patient Log. Cancer Treat Rep. 1987;71:559-65.
6. Javid SH, Unger JM, Gralow JR, et al. A prospective analysis of the influence of older age on physician and patient decision-making when considering enrollment in breast cancer clinical trials (SWOG S0316). Oncologist. 2012;17:1180-90.
7. Klabunde CN, Springer BC, Butler B, et al. Factors influencing enrollment in clinical trials for cancer treatment. South Med J. 1999;92:1189-93.
8. Unger JM, Barlow WE, Martin DP et al. Comparison of survival outcomes among cancer patients treated in and out of clinical trials. J Natl Cancer Inst. 2014;106:dju002.
9. U.S. Food and Drug Administration. 2015-2016 global participation in clinical trials report. July 2017. https://www.fda.gov/downloads/Drugs/InformationOnDrugs/UCM570195.pdf. Accessed January 24, 2019.
10. Minasian LM, Carpenter WR, Weiner BJ, et al. Translating research into evidence-based practice: the National Cancer Institute Community Clinical Oncology Program. Cancer. 2010;116:4440-9.
11. Clauser SB, Johnson MR, O’Brien DM, et al. Improving clinical research and cancer care delivery in community settings: evaluating the NCI community cancer centers program. Implement Sci. 2009;4:63.
12. Hirsch BR, Locke SC, Abernethy AP. Experience of the National Cancer Institute Community Cancer Centers Program on Community-Based Cancer Clinical Trials Activity. J Oncol Pract. 2016;12:e350-8.
13. Copur MS, Gulzow M, Zhou Y, et al. Impact of National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) and NCI Community Oncology Research Program (NCORP) on clinical trial (CT) activities in a community cancer center. J Clin Oncol. Published online June 1, 2018.
14. Dilts DM. Robbing peter to pay paul: financing clinical trial follow-up. J Clin Oncol. 2012;30:1404-5.
15. Baer AR, Kelly CA, Bruinooge SS, et al. Challenges to National Cancer Institute-supported cooperative group clinical trial participation: an ASCO survey of cooperative group sites. J Oncol Pract. 2010;6:114-7.
16. National Cancer Institute Community Oncology Research Program (NCORP) Program Guidelines. https://ncorp.cancer.gov/resources/faqs.html. Revised May 2018. Accessed January 28, 2019.
17. Vose JM, Levit LA, Hurley P, et al. Addressing administrative and regulatory burden in cancer clinical trials: summary of a stakeholder survey and workshop hosted by the American Society of Clinical Oncology and the Association of American Cancer Institutes. J Clin Oncol. 2016;34:3796-3802.
18. Unger JM, Cook E, Tai E, et al. Role of clinical trial participation in cancer research: barriers, evidence, and strategies. Am Soc Clin Oncol Educ Book. 2016;35:185-98.
19. American Cancer Society Cancer Action Network. Barriers to patient enrollment in therapeutic clinical trials for cancer. https://www.fightcancer.org/policy-resources/clinical-trial-barriers. Published April 11, 2018. Accessed January 24, 2019.
20. Hirsch BR, Califf RM, Cheng SK, et al. Characteristics of oncology clinical trials: insights from a systematic analysis of ClinicalTrials.gov. JAMA Intern Med. 2013;173:972-9.
21. McAlearney AS, Reiter KL, Weiner BJ, et al. Challenges and facilitators of community clinical oncology program participation: a qualitative study. J Healthc Manag. 2013;58: 29-44; discussion 45-6.
22. Somkin CP, Ackerson L, Husson G, et al. Effect of medical oncologists' attitudes on accrual to clinical trials in a community setting. J Oncol Pract. 2013;9:e275-83.
23. Fenton L, Rigney M, Herbst RS. Clinical trial awareness, attitudes, and participation among patients with cancer and oncologists. Community Oncol. 2009;6:207-13, 228.
24. Copur MS, Ramaekers R, Gonen M, et al. Impact of the National Cancer Institute Community Cancer Centers Program on clinical trial and related activities at a community cancer center in rural Nebraska. J Oncol Pract. 2016;12:67-8, e44-51.
25. Freedman DH. Clinical trials have the best medicine but do not enroll the patients who need it. Sci Am. 2019;320:61-5.