Table 1.

Barriers to enrollment in clinical trials

Provider barriers
System-related barriers
Unger, 2019⁵	Systematic review and meta-analysis including 13 studies (9 in academic and 4 in community settings) with 8883 patients	55.6% (95%CI], 3.7-67.3%) - trial unavailable at patient’s institution 21.5% (95%CI, 10.9-34.6%) - ineligible for available trial 14.8% (95%CI 9.0-21.7%) eligible but did not enroll 8.1% (95%CI, 6.3-10.0%) eligible and enrolled	Structural and clinical factors are reasons more than ¾ of patients with diagnosis of cancer (77.1%) did not participate in clinical trials - 55.6% because not available and 21.5% ineligible for available Rates of trial enrollment differed between academic and community settings, but not rates of trial unavailability, ineligibility, or non-enrollment Need to address structural and clinical barriers to trial participation, which combined make trial participation unachievable for more than three of four cancer patients.
Unger, 2019⁵		Rates of trial enrollment in academic settings = 15.9% [95%CI, 13.8-18.2%] Rates of trial enrollment in community settings = 7.0% [95%CI, 5.1-9.1%] – p <0.001 compared to academic center
Hamel, 2016⁸	Used a multilevel model as a framework to identify potential barriers to trial enrollment of racial and ethnic minorities at system, individual, and interpersonal levels Reviewed exactly how each level directly or indirectly contributes to doctor-patient communication	Barriers at the level of health care systems and hospitals include limited number of available trials hospital infrastructures that lack resources to support trials; financial costs to hospitals; and restrictive study designs and eligibility criteria Health care professionals may not fully agree with or understand the scientific value of trials in general or the details of specific trials Some clinicians find it difficult to reconcile roles of physician and researcher, or are concerned about unduly influencing patient decisions about enrolling	Barriers to enrolling a diverse population of patients in clinical trials are complex and multilevel Interventions focused on each level have been relatively successful, but multilevel interventions have the greatest potential for success Interventions to increase enrollment of racial and ethnic minorities in clinical trials, should address barriers at multiple levels Many barriers have disproportionate effect on minority enrollment because they receive care at under-resourced hospital systems
Provider attitudes
Hamel, 2016⁸	Used a multilevel model as a framework to identify potential barriers to trial enrollment of racial and ethnic minorities at system, individual, and interpersonal levels	Attitudes of health care professionals about trials and discussing such trials can affect quality of communication during discussions of clinical trials and impact recruitment Health care professionals may not fully agree with/understand scientific value of trials in general or the details of specific trials, or may have concerns about practical issues such as strict protocol designs, patient inconvenience, and added work for the health care staff Some attitudinal factors are specific to enrollment of minority patients, such as concern about harming the therapeutic relationship Conscious and unconscious implicit biases toward members of minority groups have an impact on clinical interactions with minority patients In one study¹⁰ as few as 20% of physicians and staff in one study agreed that clinical trials absolutely provide the best treatment available, and only 44% agreed benefits of clinical trial participation outweighed risks or harms. However, 57% felt participation in a clinical trial helps a patient be more in control of their disease and treatment	Physician bias and its impact on decision to offer a clinical trial all impact enrollment but has not been fully investigated. Differences in attitudes between providers and patients are important to understand in order to focus future initiatives to raise awareness about in congruency between each group and reduce implicit biases
Ibraheem, 2017⁹	Insight from Experts
Hillyer, 2020¹⁰	Online survey of physicians and research staff involved in clinical research at a comprehensive cancer center and interviews of adult cancer patients not currently enrolled in a trial
Patient Level Barriers
Mills, 2006¹⁹	Systematic review to assess studies and estimated the frequency with which patients identified particular issues as barriers to participation in experimental and randomized trials	Analyzed 12 qualitative (n=722) and 21 quantitative (n=5452) studies. Most common barriers included: Concerns with the trial setting Dislike of randomization General discomfort with research process Complexity and stringency of protocol Presence of placebo or no-treatment group Potential side-effects Unaware of trial opportunities Idea clinical trials not appropriate for serious diseases Fear trial involvement would have negative effect on relationship with physician Physician’s attitudes towards trial Meta-analysis confirmed the findings of our systematic review	Identified barriers to participation in clinical trials should help trialists develop strategies to attain maximum participation and cooperation in cancer trials, while informing and protecting participants
Ford, 2008¹⁵	Systematic review to determine barriers to participation of underrepresented populations in cancer-related trials 5257 studies cited; 65 eligible for inclusion Trials included: recruitment into cancer therapeutic trials (n=46), prevention trials (n=15), and both prevention and treatment trials (n=4)	Numerous factors reported as barriers to participation in cancer-related trials. Only 20 studies reported statistically significant associations between hypothesized barriers and enrollment. Most articles reported an association between specific sociodemographic characteristics, such as older age, socioeconomic status, and racial/ethnic minority status, along with lack/inadequate health insurance and reduced enrollment Additional opportunity barriers include study design, namely, comorbid conditions and age-based exclusion, lack of provider referral, and the extent of managed care competition	Underrepresented populations face numerous barriers to participation in cancer-related Racial and ethnic minorities, older adults, rural residents, and individuals of low socioeconomic status are underrepresented among participants in cancer-related trials.
Meropol, 2007¹⁸	Survey distributed to all medical oncologists in Pennsylvania and a subset of their patients to assess relevant background information and practical and psychosocial barriers to clinical trial participation	137 oncologists and 170 patients completed the surveys, 84% of patients aware of clinical trials Oncologists and patients generally agreed clinical trials important to improving cancer treatment. However, oncologists and patients more likely to consider clinical trials in advanced or refractory disease Random assignment and fear of receiving a placebo were ranked highly by both patients and oncologists as a barrier. Patients identified fear of side effects as the greatest barrier to clinical trial participation, whereas oncologists ranked this psychosocial barrier as least important to their patients	Although oncologists and patients aware of clinical trials and have favorable attitudes, psychosocial barriers exist for patients that may impact participation in clinical trials Important discrepancies exist between perceptions of oncologists and patients regarding psychosocial barriers To optimize trial participation, need to characterize barriers perceived by oncologists and patients to help improve communication and decision making about enrollment
Unger, 2019²⁰	5499 patients with a diagnosis of breast, lung, colorectal, or prostate cancer who made a treatment decision within the previous 3 months completed a national survey embedded within a web-based cancer treatment-decision tool accessible on multiple cancer-oriented websites	3420/5499 (62.6%) women and 2079/5499 (37.8%) were 3610/5499 (65.6%) ≥1 comorbidity Compared with the absence of comorbidities, ≥1 comorbidity associated with decreased risk of: Trial discussions (44.1% vs 37.2%; OR, 0.86; 95%CI, 0.75-0.97; P = .02) Trial offers (21.7% vs 15.7%; OR, 0.82; 95%CI, 0.70-0.96; P = .02). Trial participation (11.3% vs 7.8%; OR, 0.76; 95%CI, 0.61-0.94; P = .01)	Independent of sociodemographic variables, the presence of comorbidities is adversely associated with trial discussions, trial offers, and trial participation itself. Updating trial eligibility criteria could lead to several thousand more patients with well-managed comorbidities participating in clinical trials each year
Hamel, 2016⁸	Used a multilevel model as a framework to identify potential barriers to trial enrollment of racial and ethnic minorities at system, individual, and interpersonal levels	Lack of transportation, inadequate insurance, lack of childcare, and poor access to health care amongst patient-level barriers to the enrollment of racial and ethnic minorities in clinical trials	Future interventions haver to address barriers at multiple levels
Unger, 2013¹¹	Internet-based treatment decision tool used to assess clinical trial participation patterns according to important income, education and demographic factors	In univariate models, older patients (P = .002) and patients with lower income (P = .001) and education (P = .02) were less likely to participate in clinical trials. In a multivariable model, income remained a statistically significant predictor of clinical trial participation (OR, 0.73; 95%CI 0.57-0.94; P = .01) Even in patients age ≥65 years, with access to Medicare, lower income predicted lower trial participation. Cost concerns much more evident among lower-income patients (P < .001)	Lower-income patients were less likely to participate in clinical trials, even when considering age group A better understanding of why income is a barrier may help identify ways to make clinical trials better available to all patients and would increase the generalizability of clinical trial results across all income levels.
Gross, 2005¹²	Case-control study comparing women ≥65 who were participants in National Cancer Institute cooperative group breast cancer trials (cases) with a population-based sample of breast cancer patients (controls) obtained from the linked SEER Medicare database	Trial participants significantly less likely than community cancer patients to reside in high-poverty zip codes (20.9% vs. 24.9%, respectively; P<0.001) or to have Medicaid insurance (2.0% vs. 10.0%; P<.0001). After adjusting for race, age, and county, trial participation remained inversely related to Residing in areas with high poverty (OR vs. residents of remaining counties, 0.78; 95%CI, 0.62-0.98) High unemployment rates (OR vs. residents of residents of counties in the lowest quartile, 0.50; 95%CI, 0.35-0.71) Having Medicaid insurance (OR vs. women without Medicaid, 0.22; 95%CI 0.13-0.37) Black race was not found to be related to trial participation (OR for black vs. white, 1.0; 95% CI, 0.67-1.47)	Low socioeconomic status was associated inversely with trial enrollment for older women with breast cancer and appeared to account for the enrollment disparities between black patients and white patients.
Avin, 2017¹³	Opinion	While the NIH Revitalization Act in 1993 requires that medical research paid for by the NIH include women and minorities, it does not provide adequate instruction on minority enrollment. Only ~6% of clinical trials in the US are funded by the NIH, so that majority of trials do not abide by this requirement	Additional financial barriers also exist, including transportation and/or lodging costs, and limited sick leave. Minority patients may have less access to clinical trials, as minorities are more likely to rely on under-resourced hospitals for care
Williams, 2018¹⁴	Opinion	Logistics can include issues surrounding costs associated with participation, transportation, and convenience	Possible solutions to issues concerning cost include ensuring studies are appropriately budgeted to account for time and commitment expectations and providing travel or meal vouchers that may ease the financial burden
Byrne, 2014¹⁶	1100 White, Hispanic, and Black participants with a diagnosis of breast, lung, colorectal, or prostate cancer were obtained through the Florida cancer registry. Participants were surveyed via telephone to obtain demographic information, past participation, and willingness to participate in clinical trials, as well as barriers and facilitators to participation.	36.5% were willing to participate in a clinical trial In multivariate models, blacks and Hispanics equally willing as whites to participate in cancer trials, but Hispanics less likely to have participated, especially non-English-speaking Hispanics compared with English-speaking Hispanics Notable barriers across race/ethnicity were mistrust and lack of knowledge of clinical trials. There were racial differences in participation rates but not in willingness to participate	36.5% willingness to participate rate not very high felt to be due to being uninformed about participating, particularly in non-English-speaking Hispanics. Barriers and facilitators to participation vary by race. Improved understanding of cultural differences that can be addressed by physicians may restore faith, comprehension, and acceptability of clinical trials by all patients.
BeLue, 2006²¹	African American participated in focus groups by gender All focus groups were audio-taped and transcribed verbatim	Different themes emerged for men versus women: Men desired to know information on funding issues, financial benefit and impact of the research Women desired to be treated respectfully and as an individual as opposed to just a study subject Researcher-participant relationship one of strongest themes related to potential female participation	African American men and women present different preferences, beliefs and barriers to participation Integrating gender preferences into researcher-participant interactions, advertisement, informed consent delivery and advertisement of research studies may lead to increased participation rates Discussing and presenting relevant information on clinical research funding mechanisms, and the business of clinical research with potential participants may be helpful in building trust Creating a process for information exchange and minimizing power imbalance between the researcher and participant may build trust

Abbreviations: CI, confidence interval; OR, odds ratio; SEER, Surveillance, Epidemiology, and End Results