Barriers to participation in clinical trials of cancer: a meta-analysis and systematic review of patient-reported factors

BACKGROUND: Enrolling participants onto clinical trials of cancer presents an important challenge. We aimed to identify the concerns of patients with cancer about, and the barriers to, participation in clinical trials. METHODS: We did a systematic review to assess studies of barriers to participation in experimental trials and randomised trials for validity and content. We estimated the frequency with which patients identified particular issues by pooling across studies that presented data for barriers to participation in clinical trials as proportions. FINDINGS: We analysed 12 qualitative studies (n=722) and 21 quantitative studies (n=5452). Two qualitative studies inquired of patients who were currently enrolled onto clinical trials, and ten inquired of patients who were eligible for enrolment onto various clinical trials. Barriers to participation in clinical trials were protocol-related, patient-related, or physician-related. The most common reasons cited as barriers included: concerns with the trial setting; a dislike of randomisation; general discomfort with the research process; complexity and stringency of the protocol; presence of a placebo or no-treatment group; potential side-effects; being unaware of trial opportunities; the idea that clinical trials are not appropriate for serious diseases; fear that trial involvement would have a negative effect on the relationship with their physician; and their physician's attitudes towards the trial. Meta-analysis confirmed the findings of our systematic review. INTERPRETATION: The identification of such barriers to the participation in clinical trials should help trialists to develop strategies that will keep to a maximum participation and cooperation in cancer trials, while informing and protecting prospective participants adequately.     

Barriers to clinical trial participation as perceived by oncologists and patients

Although clinical trial research is required for the development of improved treatment strategies, very few cancer patients participate in these studies. The purpose of this study was to describe psychosocial barriers to clinical trial participation among oncologists and their cancer patients. A survey was distributed to all medical oncologists in Pennsylvania and a subset of their patients. Relevant background information and assessment of practical and psychosocial barriers to clinical trial participation were assessed. Among 137 oncologists and 170 patients who completed the surveys, 84% of patients were aware of clinical trials, and oncologists and patients generally agreed that clinical trials are important to improving cancer treatment. However, oncologists and patients were more likely to consider clinical trials in advanced or refractory disease. When considering 7 potential barriers to clinical trials, random assignment and fear of receiving a placebo were ranked highly by both patients and oncologists. 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. Overall, the study found that although oncologists and patients are aware of clinical trials and have favorable attitudes toward them, psychosocial barriers exist for patients that may impact participation in clinical trials. Furthermore, important discrepancies exist between the perceptions of oncologists and those of patients regarding what the psychosocial barriers are. We concluded that characterizing oncologist and patient perceived barriers can help improve communication and decision making about clinical trials, such that participation may be optimized.     

Barriers to recruiting underrepresented populations to cancer clinical trials: a systematic review

Racial and ethnic minorities, older adults, rural residents, and individuals of low socioeconomic status are underrepresented among participants in cancer-related trials. The authors conducted a systematic review to determine the barriers to participation of underrepresented populations in cancer-related trials. Their search included English-language publications that reported original data on the recruitment of underrepresented groups to cancer treatment or prevention trials between 1966 and December 2005 in multiple electronic databases. They also hand-searched titles in 34 journals from January 2003 to December 2005 and they examined reference lists for eligible articles. Titles and abstracts were reviewed to identify relevant studies. Data on barriers to participation were synthesized both qualitatively and based on statistically significant associations with trial enrollment. Of 5257 studies that were cited, 65 studies were eligible for inclusion in the current analysis, including 46 studies on recruitment into cancer therapeutic trials, 15 studies on recruitment into prevention trials, and 4 studies on recruitment into both prevention and treatment trials. Numerous factors were reported as barriers to participation in cancer-related trials. However, only 20 of the studies reported statistically significant associations between hypothesized barriers and enrollment. The available evidence had limitations in quality regarding representativeness, justification of study methods, the reliability and validity of data-collection methods, potential for bias, and data analysis. The results indicated that underrepresented populations face numerous barriers to participation in cancer-related trials. The current systematic review highlighting the literature on recruitment of underrepresented populations to cancer trials and may be used as the evidence base toward developing an agenda for etiologic and intervention research to reduce the disparities in participation in cancer-related trials.     

Attitudinal barriers to participation in oncology clinical trials: factor analysis and correlates of barriers

Patient participation in cancer clinical trials is low. Little is known about attitudinal barriers to participation, particularly among patients who may be offered a trial during an imminent initial oncology consult. The aims of the present study were to confirm the presence of proposed subscales of a recently developed cancer clinical trial attitudinal barriers measure, describe the most common cancer clinical trials attitudinal barriers, and evaluate socio‐demographic, medical and financial factors associated with attitudinal barriers. A total of 1256 patients completed a survey assessing demographic factors, perceived financial burden, prior trial participation and attitudinal barriers to clinical trials participation. Results of a factor analysis did not confirm the presence of the proposed four attitudinal barriers subscale/factors. Rather, a single factor represented the best fit to the data. The most highly‐rated barriers were fear of side‐effects, worry about health insurance and efficacy concerns. Results suggested that less educated patients, patients with non‐metastatic disease, patients with no previous oncology clinical trial participation, and patients reporting greater perceived financial burden from cancer care were associated with higher barriers. These patients may need extra attention in terms of decisional support. Overall, patients with fewer personal resources (education, financial issues) report more attitudinal barriers and should be targeted for additional decisional support.     

Older adult participation in cancer clinical trials: A systematic review of barriers and interventions

Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence-based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real-world data.     

Accrual to breast cancer clinical trials at a university-affiliated hospital in metropolitan Detroit

Despite the large number of available studies, most women with breast cancer do not participate in clinical trials, and this is especially true among lower income and minority women. In this study the authors surveyed the practice patterns of four medical oncologists who comprised the clinical breast service at a large urban university hospital to develop a better understanding of the clinical trials enrollment process for women with breast cancer. Of 136 new female breast cancer patients seen by the four physicians over a 7-month period, there were 47 women (34%) offered participation in a clinical trial, and 16 women (12%) were eventually enrolled. Women who were offered participation were more likely to be younger (p = 0.068) and to have earlier stage disease then were women not offered participation (p = 0.008). Women enrolled into a trial were also more likely to be younger, although this difference was not statistically significant (p = 0.114). Patient race was not associated with the accrual or enrollment process. Over half of the women were not offered participation in clinical trials because of the lack of available studies. Further work evaluating the process of patient enrollment and physician and patient barriers is necessary to develop effective strategies for recruitment into breast cancer clinical trials.     

Results from a Theory-Guided Survey to Support Breast Cancer Trial Participation: Barriers,Enablers, and What to Do about them

Background: Ensuring adequate, informed, and timely participation in clinical trials is a multifactorial problem. We have previously developed a systematic, tailorable survey development approach that is informed by theory, can identify barriers and enablers to participation, and can suggest recruitment strategies to address these issues. In this study, we surveyed subscribers to the Canadian Breast Cancer Network (CBCN) in order to identify a comprehensive list of theory-informed barriers and enablers relevant to participation in a hypothetical breast cancer trial. Methods: We developed and conducted an online survey of breast cancer patients informed by the Theoretical Domains Framework and designed to determine previous experience with clinical trials, knowledge about clinical trials, and importance of a comprehensive list of barriers and enablers to trial participation. Participants were contacted by email or through social media. Results: From 2451 subscribers of the CBCN, we received 244 responses and 210 completed surveys (244/2451 or 9.9% participation, 210/244 or 86.1% completion). A total of 38% of respondents indicated experience in trial participation, but 83% indicated confidence in their knowledge about clinical trials. Those who had previously participated in clinical trials were more confident in their knowledge (χ²= 6.77, p = 0.009) and answered more knowledge questions (t = −3.90 p = 0.000). Endorsed barriers and enablers to participation included 39 factors across 12 of 14 domains relevant to behaviour change. Our approach identifies barriers that might be meaningfully addressed by careful knowledge provision (‘If I would learn more about my condition’; ‘If I find the trial documents hard to understand’), those that may require other theory-informed approaches to address (‘my feelings about the quality of my drug plan’; ‘my worry over unknown side effects’), and those that may require tailored approaches depending on participant differences such as previous experience in trials (‘If there were patient-friendly decision-making tools to help you make your participation decision’). Discussion: This work demonstrates that a comprehensive, theory-guided survey of barriers and enablers to participation in breast cancer clinical trials is feasible, can lead to detailed knowledge about the issues related to participation in specific trials, and most importantly, can lead to insights about evidence-based ways to better support patient participation.     

Scoping to analyze oncology trial participation in Australia

Equity in oncology clinical trial participation has been declared a global priority. Australia is a key stakeholder in the global clinical trials sphere and managed to maintain high clinical trial activity during the COVID pandemic. Despite these successes, there is paucity of understanding about what influences clinical trial participation in Australia. In the international context, systematic reviews have highlighted that sociodemographic barriers, access to health care, clinical trial inclusion criteria, and attitudes of physicians and patients are factors which influence oncology trial participation. Exploring the factors in Australian health services which influence trial participation is now of significant importance. The lack of clear evidence directly highlights a need to assess the factors that influence oncology trial participation in Australia. We call for review of existing data to identify future directions in Australia which will potentially give deeper insights for the international clinical trial community.     

Factors that predict the referral of breast cancer patients onto clinical trials by their surgeons and medical oncologists.

PURPOSE: To improve understanding of physicians' reluctance to refer patients to clinical trials. METHODS: This study was conducted in a large metropolitan region from 1993 to 1995 using a two-staged population-based sampling strategy. A total of 147 physicians discussed 245 patient cases and their own knowledge, attitudes, and practices toward clinical trials. RESULTS: Ninety-three patients (38. 0%) were offered a trial, and 49 (52.7%) of them agreed to participate. Forty-five patients (18.4%) actually received their adjuvant therapy on trial. Older patients and those with a poorer prognosis were less likely to be referred. Patients who delayed their decision were more than three times as likely to participate in a trial and more than eight times as likely to participate when they were reported to be actively involved in making the decision. Generally, physicians in university settings and who had formal support from a cooperative group were more likely to refer patients to trials. More specifically, surgeons referred more patients to trials when they felt comfortable explaining trials or believed that treatment should not stray from protocol. Oncologists were less likely to make referrals if they perceived the paperwork to be onerous or entry requirements to be too stringent. Surgeons' participation in recommending adjuvant therapy to patients resulted in more trial referrals unless they treated their patients with tamoxifen. CONCLUSION: (1) Physicians still need to overcome attitudinal and practical barriers to trial participation, (2) more support for physicians is needed, (3) surgeons may play a pivotal role in the recruitment of patients to adjuvant therapy trials, and (4) garnering patient enthusiasm for trial participation and involving them in the choice of adjuvant therapy may be key components to increasing trial enrollment.     

Hope for a cure and altruism are the main motives behind participation in phase 3 clinical cancer trials

It is necessary to carry out randomised clinical cancer trials (RCTs) in order to evaluate new, potentially useful treatments for future cancer patients. Participation in clinical trials plays an important role in determining whether a new treatment is the best therapy or not. Therefore, it is important to understand on what basis patients decide to participate in clinical trials and to investigate the implications of this understanding for optimising the information process related to study participation. The aims of this study were to (1) describe motives associated with participation in RCTs, (2) assess if patients comprehend the information related to trial enrolment, and (3) describe patient experiences of trial participation. Questionnaires were sent to 96 cancer patients participating in one of nine ongoing clinical phase 3 trials at the Department of Oncology, Uppsala University Hospital in Sweden. Eighty‐eight patients completed the questionnaire (response rate 92%); 95% of these were patients in adjuvant therapy and 5% participated in clinical trials on palliative care. Two main reasons for participation were identified: personal hope for a cure and altruism. Patients show adequate understanding of the information provided to them in the consent process and participation entails high patient satisfaction.     

Addressing the current challenges of non-small-cell lung cancer clinical trial accrual

Conducting research in patients with non-small-cell lung cancer (NSCLC) is challenging, primarily because of low patient accrual rates resulting from patient-, physician-, protocol-, and healthcare system-related barriers. The Coalition of Cancer Cooperative Groups convened a 1-day program entitled Addressing the Current Challenges of NSCLC Clinical Trial Accrual to develop specific strategies for enhancing accrual into NSCLC clinical trials and to increase and sustain the level of discussion with and among cooperative group and community-based researchers. Some of the important areas that were highlighted at the meeting included predictors of successful and unsuccessful trial accrual based on 6 NSCLC trials, of which 4 were considered high-priority NSCLC trials; issues surrounding the process of clinical trial activation; and the role of patient advocates in enhancing trial accrual. Efforts by multidisciplinary teams comprising clinical and laboratory researchers, patient advocates, governmental agencies, and private industries are needed to improve NSCLC trial activation and accrual, with a focus on commitment to ongoing communication among all constituents, measures to improve the activation process, and increased study awareness at the community oncology and patient levels.     

Attitudes, knowledge and barriers to participation in cancer clinical trials among rural and remote patients

Aim: To assess the knowledge of randomized clinical trials and willingness and barriers to participation among rural, remote and regional cancer patients of North Queensland. Methods: A survey was conducted in medical oncology outpatient clinics at the Townsville and Mt Isa hospitals on patients, following their informed consent, using questionnaires. Rurality was defined according to the rural remote and metropolitan area classification. Results: Of the 180 patients approached, 178 participated. The median distance to the regional trial center for rural participants was 180 km (range 80–1300 km). 45.4% lived in rural or remote areas and the rest lived in Townsville, a regional metropolitan center. Their overall knowledge was low, with a median knowledge score of 3 (inter‐quartile ranges n = 2.5). For randomized controlled trials there were no significant relationships between willingness to participate and rurality or education level (P = 0.981). Cost of travel (41.1% rural or remote; 23.5% regional; P < 0.001) and the need for family or friends to accompany them (38.9% rural or remote; 24.1% regional, P = 0.021) were more important for rural/remote than regional patients as factors affecting participation. Conclusion: Rural and remote patients are as interested in participating in randomized clinical trials as regional patients. Their knowledge of trials is poor and education earlier in the consultations is needed. Since cost of travel and the need for family members to accompany them are important for rural patients trial budgets should include the cost of travel to encourage participation.     

Understanding opioid tolerance in cancer pain

PURPOSE/OBJECTIVES: To review opioid tolerance in chronic cancer pain, define the phenomenon and its scope, review physiologic mechanisms, and discuss clinical strategies to identify and manage this complex issue. DATA SOURCES: Review articles, case studies, original research, and published guidelines. DATA SYNTHESIS: Novel therapies to prevent/reverse tolerance are being investigated with a possible future role for N-methyl-d-aspartate antagonists. CONCLUSIONS: Greater nursing research is needed to identify patient risk factors for tolerance development and clinical measurement of the phenomenon. Understanding cellular mechanisms for tolerance may contribute to better management. IMPLICATIONS FOR NURSING PRACTICE: Nursing knowledge of tolerance is important to provide the basis for accurate patient assessment, education, and pain management.     

Dissemination of information on legislative mandates and consensus-based programs addressing payment of the costs of routine care in clinical trials through the World Wide Web

BACKGROUND: Legislative and consensus-based programs that ensure payment for routine care costs in a trial have been enacted by a number of states and government-sponsored health benefits programs. To eliminate the potential for denial of payment by a health plan that can act as a barrier to participation, the public must be aware that these programs exist and what they entail. METHODS: World Wide Web sites are utilized by patients and their surrogates as a prime source of healthcare-related information. A review of cancer research organization and advocate group web sites was performed to document the degree to which these sites provided information on clinical trial coverage programs. The objective was to determine whether patients were being given sufficient information to overcome barriers to participation related to the existence of clinical trials, their potential benefits, and health plan payment. RESULTS: Fewer than 5% of the 373 sites reviewed provided sufficient information to communicate to a patient that 1) the institution participates in sponsored cancer clinical research, 2) patients can derive direct benefits by participating in a clinical trial, and 3) payment for treatment in a clinical trial is largely provided by their health plan. CONCLUSIONS: Sites on the World Wide Web are a key source of healthcare-related information for patients and their surrogates. Organizations involved in clinical cancer research should examine their web sites to ensure that the content it contains is sufficiently detailed, accessible, and readable to inform potential participants fully of the clinical trial options.     

Lessons learned from investigator-initiated clinical trials for localized pancreatic cancer

Investigator-initiated trials (IITs) are clinical trials in which the clinician is both the sponsor and the investigator. IITs have also been developed to test strategies designed to optimize existing therapies or treatment approaches that may not be supported by industry sponsors or may be too novel to gain the consensus to be supported by cooperative groups. The role of the investigator is comprehensive and includes protocol development, securing funding for the administration of the trial, recruitment and monitoring of subjects, and assurance for the protection of human subjects. We will briefly review the importance of surgeons in developing IITs and provide insights into logistical barriers from conception to completion of the trial.     

Globalization of clinical trials

Based on reviews of the Japanese clinical trial situation in lung cancer, gastric cancer, prostate cancer and breast cancer, it was clear that much progress has been made in short time. There are considerable differences between Japan and the West and also differences between clinical areas in Japan. For regulatory purposes bridging studies have become increasingly important. Use of identical protocols are required for effective bridging. Participations in global phase III trials is the best way of achieving registration in Japan. For successful global trials in Japan it is important to include Japanese investigators in the preparation of the protocol and to recognise the challenges facing such a project. Clinical practice in diagnosis and treatment have many differences, thus it is recommended to have clear and detailed information in the protocol. Hard end points like survival are important since they are not biased by cultural differences. There are clear difficulties with HE or QOL outcomes. The emergence of focus on evidence based medicine is also happening in Japan and will help to harmonize documentation across the world. For large adjuvant or prevention cancer global trials are essential. To facilitate global studies further development of infrastructure is necessary in Japan. Use of electronic data capture web based communication etc. will help overcome communication difficulties. Other improvements that will make Japanese participation in global trials easier and better include establishment of clinical trial centre at each hospital, introduction of trial coordinators or study nurses and an improved collaboration with company staff. A critical issue that also need addressing is agreement of centre target recruitment. We need to introduce a new flexible system in Japan if participation in global trial is to be optimised. If we can address these issues Japanese investigators and collaborative groups should be able to initiate and lead global trials in the future.     

Barriers to the participation of African-American patients with cancer in clinical trials: a pilot study

BACKGROUND: African-American patients have been under-represented in oncology clinical trials. Better understanding barriers to African-American participation may help increase the accrual of African-American patients onto clinical trials. METHODS: Two hundred eighteen patients with malignant disease (72 African-American patients and 146 white patients) were recruited from the Duke Cancer Clinic and from Duke Oncology Outreach Clinics (DOORS). Patients were interviewed using a standardized survey. Questions included patients' knowledge of cancer, religious/spiritual beliefs, satisfaction with medical care, knowledge of clinical trials, reasons for participating or refusing to participate in a clinical trial, financial/transportation issues, and demographic factors, such as age and education. Data on attitudes and belief were analyzed for group differences between African-American patients and white patients as well as between patients who were treated at the Duke Cancer Clinic and patients who were treated at DOORS clinics. RESULTS: Willingness to participate in a clinical trial depended on both race and clinic site. Forty-five percent of white patients, compared with 31% of African-American patients, were willing to participate in a clinical trial (P = 0.05). white and African-American patients who were treated at the Duke Cancer Clinic were more willing to participate in a trial compared with their counterparts who were treated at DOORS clinics (47% vs. 37%, respectively; P = 0.09). The greatest differences between groups (African-American patients vs. white patients and Duke Cancer Clinic patients vs. DOORS patients) were education and income: Much greater percentages of African-American patients and DOORS patients did not complete high school and had annual incomes < $15,000. In addition, more African-American patients than white patients believed that God would determine whether they would be cured or would die from their disease. In a multivariate analysis, education, income, and belief that God would determine the patient's outcome also were correlated with a decreased willingness to participate in clinical trials. CONCLUSIONS: Factors associated with religion, education, and income, rather than race, may be major barriers to clinical trial participation. Interventions that target education and income may increase the recruitment of African-American oncology patients onto clinical trials.     

Can we predict trial failure among older adult-specific clinical trials using trial-level factors?

IntroductionConducting older adult-specific clinical trials can help overcome the lack of clinical evidence for older adults due to their underrepresentation in clinical trials. Understanding factors contributing to the successful completion of such trials can help trial sponsors and researchers prioritize studies and optimize study design. We aimed to develop a model that predicts trial failure among older adult-specific cancer clinical trials using trial-level factors.Materials and methodsWe identified phase 2–4 interventional cancer clinical trials that ended between 2008 and 2019 and had the minimum age limit of 60 years old or older using Aggregate Analysis of ClinicalTrials.gov data. We defined trial failure as closed early for reasons other than interim results or toxicity or completed with a sample of <85% of the targeted size. Candidate trial-level predictors were identified from a literature review. We evaluated eight types of machine learning algorithms to find the best model. Model fitting and testing were performed using 5-fold nested cross-validation. We evaluated the model performance using the area under receiver operating characteristic curve (AUROC).ResultsOf 209 older adult-specific clinical trials, 87 were failed trials per the definition of trial failure. The model with the highest AUROC in the validation set was the least absolute shrinkage and selection operator (AUROC in the test set = 0.70; 95% confidence interval [CI]: 0.53, 0.86). Trial-level factors included in the best model were the study sponsor, the number of participating centers, the number of modalities, the level of restriction on performance score, study location, the number of arms, life expectancy restriction, and the number of target size. Among these factors, the number of centers (odds ratio [OR] = 0.83, 95% CI: 0.71, 0.94), study being in non-US only vs. US only (OR = 0.32, 95% CI: 0.12, 0.82), and life expectancy restriction (OR = 2.17, 95% CI: 1.04, 4.73) were significantly associated with the trial failure.DiscussionWe identified trial-level factors predictive of trial failure among older adult-specific clinical trials and developed a prediction model that can help estimate the risk of failure before a study is conducted. The study findings could aid in the design and prioritization of future older adult-specific clinical trials.