The infrastructure around the conduct of clinical trials has been designed to anticipate a low, albeit steady, trial participation rate. To understand the impact of clinical trial participation on cancer population mortality and survival, one might imagine a counterfactual system in which the cancer clinical trial participation rate was much higher. Fortunately such a system already exists.
These data are consistent with the idea that a clinical trial system that enrolls patients at higher rates produces treatment advances at a faster rate and concurrent survival increases and mortality reductions in the cancer population. In this context, the issue of clinical trial enrollment is viewed as foundational, lying at the heart of the cancer clinical trial endeavor.
In this paper, we attempt, first, to characterize the specific barriers to cancer clinical trial participation. We consider as well the distinction between clinical trial enrollment between children and adolescents with cancer. As suggested above, these age-proximal patient groups provide a natural observational contrast illuminating the association between clinical trial enrollment rates and corresponding improvements in outcomes in the cancer population.
We present original data to make this case. Finally, we examine global and local strategies to improve cancer clinical trial participation. In this multi-factorial decision-making environment, patients may face several barriers to trial participation. As a guide to understanding the trial decision-making process, we present a simplified flow diagram Figure 1 illustrating a representative pathway through which a patient may receive care.
This model has been the basis for multiple studies examining barriers to clinical trial participation. If a trial is available, an evaluation of trial eligibility is made, and if eligible, a trial is discussed with the patient. The trial may then be offered to the patient, at which point the patient makes a decision about whether to participate. An important note is that under this model, patient attitudes toward clinical trial participation only come into play at the end of an otherwise long process.
We have categorized barriers to trial participation as structural especially, the absence of an available clinical trial , clinical i. It is recognized that there is greater fluidity between these categories than the model allows, but simplifications were made to facilitate discussion. To participate in a clinical trial, patients must first have access to a cancer clinic. Access to a clinic can be influenced by many different structural factors such as transportation, travel costs, access to insurance, and availability of child care.
Multiple prospective studies of the cancer care decision-making process have examined the extent to which trials are unavailable for patients. Lara and colleagues prospectively tracked barriers to cancer clinical trials at the UCD cancer center from — Javid and colleagues registered patients to a prospective survey study prior to their treatment decision regarding their cancer care at a diverse set of eight institutions.
Even if a trial is available, patients may not be eligible. Studies have found that a common reason for patient ineligibility to available protocols is narrow eligibility criteria. On the one hand, eligibility must be sufficiently narrow to produce a treatment effect that is approximately consistent across the cohort. On the other hand, eligibility should be sufficiently inclusive that the trial targets a meaningful population of patients to which a new treatment would apply.
In the event, trials are often criticized for having eligibility criteria that are too narrow, sacrificing generalizability. One recent paper comprehensively catalogued the trial eligibility criteria for a set of 21 trials in diverse cancer settings. Although pre-specified trial eligibility criteria that protect patient safety are crucial, it is also possible that certain kinds of exclusions are unnecessary.
A recent report indicated trial eligibility criteria have increased in recent years for both academic group and pharmaceutical sponsored clinical trials. As the agent linking patients to their cancer care, physicians play an obvious and vital role in clinical trial participation. A number of factors have been found to deter physician recommendation for trial participation. In their role of guiding patient care, physicians may have a strong inclination towards a specific treatment for a given patient. Physicians often lack appropriate incentives to participate in clinical research.
Efforts to reduce structural, clinical, and physician barriers to trial participation are critical. However the ultimate decision regarding trial participation rests with the patient.
However, research on the nature of ethical conflicts is needed. One of its first concerns is to ensure high-quality advice and psychological support for all cancer patients and survivors and their caretakers. Physicians have a powerful motivation to rescue. Disruptive behavior and clinical outcomes: Perceptions of nurses and physicians. Agrawal, M.
Some proportion of patients are influenced by altruistic motivations. Patients have frequently reported being uneasy or fearful about the prospect of participating in a clinical trials. Attention must also be paid to providing consent forms which are easy to read, since more complicated consent forms can themselves induce anxiety. More generally, a fear of experimentation may be expressed through a dislike of randomization.
Fear of randomization has been identified as the most commonly cited reason by patients for declining trial participation. Patients are sometimes uneasy as well about the potential toxic effects of chemotherapy on trials, especially for the experimental therapies. Demographic and socioeconomic disparities in trial enrollment can occur anywhere along the pathway from initial clinic visit until the patient ultimately makes their treatment decision. The most consistent and largest disparity pertains to age.
Recognizing this, in the year , Medicare was directed to cover the routine care costs of clinical trial participation for its patients.
Evidence as to the association of race with trial participation is mixed. A study by Murthy and colleagues found that black patients were underrepresented in NCI sponsored breast, lung, colorectal, and prostate cancer clinical trials from — Females may be somewhat underrepresented in the non-sex specific cancers, although the magnitude of the disparity is likely small.
The examination of socioeconomic factors as a barrier to participation has historically been hindered by the lack of collection of patient-level SES data. This is unfortunate given the frequency with which the direct and indirect costs of trial participation have been cited as meaningful barriers.
The first utilized a web-based survey to engage patients in their decision making process. Utilizing data from a prospective barriers study, this observation was confirmed. A prior study of the impact of the year Medicare policy change on trial participation found that patients with Medicare plus private insurance participated at a higher rate following the year policy change, whereas patients with Medicare alone participated at rates similar to those prior to the policy change.
The potential barriers to trial enrollment that patients face are numerous. But just how important are clinical trials for progress against cancer? The answer to this question is crucial, since if trial participation is ultimately unrelated to cancer population survival gains, the issue of barriers to trial participation has little importance. To examine this, we studied the relationship between adolescents and young adults AYAs and cancer population outcomes over time.
Concomitantly, cancer has become the most frequent cause of death due to disease in AYAs. Baseline is — average. Data source is SEER 9 regions. The survival disparity between AYAs and other patients may be due in part to early achievements in improving survival for AYAs, after which resources were directed towards research in other age groups. Also, cancers for AYAs have potentially complex biological signatures that neither pediatric oncologists nor adult-treating medical and hematologist oncologists are accustomed to treating.
For this analysis, , patient entries during — were examined. In addition, we used cancer population data derived from the Surveillance, Epidemiology, and End Results registry, U. Census data, and joinpoint analyses to examine trends in U. Figure 3 shows the relationship between the average percent change APC in the 5-year cancer-specific survival rate from to and the accrual rate to national cancer treatment trials during — Although this comparison is confounded by time, there was a nearly correlation over the entire age range that was strongly statistically significant.
Patients 15 to 34 years of age had the lowest APC in 5-year survival. A similar pattern was found with respect to cancer mortality as shown in Figure 4 , which isolates those 0—40 years of age. Those 20—24 years of age had a particularly poor reduction in cancer mortality, as well as the lowest absolute number of clinical trial accruals. The open columns represent trial accruals during — and the colored bars the average percent change APC in 5-year relative survival rate of all invasive cancer except Kaposi sarcoma during — The red bars indicate the AYA age group. The inset compares the APC in 5-year survival rate with the treatment trial accruals.
The open columns represent trial accruals during — and the colored bars the average percent reduction in national cancer mortality rate during — The inset compares the mortality rate reduction with the treatment trial accruals. The greatest effort during the last decade to increase accruals in AYAs was directed at ALL, the most common pediatric cancer. New clinical trials in ALL specifically designed for AYAs were launched, 79 , 80 , 81 the National Comprehensive Cancer Network released practice guidelines for ALL, 82 and an increasing number of presentations and publications on the topic occurred at national meetings and appeared in the peer-reviewed medical literature.
The heavy curves represent — and the thin curves — Census Bureau. Hence, ALL was examined more closely for relationships between survival improvement and clinical trial participation. Figure 6 also shows the 5-year leukemia-specific survival rate for patients with ALL as a function of single year of age. Each year of age was averaged from 2 consecutive years.
Joinpoint analysis of survival data identified ages 17 and 20; 74 linear regressions for survival data are for age ranges 5—17, 17—20, and 20—70 years. Survival data were obtained from SEER 18 regions. These data enable three fundamental conclusions. First, both survival prolongation and mortality reduction in patients with cancer are correlated with clinical trial activity. Second, the dependency of survival prolongation on treatment trial accrual has been apparent at all ages.
Third, AYAs have had the least trial participation and the least survival prolongation and mortality reduction, particularly among patients 20 to 29 years of age. It has been previously observed that the age-dependent rate in the reduction of deaths attributed to cancer in the United States is correlated with the age-dependent accrual of young adults to national cancer treatment trials during the same era.
More is needed to overcome the national AYA cancer death problem, beginning with increased clinical trial availability, access, referrals, participation and conduct. We have illustrated the nature of clinical trial enrollment barriers and established the potential link between trial enrollment and improvements in cancer population survival. Efforts to improve trial enrollment of cancer patients are clearly needed. In this context, we propose the following global and local strategies to improve trial participation.
At the beginning of this paper, we delineated many of the specific challenges to clinical trial enrollment. Given the need to accrue large numbers of patients in a shortened timeline and the increased complexity of U. In the view of Barrios and colleagues, the globalization of clinical trial research is unavoidable. The importance of differing cultural, scientific, ethical, governmental, and logistical issues in each region must be considered. Availability may be impacted by local religious customs concerning contraceptive studies and ethical guidelines limiting pediatric clinical trials.
An additional ethical issue in low resource countries involves whether to develop local resources for testing or to use international vendors for that purpose. Although developing local resources provides an often needed benefit, this could involve higher costs and may also be deterred by local shipping laws and other logistical barriers. A continuous series of strategies was implemented for patient recruitment and retention throughout the life of the trial. The strategies target physicians, research staff, local sites, patients, and the local community.
The local sites were offered additional site funding for accelerated recruitment and START educational teleconferencing. The local community was reached through local media outreach, public awareness advertisements, and engagement of local site liaisons. Enrollment to the trial ran from through and reached full accrual patients randomized, indicating a highly successful recruitment effort. Domestic trials may also partner with international collaborators to augment trial enrollment. Increasingly, social media platforms provide an opportunity to communicate about clinical trials with potential trial researchers and participants.
The FDA has provided no specific guidance on the use of social media in clinical research. The Office of the Inspector General has released guidance regarding the use of clinical trial websites, indicating that IRB approval of a clinical trial listing, if limited to selected basic information, is not required. InVentiv Health, a contract research organization, has provided specific plans to assist researchers to plan digital recruitment campaigns.
Often researchers using Facebook attempt to recruit from the initial audience prior to forming a relationship. A better approach may be to first grow and engage your audience first before patients are recruited. Patients with concomitant illnesses are often excluded from trials to ensure safety and to isolate the cancer as the primary source of morbidity in the patient. Unfortunately this has the effect of excluding many patients from trials, especially older patients with a greater comorbid burden.
Such an approach would improve access to trials, especially for older patients, and — since histology and stage explain the vast majority of variation in cancer outcomes, rather than comorbid conditions — would result in only limited loss of power to test the efficacy of new treatments. Researchers should also consider increasing the number of trials targeted to older patients, with due consideration to potential safety issues. Fortunately CGA time requirements have led to the development of prescreening tools used to determine whether full screening with CGA is required, though there are inconsistent results regarding the validity of these tools.
If marginal direct costs are prohibitive for some patients, then measures to cover these costs would remove a critical barrier to enrollment. One approach would be to cover the excess costs of clinical trials for all patients, since even in an insured population, co-pays and co-insurance have been shown to deter clinical trial participation.
In the U. Measures to address socioeconomic disparities in recruitment may have a preferentially beneficial impact on minority patients. Larger supplemental site grants were awarded to fifteen SELECT sites with potential to increase minority recruitment through a competitive award mechanism. These additional funds were most commonly used to provide additional staff time for minority recruitment. Both patients and physicians have been found to regard clinical trial participation as a positive approach to cancer care. Clinical trials are the key step in advancing new treatments from the research setting to the cancer care clinic.
Therefore, a thorough understanding the nature of trial enrollment patterns and barriers to enrollment is of paramount importance.
The literature indicates that structural barriers preclude patient participation in trials for half of all cancer patients. Among patients for whom a trial is available, about half or a quarter of all patients are excluded due to eligibility issues with trial exclusion criteria. The remaining patients are sometimes not offered the chance to participate due to physician concerns, or decline due to patient concerns. Structural, clinical, and attitudinal barriers to trials can differ according to some important factors, especially age. Increasing accrual to clinical trials is important for multiple reasons.
Faster accrual would allow trials to be conducted more quickly. The predominant reason that trials fail to complete is poor accrual. Moreover, when clinical trials close because of failure to accrue, non-financial costs are also incurred. Patients have exposures to study drugs with potential or realized adverse events. Patients and research staff may experience psychological effects such as loss of trust and morale. Informed consent documents rare rarely include the risk of closure due to lack of study participation, despite the fact that about 1 in 4 randomized phase III trials have just such an outcome.
The more rapid completion of trials would allow new treatments to be developed more quickly. We have shown data indicating a compelling relationship between the incidence of clinical trial enrollments and improvements in cancer population survival outcomes. Our focus was a natural observational contrast between AYAs and other age groups with cancer. We found a slower rate of progress in AYAs compared to younger and older patients, which underscores the need to increase the number of clinical trials available to AYAs with cancer and their participation in them.
By extension, this observation also points to the need to increase trial enrollment for patients of any age group, or any demographic group, since this could have a beneficial impact on increasing survival and reducing mortality from cancer. Another important reason to increase clinical trial accrual is to improve the generalizability of clinical trial results. Figure 7 illustrates how the vast majority of cancer patients of all ages — but especially those over about 15 years of age — do not participate in clinical trials.
Thus trial results must generalize to non-trial patients, at least to some degree. But they may not do so in an efficient manner, and cancer population survival gains may be lost in the process. Under this rubric, greater participation leads to greater generalizability which leads to better cancer population outcomes. Cancer trial samples, in particular, are usually younger, healthier, and perhaps wealthier than the typical non-trial cancer patient.
To the extent that trials are more inclusive with respect to comorbid or other conditions, adequately represent the demographic makeup of the U. Modified from Bleyer A. Finally, increased accrual to trials is important to patients, since trials provide opportunity to receive the newest treatments. The principle of equipoise posits that a properly designed treatment trial tests a new or modified form of therapy that is not known to have that benefit otherwise the trial would not be justified in conducting.
Barriers to trial participation are structural, clinical, and attitudinal, and they differ according to demographic and socioeconomic factors. In this article, we characterize the nature of cancer clinical trial barriers, and we consider global and local strategies for reducing barriers. We also consider the specific case of adolescents with cancer and show that the low rate of trial enrollment in this age group strongly correlates with limited improvements in cancer population outcomes compared with other age groups. Our analysis suggests that a clinical trial system that enrolls patients at a higher rate produces treatment advances at a faster rate and corresponding improvements in cancer population outcomes.
Fewer barriers to trial participation would enable trials to be completed more quickly and would improve the generalizability of trial results. Moreover, increased accrual to trials is important for patients, because trials provide patients the opportunity to receive the newest treatments. The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Author manuscript; available in PMC Jul 3. PMID: Joseph M.
Unger , Ph. Correspondence to: Joseph M. Copyright notice. See other articles in PMC that cite the published article. Open in a separate window. Figure 1. Structural Barriers To participate in a clinical trial, patients must first have access to a cancer clinic.
The care of cancer patients raises complex ethical issues and this updated edition to the care of oncology patients in treatment as well as research settings. Peter Angelos Numerous ethical issues arise in the care of oncology patients. Although much has been Cancer Treatment and Research. Free Preview cover .
Clinical Barriers Even if a trial is available, patients may not be eligible. Physician Attitudes As the agent linking patients to their cancer care, physicians play an obvious and vital role in clinical trial participation. Patient Attitudes toward Clinical Trials Efforts to reduce structural, clinical, and physician barriers to trial participation are critical.
Demographic and Socioeconomic Disparities Demographic and socioeconomic disparities in trial enrollment can occur anywhere along the pathway from initial clinic visit until the patient ultimately makes their treatment decision. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Clinical Trials Impact Summary These data enable three fundamental conclusions. Global strategies At the beginning of this paper, we delineated many of the specific challenges to clinical trial enrollment. Incorporate error reduction strategies and consider regional variations in the standards of care and their impact on trial results.
Invest in research and evidence-based cancer care relevant to each region, including cancer registries and clinical trial infrastructure. Local Strategies Social Media Increasingly, social media platforms provide an opportunity to communicate about clinical trials with potential trial researchers and participants. All communications should be vetted for sensitivity and potential for harm, even if the content does not require IRB approval.
If user generated content is allowed, which is essential to creating a robust online community, close monitoring is required for patient protection and study integrity. Table 2 Proposed steps to plan digital recruitment campaigns[inVentiv]. Strategies to Address Demographic and Socioeconomic Barriers Elderly Recruitment Patients with concomitant illnesses are often excluded from trials to ensure safety and to isolate the cancer as the primary source of morbidity in the patient.
Strategies to Address Socioeconomic Barriers If marginal direct costs are prohibitive for some patients, then measures to cover these costs would remove a critical barrier to enrollment. Figure 7. An analysis of the specific case of adolescents with cancer illustrates how a clinical trial system that enrolls patients at higher rates produces treatment advances at a faster rate and corresponding improvements in cancer population outcomes. Fewer barriers to trial participation would allow trials to be completed more quickly and would improve the generalizability of trial results, but crucially as well, increased accrual to trials is important to patients, since trials provide patients the opportunity to receive the newest treatments.
References 1. Participation in cancer clinical trials: race-, sex-, and age-based disparities. J Natl Cancer Inst. Public attitudes toward participation in cancer clinical trials. Friederike H. Winkler Corresponding Author E-mail address: eva. Tools Request permission Export citation Add to favorites Track citation. Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. Get access to the full version of this article.
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