SYNTHESIS OF EVIDENCE SUBSTANTIATING POTENTIAL INTERVENTIONS

CARE DELIVERY AND PRACTICE MANAGEMENT

Overcoming Barriers to Clinical Trial Enrollment Ryan D. Nipp, MD1; Kessely Hong, PhD, MPA2; and Electra D. Paskett, PhD3

o verview

Clinical trials are imperative for testing novel cancer therapies, advancing the science of cancer care, and

determining the best treatment strategies to enhance outcomes for patients with cancer. However, barriers to

clinical trial enrollment contribute to low participation in cancer clinical trials. Many factors play a role in the

persistently low rates of trial participation, including financial barriers, logistical concerns, and the lack of

resources for patients and clinicians to support clinical trial enrollment and retention. Furthermore, restrictive

eligibility criteria often result in the exclusion of certain patient populations, which thus adds to the widening

disparities seen between patients who enroll in trials and those treated in routine practice. Moreover, ad-

ditional factors, such as difficulty by patients and clinicians in coping with the uncertainty inherent to clinical

trial participation, contribute to low trial enrollment and represent key components of the decision-making

process. Specifically, patients and clinicians may struggle to assess the risk-benefit ratio and may incorrectly

estimate the probability and severity of challenges associated with clinical trial participation, thus com-

plicating the informed consent process. Importantly, research has increasingly focused on overcoming barriers

to clinical trial enrollment. A promising solution involves the use of patient navigators to help enhance clinical

trial recruitment, enrollment, and retention. Although clinical trials are essential for improving and prolonging

the lives of patients with cancer, barriers exist that can impede trial enrollment; yet, efforts to recognize and

address these barriers and enhance trial enrollment are being investigated.

THE BURDEN OF FINANCIAL TOXICITY

Increasingly, data demonstrate that patients with cancer often experience financial burdens related to their cancer and cancer care.1-11 Previous research suggests that patients with a history of cancer expe- rience economic hardships related to job loss, missed work, and trouble obtaining affordable health in- surance.12-16 In addition, patients with cancer experi- ence high out-of-pocket medical expenditures related to their cancer care, which—when coupled with the loss of income—can exacerbate their economic hardship.5,9-11 Research has demonstrated that fi- nancial burden correlates with poor quality of life, high symptom burden, and potentially worse overall sur- vival.4,17,18 Notably, the financial burden experienced by patients with cancer can influence the decision to forgo needed health care or to become nonadherent to their prescribed medicines in an effort to defray costs,19-21 which may jeopardize their health.22-24

Therefore, the financial burden associated with can- cer has been described as a detrimental and in- adequately recognized adverse effect,25 also known as financial toxicity.

Financial Issues Represent a Barrier to Clinical Trial

Enrollment and Participation

Although cancer clinical trials seek to improve upon the standard of care and often represent the best available treatment option for many patients with cancer, only

a small proportion of eligible patients choose to enroll.26-29

Recently, growing attention has focused on the financial and logistic barriers that contribute to persistently low trial participation rates.28,30-34 Studies have shown that patient populations with historically lower financial resources, including uninsured and minority patients, are often underrepresented in cancer clinical trials.26,35-37 Similarly, patients with higher socioeconomic status seem to enroll in cancer clinical trials more frequently.38-41 These disparities in clinical trial enrollment have important downstream effects, which contribute to the lack of data about the impact of certain therapies on patients seen in real-world practice.42,43 Thus, financial issues represent a barrier to clinical trial participation and may play a role in the persistence of disparities in cancer care (Sidebar 1).

Importantly, clinical trial participants represent a pop- ulation at particularly high risk for experiencing fi- nancial burden. Although routine cancer care can result in substantial economic hardship for patients and their families,1,3,44-46 such as high out-of-pocket expenses and risk of bankruptcy, trial participants are uniquely vulnerable to experiencing financial toxicity. Cancer clinical trial participants face the same financial issues that affect all patients with cancer, yet these individuals must also endure the additional costs of more frequent clinical visits and travel to the site of the clinical trial.1,30,47-49 Therefore, as patients and

Author affiliations and support information (if applicable) appear at the end of this article.

Accepted on May 17, 2019 and published at ascopubs.org on May 17, 2019: DOI https://doi.org/ 10.1200/EDBK_ 243729

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clinicians discuss the possibility of clinical trial enrollment, they must also weigh the potential economic consequences of trial participation, which may dissuade patients from enrolling and/or may motivate clinicians to dampen their enthusiasm about the trial.

Financial concerns may help explain why certain patients decide to forgo clinical trial enrollment. In a study of more than 1,000 patients with cancer, researchers sought to assess barriers to cancer clinical trial participation.50 Im- portantly, this study demonstrated that worries about health insurance coverage of clinical care costs represented one of the strongest barriers to trial enrollment.50 In another study,

researchers sought to understand reasons why patients decline cancer clinical trial participation.30 This study found that distance from the cancer center and insurance denial were common reasons that patients decided not to par- ticipate in cancer clinical trials.30 Furthermore, in another study that sought to understand barriers to clinical trial enrollment, investigators demonstrated that lower education and income levels were associated with a decreased will- ingness to participate in clinical trials.51 Collectively, these studies support the notion that financial barriers likely play an important role in patient decisions to participate in cancer clinical trials, and they highlight the need for efforts to address these barriers to enhance trial accrual.

Potential Solutions to Address the Financial Burden of

Cancer Clinical Trials

Despite the existence of financial barriers to clinical trial enrollment and participation, few practical solutions have emerged to prevent and alleviate the financial burden of cancer clinical trial participation. Historically, many of the efforts to address the financial burden of trial participation focused primarily on providing accommodations to children with cancer and their families. For example, programs as- sociated with the Ronald MacDonald House and the American Cancer Society Hope Lodge, as well as in- stitutional support from St. Jude, have helped support children’s cancer treatment and clinical research. For adults with cancer, a National Institutes of Health program has helped support travel, meals, and lodging for participants in cancer clinical trials.52 Although these efforts seek to ad- dress the financial concerns associated with clinical trial participation, evidence supporting these efforts as ways to enhance clinical trial enrollment and retention is lacking.

More recently, research suggests that financial assistance programs could help address the financial burden of cancer clinical trial participation. In a pilot study at a single

PRACTICAL APPLICATIONS

• Clinical trials are critical for advancing the science of cancer care, yet barriers to clinical trial enrollment contribute to low participation in cancer clinical trials.

• Multiple factors likely play a role in the persis- tently low rates of trial participation, including financial barriers, logistical concerns, and the lack of resources for patients and clinicians to support clinical trial enrollment and retention.

• Despite the presence of financial barriers to clinical trial enrollment and participation, few practical solutions have emerged to prevent and alleviate the financial burden of cancer clinical trial participation.

• Patients and clinicians have difficulty coping with the uncertainty inherent to clinical trial participation, and this remains another barrier to trial enrollment; predicting and managing this uncertainty represents a key component of the decision-making process.

SIDEBAR 1. The Financial Burden Associated With Clinical Trial Participation Financial Barriers to Clinical Trial Enrollment

• Routine care costs, such as copayments, coinsurance, or deductibles • Time away from work for frequent clinical visits and travel to the site of the clinical trial • Lodging, meals, dependent care, and transportation required for clinical trial participation • Unknown adverse effects of investigational agent and therefore unknown expenses relating to treatment of adverse effects (e.g., supportive care medications, urgent care visits, hospitalizations)

Potential Solutions to Address the Financial Burden of Cancer Clinical Trials

• Clarify definitions of routine care costs • Streamline prior authorization processes • Provide patients with clear and transparent information about potential trial-related financial burden and resources available to help, such as financial navigation and counseling

• Allow for ethically appropriate financial assistance for trial-related out-of-pocket expenses • Conduct additional research to help recognize and address the financial burden of clinical trials

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academic cancer center, investigators evaluated the impact of a program that provides financial assistance for trial-related expenses, such as travel and lodging, on clinical trial partic- ipation.6,53 Notably, implementation of this intervention was associated with increased trial accrual.6 Specifically, the in- vestigators found that clinical trial enrollment increased after implementation of the financial assistance program. Impor- tantly, this program enrolled a population at high risk for ex- periencing financial burden related to trial participation, which could have precluded their ability to remain on trial for pro- longed periods of time. Program participants were more likely to be younger, be enrolled in phase I trials, reside a farther distance from the trial site, and live on lower incomes. In addition to investigating the impact of this financial assistance program on clinical trial enrollment rates, the authors surveyed participants to understand whether this program also helped to address patient-reported financial burden.53 As expected, patients eligible for financial assistance expressed greater concerns about financial burden at baseline compared with a matched control group who did not request financial as- sistance. However, the authors found that the patients who received financial assistance experienced improvements over time compared with control patients regarding their concerns about the cost of travel and lodging associated with clinical trials. Collectively, these data suggest encouraging results that financial assistance programs could help address the financial burden associated with clinical trial participation.

On the basis of this research and others, guidelines exist to help address the financial burden of clinical trial participation.34

Specifically, a recent ASCO Policy Statement highlighted the need to focus on a few key objectives.34 First, the authors mentioned the need for more clarity about clinical trial cost payment policies, including clearly defined routine care costs and streamlining of the prior authorization process. Second, patients must be provided with clear and transparent information about the potential trial-related financial burden. For example, patients must know what potential out-of-pocket expenses to expect, and patients also need information about options to help with the financial burden, such as financial navigation and counseling. Third, the ASCO Policy Statement underscored the need for financial assistance to help patients with trial-related out-of-pocket expenses. Last, the authors noted the need for additional research to better understand how best to recognize and address the financial burden associated with cancer clinical trial participation. In summary, clinical trials are essential for evaluating novel treatment strategies for patients with cancer, and efforts are critically needed to help overcome the financial barriers that may discourage participation in clinical trials.

DECISION-MAKING: THE INFORMED-CONSENT PROCESS

Additional Barriers to Clinical Trial Enrollment

In addition to financial barriers, many other impediments to clinical trial enrollment exist. One important barrier relates to

patient and clinician difficulty in coping with the uncertainty inherent to clinical trial participation. Predicting and man- aging this uncertainty represent key components of the decision-making process. Specifically, patients and clini- cians may struggle to assess the risk-benefit ratio and may over-weigh the probability and severity of various types of adverse outcomes associated with clinical trial participation, thus complicating the informed consent process.

Uncertainty About Risk May Impede Clinicians From

Offering Clinical Trials to Patients

Clinicians often seek to have a reasonable estimate of the probability and range of severity of potential negative health outcomes and adverse effects that result from clinical trial participation. However, in their dual role as both caregiver and researcher, oncology clinicians who participate in clinical trial research may focus on, and thereby may be likely to misestimate, other additional sources of risk, which might influence their willingness to offer participation in clinical trials to specific patient subgroups (Sidebar 2).

First, oncologists may be concerned about the risk that patients will be unable to comply with all components of a clinical trial, which could reduce the validity of the data yielded from the trial. Thus, oncology clinicians may be motivated to encourage participation among patients who they believe have the capacity to comply with all aspects of the trial regimen. In prior work, Hamel et al54 discussed research demonstrating the presence of implicit bias on the part of physicians toward minority patients (although not all of the studies were directly related to clinical trial participation). For example, physicians who scored high in implicit bias may assume that patients who are from minority groups are at greater risk of noncompliance with treatment recom- mendations.55 Hamel et al54 also explained that “physi- cians may limit offers for trial enrollment to those patients they perceive as good study candidates so that the studies will be conducted in a timely and efficient manner.” Re- search also demonstrates that white patients are more likely to be offered an opportunity to participate in clinical trials than are patients who belong to ethnic or racial minorities.54,56-58

Second, clinicians may be concerned about the risk of damaging their long-term relationships with their patients and may be motivated to avoid offering a trial if they believe their offers would be rejected and cause their patients to view them with suspicion.54 In one study, numerous com- munity physicians interviewed in a focus group expressed reluctance to discuss clinical trials with black patients with cancer because of a perception that these patients might experience mistrust.59 Another study interviewed researchers, cancer center leaders, referring clinicians, and researcher staff across several U.S. cancer centers and found that all four groups “perceived some skepticism

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among racial and ethnic minorities about participating in clinical trials,” which they partially attributed to distrust in clinical research that is based on historical research abuses, such as the U.S. Public Health Service Syphilis Study at Tuskegee.60 However, studies demonstrate that white and minority patients have similar rates of accepting clinical trial participation, conditional upon receiving an offer.54,58,61-63

Uncertainty About Risk May Reduce Patient Willingness to

Participate in Clinical Trials

Even when offered the opportunity to participate in clinical trials, patient concerns about different types of risk may motivate them to forgo participation. Patients may be concerned about both the motives of clinical trial re- searchers and adverse health outcomes or side effects of experimental treatment. Notably, poor communication be- tween a patient and medical team can exacerbate patient concerns and reduce opportunities for them to have their concerns addressed.

Despite similar clinical trial enrollment rates between white and minority patients who are offered the chance to par- ticipate, research shows that minority patient rejection of clinical trial participation opportunities most often stems from mistrust in research and the medical system.41,54 In addition, an examination of studies on shared decision- making in the treatment of patients with cancer (not limited to clinical trials) found that patients focus heavily on the potential adverse effects of treatment when making treat- ment decisions.64 Research has also shown that minority patients are more likely to have lower-quality communication with their physicians, which can reduce the opportunity to adequately address fears and questions.65 For example, an analysis of video recordings of physician communication

about clinical trials with black and white patients showed that physicians spent less time discussing clinical trials with black patients and specifically less time explaining the benefits and risks of trial participation.65 In addition, more generally, studies suggest that black patients may be less likely to ask their clinical teams questions.65,66 Thus, the status quo may seem relatively appealing to patients with regard to clinical trial par- ticipation if the risks of adverse effects from participation loom large in their minds and their concerns are not addressed.

Potential Strategies to Better Manage the Uncertainty

Associated With Clinical Trial Decision-Making

The reluctance of both clinicians and patients, respectively, to offer and participate in clinical trials may be partially addressed by strategies to improve communication and mutual understanding. Some attempted strategies include the introduction of patient navigation and physician con- sideration of patient concerns, needs, and preferences to enable shared decision-making.64,67 One way to facilitate discussion of patient concerns (extending beyond the clinical trial setting) is through the use of a question-prompt list (often a list of questions related to the physical and psychosocial aspects of a medical condition that patients can ask their clinical teams during clinic visits; the list is shared with patients to encourage them to ask questions).54

Hamel et al54 recommend adapting question-prompt lists to encourage informed clinical trial participation by minority populations. Having an opportunity to hear and address patient concerns (e.g., by letting patients know of treatment options for potential adverse effects or sharing options to ease financial concerns) could also help clinicians feel more secure in maintaining patient trust. Addressing patient concerns also could empower clinicians to have greater

SIDEBAR 2. Decision-Making in Cancer Clinical Trials Key Components of Clinician Risk-Estimation Errors Related to Clinical Trial Participation

• Clinicians may overestimate the risk of losing the trust of minority patients by offering participation in a clinical trial. • Clinicians may underestimate the likelihood of willingness of minority patients to participate, conditional upon being offered a clinical trial.

• Clinicians may overestimate the likelihood that minority patients enrolled in a trial will fail to fully complete the trial requirements.

Key Components of Patient Risk-Estimation Errors Related to Clinical Trial Participation

• Patients may over-weight the risk and/or severity of adverse effects of clinical trial participation relative to other options. • Minority patients may have concerns about the ethical motivations of clinical trial research. • Poor communication between clinicians and minority patients may exacerbate mutual concerns.

Potential Strategies to Better Manage the Uncertainty Around Clinical Trial Decision-Making

• Communication between patients and clinicians may be enhanced by using patient navigation and patient question- prompt lists.

• Patient attitudes toward the risk of clinical trial participation could be affected by the framing of the risks associated with the decision to participate in a clinical trial relative to other options.

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confidence that patients fully understand study participation requirements and have the measures in place to enable full adherence to study requirements.

Research about the psychology of choice by Tversky and Kahneman68 demonstrates that people are more likely to behave in a risk-seeking manner (e.g., selecting a riskier option instead of a more certain option of equivalent ex- pected value) when their decision is framed as an op- portunity to avoid a certain loss (but with the risk of facing a greater loss) compared with when their decision is framed as an opportunity to increase a gain (but with the risk of no gain). Consequently, this would imply that pa- tients may be more inclined to choose participation in a clinical trial if the likely negative effects of the disease without clinical trial participation are described first and followed by information about the estimated probability that participation in the trial can avoid these losses (albeit with potential added risks). Medical ethicists can provide assistance to ensure that all information about risks and the severity of potential outcomes for a variety of clinical trial and nonclinical trial treatment options is clearly presented to patients and their loved ones. Ultimately, additional work is urgently needed to better understand how to enhance the informed consent process in a way that reduces clinician and patient errors in forecasting different types of risk.

THE ROLE OF PATIENT NAVIGATORS IN CLINICAL TRIAL PARTICIPATION

It is well established that few patients with cancer partici- pate in clinical trials and that even fewer racial and ethnic minorities participate.26,69,70 Without the inclusion of rep- resentative populations, treatments cannot be widely en- dorsed as effective in all populations. Drawing from the

Accrual to Clinical Trials Framework,71 reasons for low enrollment into clinical trials can be conceptualized into multiple levels, including the community, the system, the provider, and the patient (Fig. 1). Each level interacts with the others, and each level has multiple influences. For example, the community can influence the beliefs of pa- tients about clinical trials; the most notable example, the U.S. Public Health Service Syphilis Study at Tuskegee, still conveys mistrust toward the health care system, especially with regard to research among minority communities.72,73

For providers, the system they work within can either impede or enhance their abilities to enroll patients in clinical trials by imposing burdens of patient volume or facilitators, such as prescreening for trial eligibility.71

Moreover, patients are often influenced by family mem- bers and friends in their decisions to join a trial,74,75

whereas physicians are influenced by factors in their training and peer groups about perceived biases or tools to help approach patients about trials.71 Regardless of the myriad reasons for historically low rates of clinical trial participation, efforts are needed to address barriers to trial accrual at many levels.

One strategy to address barriers at multiple levels is patient navigation (PN). Dr. Harold Freeman formally described and implemented PN in 1990 in response to the high rates of late-stage breast cancer and mortality in the community of Harlem, where he practiced as a surgeon.76 Dr. Freeman employed women from the community to educate and address barriers to receiving mammography and follow-up visits for a positive test. As a result, others began using PN across the cancer control continuum. PN works first by identifying barriers to the specific action recommended and then by facilitating strategies to eliminate these barriers on an individual basis. Barriers can be at the patient level (e.g., education about the need for a test), at the system level (e.g., unable to get an appointment at a convenient time), or even at the community level (e.g., no public transportation to the clinic) and can include factors related to the social determinants of health (e.g., homelessness).77 Navigators can be lay or for- mally trained as nurses or social workers, but, to be most effective, they must be good communicators, familiar with social services in the area, and respectful of all cultures and persons.78,79 Many PN programs employ individuals who are racially, ethnically, and culturally matched to the population they serve and, often, bilingual.

Mostly, PN has been demonstrated to be effective in re- ducing the numbers of patients lost to follow-up, the delays in receiving diagnostic resolution, and the lags in starting treatment after an abnormal screening test; more recently, PN has increased the numbers of patients who complete treatment.80-82 Few studies have used PN to increase accrual to clinical trials or increase adherence and retentionFIGURE 1. ACT: Accrual to Clinical Trials

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of participants in clinical trials. In 2014, Ghebre et al83

published a review of PN studies that focused on en- hancing minority accrual to clinical trials. Although they found 12 studies that focused on a variety of racial and ethnic groups to include in their review, the studies only focused on training the navigators; no study used a suitable design to assess the effect of PN on the outcome of trial accrual. Fouad et al84 reported a community-based ap- proach that used a community health advisor (CHA) model to enroll minority and low-income women in a clinical trial and to improve adherence and retention among those enrolled. Although the study design did not allow an as- sessment of the effect of the CHA model on accrual rates, adherence to subsequent clinic visits in the study was significantly higher among the women who were recruited by a CHA (80% vs. 65% in control group, p , .0001). A second study by Fouad et al85 assessed PN as a factor in the recruitment and retention of black patients in therapeutic trials at the University of Alabama–Birmingham Compre- hensive Cancer Center. Navigators were trained and then asked to assist black patients with cancer who were po- tentially eligible for clinical trials. Specifically, the navigators provided education and individual support/assistance.

Because the study used a nonrandomized design and lacked a control group, the investigators could not assess the effect of PN on accrual. However, important findings from this work included the following: 75% of navigated patients completed the trial compared with 38% of those who did not receive PN (p , .001); and, during the study period, accrual of black patients to therapeutic clinical trials at the institution in- creased from 9% to 16% (from 2007 to 2014).

Last, the Education Network to Advance Cancer Clinical Trials sponsored a demonstration project at multiple sites—Ohio State University Cancer Care Center, Columbus, OH; and Greenville Health System Cancer Institute, Greenville, SC—from July 2013 to March 2014 (written communication with Margo Michaels, January 2019). The goals of the project were to increase discussions about clinical trials and increase trial participation. The strategies the navigators used included patient education about clinical trials, question listing (before patients saw research staff), and patient activation (to have an active role in de- cision-making). The flow of the PN activities and clinical care is shown in Figure 2. Although the program did not achieve its recruitment goal or show a benefit in accrual, several important findings were observed: (1) self-efficacy

FIGURE 2. Cancer Clinical Trial Patient Navigation: When Is the “Button Pushed”

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increased significantly among participants from pre- to post- test times; (2) knowledge about clinical trials increased; and (3) the likelihood of joining a clinical trial increased.

Taking all of this prior work into account, several recom- mendations are apparent. First, patients do appear to benefit from the support of a navigator who is in their corner. Second, having PN programs can improve many metrics related to clinical trial accrual, such as knowledge and retention. Third, integrating PN into the clinical trial accrual process is feasible. Notably, the Education Network to Advance Cancer Clinical Trials program recommended that

documentation of prescreening of all patients for clinical trial eligibility and the inclusion of clinical trial navigators should be mandated (written communication with Margo Michaels, January 2019). With training of the research and clinical staff as well as adequately trained navigators, such sug- gestions have the potential to increase not only overall accrual to clinical trials but also accrual of racial and ethnic minorities. To accomplish this, adequate funding of PN programs and appropriate study designs to assess the impact of PN, in addition to the willingness of study sites to test these strategies, are needed.

AFFILIATIONS 1Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 2Harvard Kennedy School, Harvard University, Boston, MA 3Department of Internal Medicine, Division of Cancer Prevention and Control, College of Medicine and Comprehensive Cancer Center, Ohio State University, Columbus, OH

CORRESPONDING AUTHOR Ryan Nipp, MD, Massachusetts General Hospital, 55 Fruit St., Yawkey, Boston, MA 02114; email: [email protected].

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND DATA AVAILABILITY STATEMENT

Disclosures provided by the authors and data availability statement (if applicable) are available with this article at DOI https://doi.org/10.1200/ EDBK_243729.

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