Improving access to therapeutic clinical trials: a randomized controlled trial of GUIDE navigation and reimbursement

Disparities in access to cancer clinical trials persist among patients with limited socioeconomic resources. Clinical trial navigation programs are an emerging solution to improve clinical trial access, although their components are varied and not well-described. Guiding participation toward Understanding, Inclusion, Diversity, and Equity in Cancer Clinical Trials (GUIDE) is an evidence-based clinical trial navigation program that focuses on financial reimbursement for trial-related expenses and clinical trial navigation services, including local resource connections. We are conducting a pilot randomized controlled trial of 100 adults with cancer who are eligible for a clinical trial to evaluate GUIDE implementation outcomes and preliminary efficacy in increasing clinical trial enrollment and retention, reducing the financial burden and resolving health-related social needs, and increasing patient trust, health-related quality of life, and resilience. Staff time and effort, participant time, overheads, and reimbursement costs of GUIDE will also be evaluated. Participants are randomized 1:1 to GUIDE with usual care versus usual care alone for a 6-month period. Usual care includes institutional social work and patient and financial navigation support. Although disparities in clinical trial participation may be addressed by clinical trial navigation programs, components of effective programs are not well-understood, in part due to a paucity of published protocols. To address these critical gaps in clinical trial representation and navigation program transparency, we present the GUIDE protocol. ClinicalTrials.gov, identifier NCT06484595.

Cancer clinical trials are critical for advancing the standard of care and improving patient outcomes (1). Historically, socioeconomically disadvantaged populations are underrepresented in clinical trials (2). Underrepresentation of socioeconomically disadvantaged populations in trials is likely multifactorial. Previously established barriers to clinical trial enrollment and retention include insurance, geographic location, health literacy, unmet health-related social needs (HRSN; such as housing, transportation, and food), and income (3–5). Underrepresentation in trials reduces the generalizability of trial results and consequently widens existing health disparities (6).

Clinical trial navigation programs, a new take on traditional navigator programs designed to assist patients in understanding and accessing the healthcare system (7), are emerging as a promising solution to trial disparities (8). These novel programs improve clinical trial access among underrepresented groups and are highly heterogeneous (8). Navigators may have a background in social work, nursing, or as community health workers, and may provide a variety of supportive services to patients considering or enrolled in clinical trials. Historically, clinical trial navigator programs have focused on education, healthcare system navigation, and/or clinical trial navigation (9–11). For example, an oncology nurse-based program at the University of Southern California increased participation among Black patients with cancer by screening eligible patients, providing education and administrative support, serving as a liaison between patients and medical and study teams, and coordinating appointments and trial procedures (12).

In recognition of the impact of HRSN on trial participation, several programs that provide both trial navigation and HRSN support have recently been developed and/or demonstrated efficacy (8, 13–15). Early evidence suggests navigator programs may increase clinical trial enrollment and retention, improve patient satisfaction, reduce HRSN, and provide cost-effective solutions (10–12, 16). Few of these programs feature financial reimbursement for trial-related expenses (17) or leverage multilevel targets by combining both reimbursement and navigation support (18). The core components of successful navigator programs remain unknown. To address this gap, we developed Guiding participation toward Understanding, Inclusion, Diversity, and Equity in Cancer Clinical Trials (GUIDE), a clinical trial navigator program, and methods for formal evaluation via a randomized controlled trial (RCT).

GUIDE is a multilevel clinical trial navigation program that offers both reimbursements for clinical trial-related expenses and navigation services. The program design is informed by patient and provider perspectives previously evaluated in a qualitative interview-based study, per established behavior intervention guidelines [obesity-related behavioral intervention trials (ORBIT) phase 1A] (19, 20). The GUIDE program differs from the majority of existing interventions in that it evaluates a multilevel clinical trial program, leveraging existing clinical trial screening to offer navigation services and reimbursements. Here, we present the GUIDE RCT protocol. This pilot study is designed to primarily evaluate GUIDE's feasibility, acceptability, and appropriateness among patients eligible for a clinical trial. The exploratory GUIDE RCT outcomes examine its preliminary efficacy across multiple domains, including trial enrollment and retention, patient trust, health-related quality of life and resilience, health-related social needs, financial burden, and program cost.

Study design

A formal evaluation of the GUIDE program’s feasibility and preliminary efficacy is ongoing via an RCT pilot of 100 patients with cancer who are eligible for a therapeutic clinical trial (Clinicaltrials.gov identifier: NCT06484595). Patients are randomized 1:1 to the GUIDE intervention with usual care or usual care alone for a 6-month period (Figure 1). Participants on the GUIDE arm receive additional support in the form of clinical trial navigation and financial reimbursements from a Guide or clinical trial navigator.

Study setting

The GUIDE pilot RCT is being conducted at the Fred Hutchinson Cancer Center, part of a National Cancer Institute-designated comprehensive cancer center in Seattle, WA, that includes Seattle Children's Hospital and the University of Washington. Participants are recruited from five clinics, namely, the Breast, Genitourinary, Lymphoma, Myeloma, and Head and Neck Cancer Clinics. These clinics participate in the clinical trial prescreening (CTPS) program. CTPS is a pre-existing clinical research nurse screening program that systematically identifies patients who meet eligibility criteria for open clinical trials and shares the determination of eligibility with the appropriate clinical teams.

Objectives

The primary objective of this study is to evaluate a) the feasibility, acceptability, and appropriateness; and b) the preliminary efficacy of a novel clinical trial navigation program. The secondary objective is to quantify GUIDE program costs for patients and healthcare systems.

Eligibility and inclusion

Participants are 18 years of age or older, speak English, and have been identified as potentially eligible for a therapeutic cancer clinical trial. Potentially eligible participants are identified via oncologist referral or the CTPS program. Eligibility for GUIDE includes having at least one HRSN defined by either (1) patient-reported transportation, food, and/or housing insecurity or financial hardship) on an institutional Supportive Care Questionnaire; (2) provider or patient-reported concern regarding trial participation due to HRSN; (3) Medicaid insurance; and/or (4) patient-reported interest in receipt of assistance with HRSN. Participants are permitted to simultaneously receive sponsor-provided reimbursement/financial assistance.

Recruitment and randomization

A CTPS clinical research nurse or an oncology provider refers potentially eligible patients to GUIDE. GUIDE staff verify participant eligibility for GUIDE and initiate contact via e-mail. If participants do not respond within 2 weeks, staff follow up via telephone. Staff screen for HRSN, review study information, and obtain consent. Participants provide consent and Health Insurance Portability and Accountability Act (HIPAA) authorization in person during a scheduled clinic visit or electronically with documentation in the Research Electronic Data Capture (REDCap) web application. Enrolled participants complete a baseline survey and receive $50 upon completion. Upon completion of the baseline survey, patients are randomized 1:1 to GUIDE with usual care or usual care alone using a permuted block randomization procedure with stratification by clinic. All participants who identify as a marginalized racial or ethnic group were invited for interviews and the remaining non-Hispanic white participants were randomly selected, for a total of 20 interviews.

Clinical trial participation, socioecological model, and GUIDE

Influences on clinical trial participation exist at multiple levels, e.g., structural/policy, community, institutional, and individual levels (Figure 2) (21, 22). Thus, we designed GUIDE as a multilevel clinical trial navigator program to address individual- and institutional-level barriers. Specifically, GUIDE connects participants to existing institutional resources and personnel and addresses individual-level HRSN and financial barriers.

GUIDE intervention arm (plus usual care)

The Guide role

Participants randomized to the GUIDE intervention arm are assigned a Guide. The Guide provides clinical trial navigation, identifies trial participation barriers, and facilitates trial-related expense reimbursement and resource connection (Table 1). The Guide’s roles and responsibilities are informed by previous findings regarding patient and provider perceptions (20). The Guide holds a master's in health administration and American Cancer Society (ACS) Leader in Oncology Navigation, Clinical Trial Navigation, and Leadership in Oncology Navigation Mastery certifications. In addition, the Guide completed the ACS Clinical Trial Navigation training, distinguishing this program from traditional patient navigation. During the initial meeting, the Guide introduces the therapeutic clinical trial under consideration or, if the patient has already consented to participate, reviews the schedule of required and optional visits and assessments, identifies trial-related barriers, and discusses resources to address these barriers. The Guide meets with the intervention participants at least monthly via phone, Zoom, or in person for 6 months, regardless of therapeutic clinical trial enrollment status.

Clinical trial-related reimbursements

Participants receive up to $2,000 in reimbursements for clinical trial-related expenses. A priori, a list of qualifying expenses is shared with the participants (Supplementary Data Sheet 1). Examples of expenses eligible for reimbursement include temporary housing, mileage, taxi/rideshare, public transportation, laundry, hotel Wi-Fi, parking, childcare, eldercare, and personal and caregiver meals needed to attend clinical trial appointments. Expenses that are not covered include first-class or luxury upgrades for airfare, personal travel extensions not related to the clinical trial, luxury accommodations, guest (non-caregiver) meals, alcohol, charity donations, excessive tips, or entertainment. Participants receive monthly updates regarding remaining funds available. Patients who incur clinical trial-related expenses to determine their eligibility for the therapeutic clinical trial are eligible for reimbursement. However, if the patient is found to be ineligible for the therapeutic trial or discontinues participation in the therapeutic trial, they are no longer eligible for reimbursements, only navigation services.

Usual care

All participants of this RCT receive usual care. This study is conducted at an NCI-designated Cancer Center in which patients have access to a multidisciplinary care team, including a patient and family resource center, housing options, nutrition, social work, spiritual health teams, and patient navigators. Patient navigators assist with healthcare navigation, including assistance with transportation, lodging, social services, support groups, financial, employment, or insurance affairs, cultural bridging, communication, and scheduling healthcare services (23). Participants in the usual care arm receive standard clinical services for the 6-month duration of the RCT; patients with identified HRSN are referred to patient navigation to address these HRSN.

Primary outcomes

Primary RCT outcomes include GUIDE feasibility, acceptability, and appropriateness in concordance with Proctor’s implementation outcomes (24). All outcomes are assessed at 6 months via patient and provider qualitative interviews and survey data.

Exploratory outcomes

Exploratory outcomes will include clinical trial enrollment (i.e., the proportion of participants in each arm that are enrolled in a clinical trial) and clinical trial retention (i.e., the proportion of participants retained in a clinical trial). Additional exploratory outcomes include patient trust, health-related quality of life, resilience, health-related social needs, and financial burden. GUIDE program costs (staff and participant time, staff effort, overheads, and reimbursement costs) will also be evaluated.

Procedures

A baseline survey of participant demographics (sex, gender, sexual orientation, race, ethnicity, annual household income, educational attainment, employment, and disability) and baseline preliminary efficacy outcomes is collected at enrollment. The outcomes and corresponding validated scales and Cronbach's alpha (a) are as follows: patient trust via the Patient Trust: Interpersonal Physician Trust Scale (a = 0.89) (25), health-related quality of life via the patient reported outcomes measurement information (PROMIS) Global Health Score (a = 0.91) (26), resilience via the Connor–Davidson Resilience Scale (a = 0.85) (27, 28), health-related social needs via the eight-item Health Leads Screening Toolkit (29), and financial burden via the 12-item Functional Assessment of Chronic Illness Therapy - Comprehensive Score for Financial Toxicity (FACIT-COST) (a = 0.92) (30). Each scale is 10 items unless otherwise noted. A 6-month follow-up survey includes a brief demographic inquiry and the five outcomes featured in the baseline survey.

A subset of participants randomized to the GUIDE intervention arm are invited to participate in a 6-month follow-up 1:1 semistructured qualitative interview, with a goal of 20 interviews to achieve thematic saturation (31). To ensure diverse representation, all the GUIDE-arm participants who identify as historically marginalized racial and ethnic groups are invited to participate in the qualitative interviews. A trained staff member conducts interviews with a 12-question interview guide that assesses GUIDE feasibility, acceptability, and appropriateness (Table 2). The interview explores general perceptions of and experience with GUIDE and each of its major components, namely, the Guide and the financial reimbursement. Participants are compensated $75 upon interview completion.

Statistical analysis

Sample size justification

The sample size of 100 participants (50 per arm) is justified by the feasibility of enrollment within the planned recruitment window, the precision of the resulting between-arm effect-size estimates, and descriptive minimum-detectable-effect-size anchors. We anticipate that this feasibility pilot study of 100 participants may be underpowered to detect small or moderate differences in the preliminary efficacy outcomes between the GUIDE and usual care arms. Assuming a 90% retention rate over 6 months, this pilot RCT has at least 80% power to detect a 0.56 standard deviation (SD) in continuous preliminary efficacy outcomes (patient trust, health-related quality of life, resilience, etc.). Equivalently, in terms of precision, the 95% confidence interval half-width on a between-arm difference in continuous outcomes is approximately ±0.4 SD. These calculations are presented as descriptors of the precision and detectability achievable with the planned sample, not as a basis for confirmatory hypothesis testing. Consistent with the ORBIT Phase IIb framework, the pilot is sized for feasibility assessment and precision of preliminary effect-size estimates that will inform sample-size planning for future trials.

Analysis plan

Descriptive statistics will characterize participant and clinical demographics, treatment, clinical trial enrollment, and retention in each arm of the study, abstracted from the electronic medical record. For clinical trial enrollment, the proportion or number of participants enrolled in a clinical trial out of the number of participants randomized to the arm will be compared between arms at 6 months. Clinical trial retention is evaluated by the proportion of participants enrolled in a clinical trial at 6 months compared to the proportion of participants enrolled in a clinical trial.

Differences in the baseline and 6-month assessments of continuous preliminary efficacy outcomes, including patient trust, health-related quality of life, resilience, and resolution of HRSN, among participants in the GUIDE intervention and usual care arms will be assessed and compared using linear regression models. Point estimates and 95% confidence intervals of between-arm differences will be calculated. Alternatively, we will also fit a linear mixed-effects model that uses measurements at both timepoints as outcomes (with intervention arm, time, and their interaction as predictors) and accounts for repeated measures by random intercepts. For binary endpoints (e.g., proportion of patients that enroll in a clinical trial), logistic regression models will be used to compare differences in proportions between the two arms. All analyses will be conducted using an intent-to-treat approach, in which missing data at 6 months are considered missing at random. Consistent with the pilot nature of the proposed work, we will focus on providing point estimates and 95% confidence intervals for differences in outcomes between the two arms, which could inform the design of fully powered studies in the future, and we will interpret the comparison cautiously. Consequently, no formal hypothesis testing is performed on the preliminary efficacy outcomes. Acknowledging the limitations of a reimbursement model requiring upfront coverage of trial-related expenses by participants, we will evaluate GUIDE primary outcomes in two subgroups, i.e., low- and high-income participants, to distinguish whether GUIDE efficacy differs by socioeconomic status.

To estimate the cost of the Guide intervention, monthly cost data will be presented separately for the implementation period and the pilot trial. It will be tabulated overall and from a patient (not including overhead or GUIDE intervention costs) and health systems perspective (not including patient time). We will report total costs, staff time and effort costs to deliver the intervention, participant time costs, overheads, and reimbursement for trial-related expense costs. To enhance the generalizability of our estimates, we will use national estimates to value time and overheads. All costs will be standardized to 2024 USD. Costs will not be discounted, given the short time horizon of this study.

Qualitative analysis

Interviews will be professionally transcribed verbatim and uploaded into Dedoose for coding. Two members of the study team trained in qualitative data analysis will code transcripts using a hybrid deductive-inductive approach, combining framework and thematic analysis (32, 33). Deductive codes representative of the primary outcomes (acceptability, feasibility, appropriateness) will be developed based on Sekhon's acceptability framework and Proctor's implementation outcomes taxonomy (24, 34). Program-specific codes will be developed to capture experiences with the overall GUIDE intervention and its components (e.g., reimbursement and the Guide). Inductive codes will be developed to capture themes not anticipated by the deductive coding structure.

Study progress

The GUIDE pilot RCT enrolled the first participant on 15 July 2024 and completed enrollment as of 14 July 2025. The GUIDE Consort Diagram, which details the flow of participant eligibility screening and enrollment, is presented in Figure 3. Data collection, including 6-month follow-up surveys and qualitative interviews, concluded in January 2026.

Case examples

To illustrate the variety of services GUIDE provides, we present the following cases:

Case 1: Patient A is an unemployed young adult pursuing higher education, covered by their parent’s private insurance. They live in a nearby suburb with a caregiver. They are considering enrollment in a phase I/II clinical trial. They endorse housing, transportation and food insecurity, and financial toxicity. They are supported by Supplemental Nutrition Assistance Program benefits. GUIDE referred Patient A to the Fred Hutch Patient and Family Assistance Fund, Blood Cancer United, Cancer Lifeline, and the National Collegiate Cancer Funds for financial assistance during the trial. Patient A utilized the reimbursement to purchase caregiver airline tickets, gas for travel, meals, and medical bills. The Guide interacted with Patient A six times and dedicated a total of 309 min (5.2 h) toward assistance for Patient A.

Case 2: Patient B is a senior with private insurance, eligible for a phase II study. They were employed prior to their diagnosis but are now unable to continue to work as a direct consequence of their cancer diagnosis and treatment. The Guide assisted Patient B in applying for financial assistance through Blood Cancer United, Leukemia and Lymphoma Foundation, CancerCare.org, the HealthWell Foundation, and the Fred Hutch Patient and Family Assistance Fund. Patient B utilized the reimbursements to cover prescriptions, meals, utility and medical bills, and meals. The Guide interacted with patient B 18 times. The Guide dedicated a total of 944 min (15.7 h) toward assistance for Patient B. These reimbursements allowed Patient B to address a maintenance problem that was inhibiting meal preparation at home.

Novel interventions to improve cancer clinical trial access are needed to advance patient outcomes. GUIDE is a clinical trial navigation program developed with oncology staff and patient input (20). GUIDE is designed to improve clinical trial enrollment and retention by addressing barriers to trial participation. GUIDE differs from other programs as it is a multilevel intervention leveraging an existing research nurse-led CTPS system to assist patients with clinical trial navigation, financial reimbursement, and resource connection. To date, clinical trial navigation programs are highly variable in design. We present the GUIDE protocol to enhance the transparency of the key components hypothesized to be necessary for a clinical trial navigation program.

The GUIDE program has several strengths. GUIDE leverages CTPS, a screening program in which clinical research nurses systematically identify potentially eligible patients for clinical trials. As CTPS is integrated into the remaining cancer clinics, future iterations of GUIDE will expand to include patients with other cancer types. Establishing a clinical trial screening program is a critical first step to implementing a clinical trial navigation program. Systematic screening may address multilevel barriers, including alleviating administrative burden, increasing provider awareness of clinical trials, and reducing provider bias in the offering of clinical trials.

Another strength of GUIDE is targeting HRSN via clinical trial-related reimbursements. Although reimbursements are precedented in addressing financial hardship for patients with cancer (35), they have rarely been featured as a component of clinical trial navigation programs (14). This paucity of interventions may be secondary to historical concerns around inducement. However, reimbursements and incentives for clinical trial participation are considered ethical and even encouraged according to the World Health Organization, National Institutes of Health, and National Academies of Sciences, Engineering and Medicine, provided they are appropriately sized and approved by a research ethics committee (36–38). These compensation methods have independently demonstrated efficacy for recruitment and retention (39, 40). Further, they enable participants to address their own unique barriers to clinical trial participation with precision and autonomy.

GUIDE offers a novel multilevel approach to reducing disparities in clinical trial access. GUIDE directly addresses institutional-level barriers by providing patients with a dedicated staff member to serve as their clinical trial “Guide.” The Guide connects patients with institutional resources such as financial and/or patient navigation, social work services, community resources, and clinical trial representatives. GUIDE also addresses individual-level barriers through financial reimbursement. This personalized approach of a Guide getting to know patients, matching each patient's unique needs to relevant resources, and ongoing check-ins enables regular communication. Relationship building is a major strength of the program.

Several lessons were learned as a result of GUIDE design and implementation. First, ethical considerations are critical to successfully implementing a financial assistance program. Our team proactively consulted the institutional medical-legal team to avoid barriers to implementing our program. Second, our team needed to create participant reimbursement processes that matched Accounts Payable requirements at our institution. Third, sustaining consistent communication with each disease-based clinic is required for effective implementation of the program, as each clinic has distinct clinical research procedures. This included multiple presentations to ensure trial visibility and stakeholder buy-in, as well as detailed discussions on preferred patient engagement methods tailored to each clinic. Finally, the determination of when to enroll participants in GUIDE proved challenging, as the timeline of clinical trial discussions and eligibility determination varies in duration and is a dynamic, multistep process. To address this challenge, the Guide approached patients after their final eligibility status was determined. This method may unintentionally exclude patients pre-emptively determined (by themselves or their providers) to have insurmountable financial or social barriers to participate in a trial, who may have ultimately benefited from GUIDE.

The primary limitations of this study are related to its implementation at a single, well-resourced institution in a comprehensive cancer center. Notably, the usual care-arm participants receive robust supportive services, which are considered the standard of care at the institution. Because GUIDE-arm participants will receive both usual care and GUIDE services, detecting a difference in trial participation between arms may prove challenging. However, GUIDE is a unique service for patients in that (1) it directly targets clinical trial participation and (2) as part of the navigation services, connects patients to existing support, such as financial, patient navigation, and social work services, when trial HRSN are identified. We rationalize that although many services exist at our cancer center, GUIDE offers a lens to HRSN that is specific to trial participation, and therefore, it is a unique program poised to address trial participation that is not currently the standard of care at any well-resourced cancer center. Nonetheless, if the GUIDE RCT results are negative, it may be difficult to conclude whether the program is broadly ineffective or ineffective in a highly resourced setting. Finally, although GUIDE may be plausibly generalizable and scalable to other high-resource settings, whether GUIDE is relevant in other care settings, such as community and/or rural settings, remains unknown.

Importantly, GUIDE must be considered in the context of a key limitation in the population it may serve. Some patients are not positioned to benefit from a reimbursement model, as it requires upfront payment with their own funds, which is not possible for the most financially disadvantaged. Recognizing this pitfall, we explored alternative modes of financial support (i.e., direct cash transfer, debit card, and gift cards) (37) but were unfortunately unable to overcome bureaucratic barriers, including inducement concerns, to implement them. Further exploration of these modes of additional support and their implementation will be critical to ensure the inclusion of patients with the greatest need. Therefore, GUIDE efficacy must be prefaced with relevance only to a patient population with the ability to pay upfront. Finally, GUIDE randomization occurs after a patient's trial eligibility is fully determined. Prior to this determination, there are many upstream trial enrollment factors that are not addressed by GUIDE. For example, trial design considerations such as permissive eligibility criteria and trial decentralization may safeguard the systematic exclusion of historically marginalized populations. Although GUIDE addresses multiple barriers, to fully address multilevel influences on trial participation, structural/policy, institutional, and community-level interventions will also be necessary.

GUIDE is an evidence-based clinical trial navigator and reimbursement program designed to reduce financial barriers to clinical trial participation. If successful, GUIDE may have the potential to reduce existing trial enrollment and retention disparities and advance cancer research equity.