Improving Rural Clinical Trial Enrollment: Recommendations From the Rural Health Working Group of the Alliance Clinical Trials Network

Individuals with cancer who live in rural areas of the United States face limited access to medical oncology providers, face long travel times for standard-of-care cancer treatment, and lack opportunities to participate in clinical trials.^1,2 A 2019 ASCO report Closing the Rural Cancer Care Gap provided a succinct overview of the challenges of rural cancer care and suggested solutions to address rural disparities.³ Of primary interest is improving the clinical trial infrastructure to encourage enrollment of rural populations through system-level changes.^4,5

Rural regions across the United States lack access to comprehensive cancer centers⁶ and have significantly lower density of oncologists than urban areas.^2,7 Furthermore, critical access hospitals, a lifeline of health care in rural regions, offer limited cancer treatment options for patients, in general, and rarely offer clinical trials.⁸ These geographic access barriers lead to substantial burden for patients and their caregivers just to receive standard therapies for cancer care. When clinical trials require additional appointment and follow-up visits, trial participation by rural patients is diminished.⁹

The novel coronavirus (SARS-CoV-2) and the resulting pandemic introduced unique challenges to oncology care and clinical trials across the United States. Cancer care delivery was halted, or services were greatly scaled back in many areas, which reduced screening for trial eligibility and even ceased clinical trial operations in some cancer centers.¹⁰ This situation, combined with patient hesitancy to travel and limited availability of ancillary services, such as imaging, further encumbered clinical trial conduct.

Adaptations to clinical trial regulatory and compliance procedures were put forward from the US Food and Drug Administration (FDA) and the National Cancer Institute (NCI) to encourage the continuation of ongoing trials and to support new trials opening despite the restrictions to in-person care delivery.¹¹ These adaptations included remote, electronic consent of individuals for trial participation, electronic-based patient monitoring, the use of telehealth visits, direct drug shipments to patients, and exceptions to receive standard of care therapy or have laboratory tests done outside of the patients enrolling location, among others.^10,12 These measures were intended to support the deployment and sustainability of clinical trials at a time when in-person contact was limited.

Alliance Clinical Trials Network enrollments from 2019 through 2022 demonstrated an increase in the percent of individuals enrolled in all trials from rural communities through the pandemic years 2020-2022. This was particularly magnified at the NCI Community Oncology Research Program sites (Appendix Fig A1, online only). While there are many possible reasons for this change, it is plausible to consider that the regulatory modifications related to COVID-19 clinical trial conduct played a role.

The Rural Health Sub-Committee (RHSC) of the Alliance Clinical Trials Network Community Oncology Committee, a community of interest that focuses on issues regarding rural clinical trials, conducted a survey of committee members in 2021 to understand member perceptions of how COVID-19–related regulatory changes affected clinical trial enrollment in their centers and clinics. The 14-question survey (Data Supplement, online only) was sent electronically to all RHSC members (N = 46) and was open for 60 days. Thirty-three RHSC members responded for a 71.7% response rate. Seventy-three percent (n = 24) of respondents reported an increase in rural patients enrolled on trials from pre-COVID (2019), 15% (n = 5) reported no change in enrollment, and 12% (n = 4) identified a decrease.

The COVID-19 regulatory process changes reported to have the greatest impact on clinical trial enrollment were remote consent (44%) and visit requirement adaptations (37%). Ironically, remote consent was also noted as the most common process change that resulted in clinic burden to enroll patients (48%). Respondents commented that there was a disproportionate burden placed on small centers or trial sites to incorporate telehealth and to use remote means of electronic telecommunications with study participants. Barriers identified included lack of computer hardware in clinics that was sufficient to conduct telecommunication visits, lacking or absent broadband connectivity reported by potential participants, low clinic staff knowledge about technology platforms, challenges with staff availability to conduct remote engagements, and lack of clinic space to accommodate a remote telehealth operations center. Reimbursement rates for remote engagements were also cited as problematic.

Respondents shared perspectives on the most common patient-level barriers to trial participation which included time and distance traveled to participate, concern about agents being tested, too much burden on family members, and number of visits required to participate. Finally, findings regarding the greatest clinic or site-level facilitators of rural enrollments were suggested as having a model for outreach and community engagement and having infrastructure resources to support trials such as common electronic health record (EHR) systems, staffing, and physical space. These findings suggest that success in enrolling individuals from rural areas requires not only study designs that can mitigate rural barriers to accessing trials but also intentional outreach and community engagement, attention to shared infrastructure resources across clinics, and common EHR tools to support trials in rural areas.

On the basis of the survey, the RHSC held working sessions over 3 months to explore broader perspectives from its members on recommendations that could leverage COVID-19–related regulatory changes and encourage attention to rural considerations in clinical trial development and conduct. The RHSC outlined the lifecycle of a clinical trial from concept design to trial deployment and sustainment and developed a framework for introducing rural considerations throughout the lifecycle. The framework focuses on three areas: (1) encouraging trial designs that are rural-friendly, (2) promoting best practices in rural community engagement, and (3) recommending business, process, and infrastructure elements that can facilitate sustainment in rural trial sites.

Using this framework alongside the expertise of our members, the RHSC developed a Rural Clinical Trial concept checklist (Table 1). The checklist intends to provide investigators insight on rural-friendly trial design elements at the inception of concept development and suggests approaches for investigators to implement these considerations into the study concept. The checklist also provides guidance to the Alliance Clinical Trials Network stakeholder groups as they help investigators review and refine concepts. Ideally, these considerations reduce unnecessary trial complexity, enhance integration of the flexible regulatory changes that resulted from the pandemic, and support trial deployment and enrollments in rural areas. The primary target audience for this checklist is investigators who are considering concept development for a national clinical trial. The checklist should be used as a guide to introduce concepts that ease the burden associated with rural oncology clinical trial participation.

TABLE 1.

Checklist

Trial Design Consideration	Methods	Approach
Classify rurality of participants13	On the basis of the goals of the study, identify a rural classification coding system to guide target recruitment and/or characterize study participants  RUCC—County-level classification of rurality on the basis of   population and proximity to metropolitan areas  RUCA Codes—Census tract and zip code classification of rurality   on the basis of geographic proximity and commuting flow into and out of urban centers  UIC—County-level classification on the basis of proximity to   nearest metropolitan area  FAR Codes—Zip code level classification on the basis of travel   time by car to nearest urban area Codes can be used to reflect rural residency at the level of the individual, however could also be used to delineate rurality at the clinic site level	Use a classification system to delineate between urban and rural study participants for accrual tracking Consider if an objective of the study is to target enrollment of rural populations and choose a classification system that aligns with the study intent to establish enrollment thresholds  eg, >50% of enrollment will be among patients residing in RUCC 4 and above areas
Low burden imaging	Minimize repeated imaging tests within the trial. Use an approach that is least-intrusive as possible Minimize the number of complex imaging tests	Consider partnerships with rural hospitals or health care centers for repeat imaging Identify mobile imaging units, if available, as potential partners Align with NCCN current guidelines for standard of care Consider insurance coverage barriers when exceeding established standards of care Broader window of image eligibility (eg, minimum of 4 weeks) Allow consideration of anatomic imaging (CT) in lieu of functional imaging (PET), when appropriate
Remote consent	Make available to all participants	Continue to allow phone consenting with witness for remote consent Collaboration and training with local health care or community centers/extension offices
Telehealth/mobile technology	Leverage to provide  Educational interventions  Patient-reported outcomes measures  Symptom and toxicity tracking	Consider app-based symptom tracking systems Expanded collaboration with local providers giving access and roles on (decentralized) clinical trial platforms (eg, Commercial Off-the-Shelf platforms like Thread Castor, Clin Capture, built into EHR if available)
Financial support for rural patients	Budget for or collaborate with local foundations to provide transportation incentives to individuals traveling a certain distance to study site Budget for or collaborate with local foundations to provide accommodations for individuals who travel extensively for trial participation	Partner with county or state services for transportation or accommodations needs Budget for transportation incentives, such as gas cards or ride share vouchers per patient The tank of gas is a significant incentive and holds both important practical and symbolic significance
Local care delivery	Identify standard-of-care trial procedures that could be carried out at local clinics or provider offices including  Local drug delivery  Biospecimen collection  Imaging	Provide training to local providers and collaborate on standard drug delivery (eg, delivery of standard of care drug agent could be administered locally [Taxol] without requirement to travel)
Rural recruitment strategies	Consider community advisors from rural health offices Communication with local primary care provider regarding patient eligibility for trial enrollment	Use community events and organizations to socialize clinical trials with the community Conduct informational sessions with local community groups for knowledge and awareness

Abbreviations: CT, computed tomography; EHR, electronic health record; FAR, Frontier and Remote; NCCN, National Comprehensive Cancer Network; PET, positron emission tomography; RUCA, rural–urban commuting area; RUCC, rural–urban continuum codes; UIC, Urban Influence Codes.

Clinical trial regulatory adaptations introduced during the pandemic provide opportunity to enhance participation of rural patients in clinical trials. Encouraging remote patient engagement strategies through telehealth, remote consents, local drug delivery, local biospecimen collection, and local imaging create opportunity by reducing the in-person burden often reported by rural clinical trial sites and trial participants.

Further research is needed to investigate successful community-based engagement strategies. This could include developing multilevel interventions targeting providers, clinics, and communities to support clinical trial success in rural areas. Additional considerations for future work could include outlining preferred resources, staffing, and infrastructure for rural clinical trial sites to provide a business case model framework that could guide health systems and clinics in establishing for clinical trial sites in rural settings. Prospective studies that disseminate and study the implementation of these tools and practices to determine their influence on improving rural clinical trial enrollments would be beneficial.

According to May 2023, the FDA extension of FDA-2020-D-1106-0002, FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency, these modifications remain in effect for 180 days beyond the original May 11, 2023, expiration of the US Public Health Emergency Declaration. It is a stated intent of the FDA to further revise this guidance after the 180-day period. This review should be accompanied by data regarding clinical trial enrollments through the COVID pandemic including quality assurance and compliance insights from the NCI cooperative groups. Encouraging the continuation of these regulatory modifications, alongside concerted efforts to simplify trial design and improve community outreach, may help to shape a future of optimized enrollment of individuals from rural areas onto clinical trials.

APPENDIX

TABLE A1.

Working Group Members

Member	Institutional Affiliation
Iddrisu Adam	Marshfield Clinic Research Institute, Marshfield, WI
Timothy Adams, MBA	Washington University in St Louis, MO
Jeffrey Allen, MD	Kootenai Health, Coeur d’Alene, ID
Allison Anbari, PhD, RN	University of Missouri, Columbia, MO
Elizabeth Anderson, PhD, RN	University of Missouri Sinclair School of Nursing, Columbia, MO
Jennifer Anderson, BS, CCRP	Illinois CancerCare, Peoria, IL
Jane Armer, PhD, RN	University of Missouri, Columbia, MO
Sonikpreet Aulakh, MBBS, MD	West Virginia University, Morgantown, WV
Anne Blaes, MD	University of Minnesota, Minneapolis, MN
Carly Bye, RN, BNS, OCN	Essentia Health, Fargo, ND
Kate Castro, RN, MS, AOCN	National Cancer Institute, Rockville, MD
Mohamad Cherry, MD	Atlantic Health Cancer Consortium, Morristown, NJ
Jessica Cintolo-Gonzalez, MD	University of Vermont, Burlington, VT
Ashley Clodfelder, PhD	Carle Cancer Center NCORP, Terre Haute, IN
Deborah Collyar	Patient Advocates In Research (PAIR), Danville, CA
Shaker R. Dakhil, MD	Cancer Center of Kansas, Wichita, KS
Amanda Dinsdale, MHA, CCRC	Montana Cancer Consortium NCORP, Billings, MT
Konstantin Dragnev, MD	Dartmouth Cancer Center, Lebanon, NH
Tamara Fischer, RN, OCN	Sanford NCORP of the North Central Plains, Fargo, ND
Kelly Hirko, PhD	Michigan State University, Cancer Research Consortium of West Michigan, East Lansing, MI
Heather Kehn, RN, BS, MPH	Metro-Minnesota Community Oncology Research Consortium, Metro Park, MN
Farrah Khan, MD	University of Vermont Medical Center, Burlington, VT
Beth Knetter	Aspirus Regional Cancer Center, CROWN Consortium, Wausau, WI
Michele M. Lacy, RN, BSN, OCN	Metro Minnesota Community Oncology Research Consortium, Metro Park, MN
Minji Lee, PhD	Mayo Clinic, Rochester, MN
Benjamin Marchello, MD	Montana Cancer Consortium, Billings, MT
Devon Noonan, PhD, MPH, FNP-BC	Duke Cancer Institute, Durham, NC
Izumi Okado, PhD	University of Hawaii Cancer Center, Honolulu, HI
Scott Okuno, MD	Mayo Clinic, Rochester, MN
Tracy Onega	University of Utah Huntsman Cancer Institute, Salt Lake City, UT
Elizabeth Pantoja	Mayo Clinic, Jacksonville, FL
Jessica Schumacher, PhD	University of Wisconsin- Madison, Madison, WI
Rebecca Snyder, MD	University of Texas MD Anderson Cancer Center, Houston, TX
Christopher Strouse	University of Iowa, Iowa City, IA
Marie Wood, MD	University of Colorado Anschutz Medical Campus, Aurora, CO
Kathleen Yost MD	Cancer Research Consortium of West Michigan, Grand Rapids, MI

FIG A1.

Percent of rural enrollments (defined by individual-level RUCC¹³ designated areas) based on NCI Site Code. LAPS, Lead Academic Participating Site; NCI, National Cancer Institute; NCORP, NCI Community Oncology Research Program; RUCC, rural–urban continuum codes.

AUTHOR CONTRIBUTIONS

Conception and design: Nicole L. Stout, Daniel Nikcevich, Tara O. Henderson, Preston Steen, Matthias Weiss, Tammie Mlodozyniec, Betsy Barnick, Electra D. Paskett

Financial support: Tammie Mlodozyniec, Electra D. Paskett

Administrative support: Tammie Mlodozyniec, Amy Koffarnus, Betsy Barnick

Provision of study materials or patients: Daniel Nikcevich, Tammie Mlodozyniec

Collection and assembly of data: Nicole L. Stout, Daniel Nikcevich, Tara O. Henderson, Matthias Weiss, Steven Ades, Tammie Mlodozyniec, Amy Koffarnus

Data analysis and interpretation: Nicole L. Stout, Daniel Nikcevich, Tara O. Henderson, Preston Steen, Matthias Weiss, Steven Ades, Tammie Mlodozyniec, Amy Koffarnus, Electra D. Paskett

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Improving Rural Clinical Trial Enrollment: Recommendations From the Rural Health Working Group of the Alliance Clinical Trials Network

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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