4

Clinical Trial Site Enablement

Panelists considered practical ways to enable established and developing sites, including community-based practices, to increase capacity to conduct more equitable and representative clinical trials. They also discussed funding mechanisms and business plans that support site enablement and cross-sector opportunities for workforce development. The session was moderated by Kathy Mickel of the Society for Clinical Research Sites (SCRS).

THE NCATS CLINICAL AND TRANSLATIONAL SCIENCE AWARD PROGRAM

Joni Rutter, director of the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH) and member of the Forum on Drug Discovery, Development, and Translation, said that, despite significant progress in promoting trial inclusivity, “there is still considerable room for improvement,” especially regarding accountability. A range of barriers contribute to the lack of equitable representation, including access challenges (e.g., lack of childcare, inability to take time off from work), socioeconomic disparities, and trust issues.

The NCATS Clinical and Translational Science Award (CTSA) Program supports activities focused on translating research into practice,¹ including those aimed at addressing health disparities, increasing access of underrepresented populations to clinical trials, and training and retention of a diverse clinical trials workforce. The CTSA network includes partnerships between major academic institutions, Federally Qualified Health Centers (FQHCs), and community health centers. It has developed decentralized methodologies to enroll diverse participants in all 50 states. Successful methods include sending medications to people’s homes and using telehealth services to improve the health of rural populations. Rutter noted the importance of community engagement in these activities and the role of community members as ambassadors for research. More incentives can strengthen connections to community networks and reduce the barriers to accessing clinical research.

Another CTSA initiative is the Trial Innovation Network, which provides resources and consultation to help address critical roadblocks in developing multisite clinical research groups.² Rutter noted that the network has become a trusted source for clinical trial recruitment, engagement, and innovative study design due to its record of stability and accomplishment.

Rutter said the National Action Plan discussed by Bierer and Hanger (Chapter 1) can serve as a framework for a future in which equitable trial participation is the norm. She also referred participants to recent frameworks for assessing clinical trial site readiness, developed by an ad hoc collaborative associated with the Forum on Drug Discovery, Development, and Translation, which outline essential practices in six domains: the research team, infrastructure, study management, data collection and management, quality oversight, and ethics and safety (Buse et al., 2023). Together, these frameworks describe a pathway for better preparing new

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¹ See https://ncats.nih.gov/research/research-activities/ctsa (accessed September 9, 2024).

² See https://trialinnovationnetwork.org/ (accessed September 9, 2024).

trial sites and for increasing trial efficiency, which could improve access to clinical trials for underserved communities. Rutter closed by saying it is now the time “to move from strategic planning to strategic doing… we have fantastic plans and a call to action that outline the best ways to plant this diverse and thriving garden, and now it’s time for us to plant those seeds, tend to the garden, and hopefully see the results as better health moving forward.”

COMMUNITY HEALTH CENTERS AS PARTNERS

More than 31 million U.S. people receive primary care services at one of nearly 1,500 nonprofit community health centers, according to Amy Flowers, director of policy research at the National Association of Community Health Centers (NACHC). These populations include those who are uninsured (20 percent) or have public insurance (60 percent), have low income (90 percent), live in a rural area (40 percent), and/or identify with a racially or ethnically minoritized group (65 percent).

Flowers said, “The lack of diversity and representativeness in clinical data is a result of systematic exclusion of people of color, people who are living near poverty, people who lack reliable transportation, [and people] who have language barriers.” While mistrust of the clinical research enterprise is frequently cited as a reason underrepresented and marginalized groups do not participate, a multitude of recent studies show that they will do so at comparable or greater rates than their nonminority counterparts when asked; “the greatest predictor of participation is being invited,” she said.

Meeting the eligibility criteria can also be more challenging for individuals in underrepresented groups. For example, those without insurance often present for care at later stages of disease than those who are insured, which excludes them from clinical studies of early interventions. Those who do qualify for a study can face transportation, language, or scheduling barriers (e.g., inability to take time off from work).

Flowers said community health centers can be ideal partners for clinical trials because they serve the populations most frequently excluded. They address barriers to care for their patients, which are often the same as the barriers to trial participation. In addition, health center board membership reflects the community it serves since at least 51 percent must be patients of the center. This makes the board “a natural pool” to draw from to engage community members in the trial process from the start, including during study design. Furthermore, planning for inclusiveness also means recruiting trial investigators who are representative of the community.

A recent NACHC report found that about 40 percent of community health centers are participating in clinical research, and an equal number

are interested in doing so.³ However, barriers to be addressed include a strained workforce (e.g., not being fairly compensated for their role) and trust issues based on experiences with the clinical research enterprise.

VALUING DIVERSE REPRESENTATION IN DEVICE TRIALS

Megan Coylewright, an interventional cardiologist and vice chief of cardiology at Erlanger Health System, one of the largest public health hospitals in the country, shared her personal experience with running device clinical trials in diverse communities. She serves on the executive steering committee for 10 large randomized global trials for cardiac devices at Erlanger. She highlighted a left atrial appendage trial as a success in enrolling a population of diverse women, noting that bringing patients together to share their stories and encourage each other to participate significantly improved enrollment among underserved populations. She also successfully negotiated with industry to cover transportation and copayments.

A barrier to achieving greater diversity in clinical trials, Coylewright said, is the “focus on winning” among principal investigators (e.g., completing the trial as fast as possible or achieving the highest enrollment in the country). She clarified that “it’s not that we don’t focus on caring about our patients and that we don’t want representation, but it’s not anything that we’re told to value” and that the U.S. Food and Drug Administration’s (FDA) and Centers for Medicare & Medicaid Services (CMS) actions toward holding sites and study principal investigators accountable for representative enrollment goals will be “one of the most important ways to make an impact.” But attention is also needed on holding the major institutions conducting the majority of device trials accountable for representative trial enrollment.

EMPOWERING PARTICIPANTS

Cheryl Willman, executive director of Mayo Clinic Cancer Programs, shared her perspective on patient engagement, drawing from her 30 years’ experience working in tribal communities and as a native of the Midwest and a person of multi-mixed-race heritage. Willman spent 25 years building the comprehensive cancer center at the University of New Mexico (UNM), where she still holds a faculty appointment. When she started at the UNM hospital, 28 percent of patients were uninsured, 55 percent were Hispanic or American Indian, and the second most frequent reason for admission through the emergency department was undiagnosed advanced

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³ Broadening Research Participation through Community Engagement. (NACHC, 2024). See https://www.nachc.org/resource/report-broadening-research-participation-through-community-engagement/ (accessed September 9, 2024).

breast cancer. As a National Cancer Institute (NCI) comprehensive cancer center, UNM is held accountable for conducting clinical trials that meet the needs of its geographic catchment areas and achieving clinical trial enrollment that reflects the diversity of those areas. Willman also described her personal joy in being part Indigenous and getting to serve communities of Indigenous people.

Willman runs the NCI-supported Participant Engagement Cancer Genome Sequencing Center in New Mexico, which focuses on comprehensive sequencing for American Indian patients.⁴ This center has the trust of the community and has created equitable partnerships that align with cultural needs. The project engaged with tribal leaders from the start to establish parameters, such as that any biospecimens must be retained locally and the community has oversight of the repository. She explained that “in the tribal tradition, a piece of tissue, even if it’s fixed [in] formalin, is still a part of [the person]” and noted that the biorepositories are blessed. The community also retains ownership of their data and shares in the benefits of their use. All sequencing is clinical grade, data are returned to the participant and their health care provider, and free genetic counseling is provided along with navigation to care and free cascade testing of family members if appropriate. She also noted that one reason Indigenous peoples are often unwilling to participate in the All of Us Research Program is because their biospecimens are retained elsewhere without their knowledge of what happens to them.

Achieving true health equity in both health care and clinical research entails empowering communities. Collaboration with tribal governments is somewhat unique, she acknowledged, because they are sovereign nations. However, Black, Hispanic, and other communities “should have that same empowerment right.”

Willman discussed two innovative in-home clinical trial programs at Mayo Clinic. The Cancer Connected Access and Remote Expertise (CARE) Beyond Walls program, which has treated 30,000 patients, grew out of the advanced care at home programs initiated during the COVID-19 pandemic.⁵ It provides patients with a tablet that facilitates around-the-clock support from a physician and nurse. Allied health teams provide care in the home, which presents an opportunity to train a new field of medical researchers who specialize in home care and clinical trials. Cancer CARE Beyond Walls demonstrates the ability to administer cancer treatment in the community setting, and Willman said that it can serve as a model for building a decentralized clinical trial infrastructure. However, she noted some resistance to this model “because it changes the whole paradigm and all the

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⁴ See https://pe-cgs.org/ (accessed September 9, 2024).

⁵ See https://newsnetwork.mayoclinic.org/discussion/transforming-cancer-care-with-treatments-at-home/ (accessed September 9, 2024).

reimbursement models.” Mayo Clinic is conducting a national clinical trial through the program for delivery of subcutaneous nivolumab in the home versus in a health care facility.⁶

The second program is the Inclusive Cancer Care Research Equity for Black Men Consortium, a Department of Defense–funded program that provides home-based prostate cancer care to Black men.⁷ Willman said those enrolled in the trial are often hesitant to go to medical facilities to the point of forgoing treatment. The program also provides patient navigation services, psycho-oncology support, and emotional support

Mayo Clinic engages communities through organizations such as churches, Veterans of Foreign Wars (VFW) posts, and community-based registries of individuals who are interested in clinical trial participation should the opportunity arise. Willman concluded by saying the goal is “meeting people where they are,” which can be assisted by digital technology to enable “in-facility, home-based, and virtual digital care to support a patient… with any illness on their entire disease journey.”

FOSTERING COMMUNITY READINESS TO CONDUCT TRIALS AT SCALE

Kristen Nwanyanwu, a retinal surgeon and associate professor of ophthalmology and visual science at Yale University, discussed the Yale Equitable Breakthroughs in Medicine Development (EQBMED) program.⁸ It focuses on scaling clinical trials in the community, which requires building relationships and establishing credibility as a trustworthy partner. EQBMED starts with an assessment of an organization’s activities and readiness to be involved in clinical trials at scale, with a holistic approach to community engagement. Although “Yale is an ivory tower institution that hasn’t always been the best neighbor,” Nwanyanwu said Yale has leaders in health equity who have the social capital to work with EQBMED partners, such as Morehouse, to build community capability to serve as clinical trial sites. A key question is how to determine a community’s readiness to run a clinical trial at scale. This can involve understanding what necessary elements are already in place, what needs to be built, and what exclusionary ingrained systems need to be removed.

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⁶ Comparison of In-Home Versus In-Clinic Administration of Subcutaneous Nivolumab Through Cancer CARE (Connected Access and Remote Expertise) Beyond Walls (CCBW) Program (NCT06265285) (ClinicalTrials.gov, 2024). See https://clinicaltrials.gov/study/NCT06265285 (accessed September 9, 2024).

⁷ See https://iccare4blackmen.org/ (accessed September 9, 2024).

⁸ EQBMED is also discussed by Nwokedi-Nwaneri in Chapter 6. See https://medicine.yale.edu/ycci/researchspectrum/collab/equitable-breakthroughs-medicine-development/ (accessed September 9, 2024).

BECOMING TRUSTWORTHY

During the discussion, panelists expanded on the topic of establishing trust as an essential element of community engagement in clinical trials. Willman emphasized the need to be present in the community to better understand and know the community. For example, Mayo Clinic maintains virtual portals in the VFW posts in Jacksonville, Florida, and holds meetings there. At FQHCs in Arizona, Mayo Clinic has started the Demand Access program to bring culturally appropriate clinical trial navigators and staff to the community. Another approach is empowering community leaders to serve as advisors. Willman said that her advisory boards consist of cancer patients, survivors, advocates, and organizations who advise Mayo Clinic on what it is doing well, what could be improved, and what areas of research are most important to their community.

Coylewright said to consider shifting focus to the actions of health care providers and institutions to make them trustworthy in the eyes of the patient. She has observed that some physicians do not see it as their fault if patients do not trust them, and as a result, they will not make efforts to engage with those populations. Flowers agreed and added that while it is important to be in the community, it is also important to “be the community,” in the sense that people can identify with those conducting the study.

Rutter said NIH strives to instill the concepts of trust and trustworthiness in its requests for applications. One way the research enterprise becomes trustworthy is recognizing the true needs of the community and pivoting to meet that need, which enables future opportunities for clinical research. Moses agreed that working with the community requires one to be “fluid and flexible.” Helping a community address their more urgent social concerns before approaching them about clinical trial participation will help engender trust.

CREATING SUSTAINABLE FUNDING AND REIMBURSEMENT MODELS

Mickel observed that “it is expensive to do clinical research at the site level,” and many sites need resources to support diverse enrollment (e.g., infrastructure, training, staffing). Data from the SCRS’s annual surveys from 2016 through 2023 indicate that, on average, only 21 percent of the sites had 6 months of operating dollars.⁹ Rutter said major NCATS initiatives require leveraging the resources of multiple partners, including pharmaceutical and biotechnology companies, small businesses, and a range of patient

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⁹ For Site Landscape Surveys, see https://myscrs.org/learning-campus/white-papers/ (accessed September 9, 2024).

and community organizations. All partners “have to pay to play,” she said, but this can include in-kind or non-tangible contributions; the important part is collective contribution and action.

Yvonne Rodriguez, founder of Egality Sciences, said that it works to enable diverse trial participation by providing support to community-based organizations in areas such as infrastructure, training, and workforce diversity. She shared that many FQHCs are hesitant to work with Egality Sciences for fear that they will lose their federal funding due to the outside financial partnership. Although Rodriguez has received confirmation from the U.S. Department of Health and Human Services (HHS) that this is not the case, she said lay guidance could be issued so that communities have confidence that their funding will not be impacted. Communities are willing to engage, and she urged participants to “take a chance on the small corporations that want to be there and have boots on the ground.”

Willman agreed that an entrepreneurial approach is needed. She said the pharmaceutical industry has been very willing to fund CARE Beyond Walls demonstration trials and noted that one site is in a very rural area, several hundred miles from Mayo Clinic. However, transforming the delivery of care could require the evolution of reimbursement models. Oncology practitioners are concerned about CARE Beyond Walls because reimbursement models provide substantial payment for in-hospital delivery of chemotherapy, but in-home delivery is reimbursed at a fraction of the cost. Demonstration projects with CMS and other payers will help understand the financial impacts of such programs and how these innovative models of care impact parameters such as comparative effectiveness and patient satisfaction. Nwanyanwu said it is important to assess and acknowledge how much increasing inclusivity and representation in trials might cost.

SUSTAINABLE PARTNERSHIPS

Cherié Butts, medical director of the therapeutic developments unit at Biogen and member of the Forum on Drug Discovery, Development, and Translation, asked how best to enable sites to manage increased interest in clinical trials without becoming overwhelmed and turning people away, and, conversely, how community engagement in clinical research can be sustained when some must be turned away due to excess interest. Nwanyanwu said EQBMED is working on these issues of scale from both directions. One outcome is a bidirectional relationship to build capacity for trials in communities that have not had access, in partnership with institutions working to improve their community engagement in trials. Willman reiterated that a functional, integrated U.S. health care system is a prerequisite to a truly inclusive clinical trial system that empowers participants. Rutter suggested

looking to decentralized clinical trials as a model for expanding capability and diversifying approaches. She also observed that many trial sponsors use the same clinical research organizations, which does not enhance diversity. In addition, engaging FQHCs and primary care networks may be one way to promote inclusion without adding further stress to the system. Moses agreed that partnering with FQHCs is a key approach for diversifying clinical trials but added that these institutions are already struggling to engage some in the community in basic medical care. She suggested looking to how the Patient-Centered Outcomes Research Institute funds small studies by community-based organizations.¹⁰ Moses added that small organizations often start community programs and services with seed funding but then don’t not have sufficient data to secure additional funding to sustain them. She further observed that this lack of sustainability feeds the lack of trust communities have in outside organizations that approach them.

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¹⁰ See https://www.pcori.org/ (accessed September 9, 2024).