5

Facilitators of Successful Inclusion in Clinical Research

The analysis draws substantially from the research paper by Franchesca Arias, Ph.D.; Nicole Rogus-Pulia, Ph.D., C.C.C.-S.L.P.; and Amy J. Kind, M.D., Ph.D., which was commissioned for this study. See Appendix C for the full research paper.

There is substantial quantitative data demonstrating the size and scope of the problem of underrepresented and excluded populations in research; however, there is a dearth of critical qualitative data about facilitators of successful representation in clinical research. The experiences of research teams who have successfully enrolled diverse participants contribute to a better understanding of the facilitators that can be leveraged to make progress. These data are needed to develop a robust science of inclusion that can help the field evaluate and scale effective, real-world engagement and recruitment strategies. To that end, this chapter provides an overview of evidence on sentiments, facilitators, beliefs, and attitudes from study investigators, staff, and participants for overcoming barriers to the inclusion of women and underrepresented minorities outlined in Chapter 4.¹ It highlights key themes and facilitators that have demonstrated effectiveness to enhance recruitment and retention of diverse populations in clinical studies. In each section, the findings include reports from 20 qualitative interviews conducted in 2021 with research teams (investigators and staff) involved in clinical trials who successfully achieved diverse enrollment. The research teams were identified using a systematic process to ensure that therapeutic areas were equally represented. (The next section summarizes the study approach; Appendix C con-

___________________

¹ The committee defines facilitators as strategies and factors that facilitate success in overcoming barriers to the increased representation of women and racial and ethnic minority population groups in clinical research.

tains the full analysis). These qualitative data are bolstered by evidence from the literature reviewed by the committee. Finally, this chapter summarizes practical and innovative facilitators, particularly those that may be replicable and scalable in future studies.

INSIGHTS INTO EFFECTIVE FACILITATORS AND STRATEGIES FOR INCLUSION

The qualitative evidence for this chapter is largely derived from a mixed-methods study that the committee requested be commissioned for this report (see Appendix C). The purpose of the study was to characterize current efforts on representativeness in clinical research and to systematically identify and describe recruitment and retention strategies that can contribute to more diverse clinical trial participant populations. Individual comprehensive interviews were conducted with research team members (an investigator or coordinator) with experience recruiting underrepresented groups. Twenty interviews were completed in 2021 that focused on understanding facilitators to recruitment and retention into clinical trials.

At the beginning of the study, the authors first identified the six diseases associated with highest mortality in the United States (heart disease, cancer, chronic lower respiratory disease, stroke, Alzheimer’s disease, and diabetes). Next, a systematic review was conducted to identify published clinical trials in these six therapeutic areas between 2001 and 2021 that successfully recruited diverse populations, defined as having at least 50 percent or higher enrollment of the county-level base rate, the state-level base rate, or the national-level base rate (for single-site studies, county-level data were used; for multisite studies, state-level data or national-level data were used, depending on whether sites were within the same state or dispersed across the United States) in at least one of the three categories of sex, race, and ethnicity mandated by the National Institutes of Health (NIH). From more than 130,000 trials that were identified, 162 trials stratified by disease and geographic location were selected. Of these, 142 trials met criteria for diverse enrollment (i.e., at least 50 percent or higher enrollment of at least one of the three NIH-mandated categories of sex, race, and ethnicity), and were invited to participate in interviews. Notably, less than 33 percent of these trials reported information about ethnicity, and less than 66 percent of trials included categories of racial/ethnic representation. Research team members (an investigator or coordinator) from each of the 142 identified studies were invited to participate in a qualitative interview (see Appendix C for full study details).

Based on 20 completed in-depth qualitative interviews with rigorous thematic analysis, 8 major themes emerged, which provided insights into key facilitators to inclusion. These themes are (1) starting with intention and agency to achieve representativeness; (2) establishing a foundation of trust with study participants and community; (3) anticipating and removing barriers to study participation; (4)

adopting a flexible approach to recruitment and data collection; (5) building a robust network by identifying all relevant stakeholders; (6) navigating scientific, professional peer, and social expectations; (7) optimizing the study team to ensure alignment with research goals; and (8) attaining resources and support to achieve representativeness. Table 5-1, at the end of the chapter, provides an overview of strategies to enhance inclusion derived from the interviews, organized by theme. Further details on each of these themes are described below.

Starting with Intention and Agency to Achieve Representativeness

From goal setting to community partnering strategies, intentionality and planning are critical themes for overcoming the systemic barriers previously outlined to the inclusion of underrepresented minorities and women in research (McMurdo et al., 2011). While planning and engagement with diverse communities is resource, time, and labor intensive, it is critical to advancing inclusion. According to research teams that participated in the analysis, “It’s a lot of work and a lot of time and it takes years. . . . We’ve been working with the same community partners now for 12, 13 years. They see us all the time.” They emphasized that a multistage process is required to achieve representativeness and that contact with communities should begin long before recruitment starts and extend long after the study ends.

Evidence suggests that to build relationships with the community, research should continue to affect changes in communities long after the study ends and throughout all stages of the study process (Gluck et al., 2018). Research teams emphasized that collaboration with community members specific to recruitment and retention strategies occurs across different stages of the study. For example,

Research teams reported that being intentional about having representation of historically underrepresented groups was instrumental to their success. Setting a priori recruitment goals for the inclusion of underrepresented groups is essential to planning and can help research teams measure progress and develop more effective engagement strategies (Javid et al., 2012).

Research teams also emphasized the importance of considering access barriers and the lived-realities of study participants in research design. For example,

Research suggests that prioritizing access to health-care resources can facilitate research inclusion for underrepresented communities (George et al., 2014).

Research teams also reported that intentionality is sometimes driven by external factors, such as requirements by funding agencies, the need to recruit from a given state or setting, and characteristics of the diseases, such as rates in diverse populations.

Establishing a Foundation of Trust with Participants and the Community at Large

Building and maintaining trust with both study participants and their larger communities is foundational to achieving equity in research (Barnes and Bennett, 2014). Research teams reported that the history of abuse in prior studies, experiences with other research groups that approached underrepresented communities for the purposes of a study and who did not remain engaged, and beliefs that research is not beneficial to the community are critical barriers to establishing trust with persons from diverse communities.

The development of trust requires a long-term commitment by principal investigators, study teams, and local institutions involved in the research. Building trust over time takes consistent engagement in the community beyond the confines of the study itself, developing meaningful relationships with study participants, and giving to the community without the expectation of anything in return (Kretzmann and McKnight, 1993). Research teams emphasized that while trust has to be built over time, trust can be broken with individuals and communities in an instant. For example, “There’s such trust building, that . . . takes a while. And if one person drops and doesn’t keep the trust, then I’m not going to be able to most likely get back that location again.”

Developing robust community partnerships that are equitable and not hierarchical in nature can mitigate distrust in communities and can help research teams effectively leverage resources for truly meaningful and translatable work in partnership with community members (Waheed et al., 2015). According to one research team member,

In addition to facilitating recruitment, establishing relationships with community leaders provided opportunities to understand the needs of the community in order to build trust over time.

Anticipating and Removing Barriers to Study Participation

To assure accessibility to study participation for members of underrepresented communities, anticipating and removing barriers to participation—which are described in Chapter 4—is critical. For example, one systematic review of 44 articles found that facilitators to research participation included tailoring recruitment strategies to each community group (George et al., 2014). Recognizing heterogeneity within cultural groups is key, and a one-size-fits-all approach will not work. Investigators should take an individualized approach, without compromising the science, to create protocols that allow for and acknowledge individual experiences. For example, according to one research team member interviewed, “There was no cultural tailoring at all. There was a ton of individualized tailoring. The intervention itself is highly individually tailored. And so we just developed personalized approaches to everyone. And, in doing that, we didn’t have to put people into categories to try to tailor to them.” Other important solutions include collaboration with interpreters to provide services to non-English-speaking prospective study participants and/or providing options for in-home or remote visits to overcome linguistic or physical access barriers. For example implementation of the asset-based community development, or ABCD, approach , which includes a high level of community assessment, engagement, and involvement before actual recruitment begins, in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) led to a 400 percent increase (from 0.8 to about 8.0 percent of the study sample (131 of 1,573) in the participation of African Americans (Green-Harris et al., 2019). These themes are also discussed in more detail in Chapter 2.

In Clark et al. (2019), study participants noted several strategies that clinical research staff could employ to overcome barriers and improve participation and retention in clinical trials, including “…rapport with participants; attentiveness and sensitivity to patients’ concerns or needs; flexible scheduling to accommodate participants after hours and on weekends; post visit follow-up telephone calls to assess participants’ well-being and address any concerns; and regular touch-base contacts with participants.”

Adopting a Flexible Approach to Recruitment and Data Collection

Research teams from the successful studies recognized the importance of flexibility to enhance recruitment and retention of diverse groups. Research teams frequently described recruitment strategies adapting and evolving as studies progressed. Recruitment techniques were incorporated or abandoned in response to study needs, and changes were guided by input from community representatives and other relevant stakeholders. This adaptability extended beyond recruitment. For example, flexibility at the time of data collection was reported as necessary to retain study participants, particularly those with limited resources or constraints on their time due to competing demands such as childcare or eldercare. For example,

Flexible approaches meeting study requirements were instrumental in the success of diverse enrollment. Several prior reports demonstrate this phenomenon. For example, one qualitative analysis of interviews with 30 Native Hawaiian women identified that disseminating study information through community channels with targeted outreach to religious and social organizations as well as face-to-face contact with researchers in a culturally tailored way would help with recruitment and retainment (Ka’opua et al., 2004). Another example comes from a recent randomized trial of a mobile health support program for diabetes self-care that utilized multiple retention strategies for minority populations. The strategies included flexibility in participation (e.g., multiple methods for data collection), communication (e.g., tracking contacts), and community building (e.g., study branding and newsletters). With these flexible and multipronged approaches, retention was greater than 90 percent at each follow-up assessment that occurred over 15 months (Nelson et al., 2021).

Recent U.S. Food and Drug Administration (FDA) guidance (Clark et al., 2019; FDA, 2020c) recognizes the need to make trial participation less burdensome to enhance recruitment, and supports the use of flexible approaches to reduce the frequency of study visits, to build in flexibility in visit windows, to consider electronic communication or digital health technology tools to replace site visits, and to consider the use of mobile staff to conduct study visits in study participants’ homes.

Building a Robust Network by Identifying All Relevant Stakeholders

Research suggests that engaging in mapping to identify all the relevant stakeholders in a community can help study teams develop more equitable study designs and identify individuals and organizations that can help drive the recruitment and retention of diverse study participants (Larkey et al., 2009).

According to the research teams that were interviewed, identifying these stakeholders and their level of needed involvement varied based on cultural preferences of the prospective study participants, the condition being studied, and the nature of the research study. The term stakeholder was defined broadly to include caregivers, family members, friends, clinical providers and administrators, community advocates, peers, religious leaders, and political figures.

Strategies for consistently engaging communities such as community advisory boards can help inform protocol development and study execution (Buck et al., 2004), whereas specific stakeholders, such as community health workers and

patient navigators, have been found to help drive the recruitment and retention of underrepresented groups in research (Choi et al., 2016). Studies consistently show that community health workers, who typically focus on informing patients about the importance of adherence to a particular healthy behavior and who patients can go to for help, support, and informal counseling, improve outcomes for patients. For example, in one study of community health workers in the Bronx (a borough of New York City), adding community health workers to a medical home led to a decline in emergency department visits and hospitalizations among patients with chronic health conditions (Findley et al., 2014). In another study, community health workers helped improve recruitment and retention of immigrant women in a randomized trial to promote mammograms and Pap tests (Choi et al., 2016). Patient navigators, who typically handle patient problems as they arise, may be inserted into health-care studies to help patients adhere to recommended care (Dohan and Schrag, 2005). In one of the foundational studies examining the effectiveness of patient navigators in expanding cancer screening and care in medically underserved populations, Freeman et al. (1995) found that patients who had a navigator were far more likely to complete recommended breast biopsies and do so in far less time than those without navigators. In fields where use of patient navigators is more common, such as cancer screenings and care, patient navigators help to catch disease at earlier stages, help ensure patients show up to follow-up appointments, and help ensure patients receive follow-up care once they have a diagnosis (TCFHA, 2012).

Important themes emerged related to patient and caregiver engagement. For example, developing relationships with caregivers and family members was identified as instrumental to recruitment and retention of underrepresented groups. According to one participant, “I realized that not talking to caregivers was a pretty big misstep in our original trial. If you have these populations that are vulnerable enough to have caregivers and other people who are already kind of with them maybe consider including them as part of the trial and obviously with patient consent, sort of incorporating it.” Further, conceptualizing study participants as partners in research was highlighted as important and requiring openness and flexibility by the study team to learn from the study participants’ experiences.

Navigating Scientific, Professional Peer, and Societal Expectations

Research teams described challenges related to scientific and societal expectations, which sometimes conflicted with maintaining scientific rigor. Many of the research teams perceived that efforts to promote representativeness, and decisions made to support these efforts, are not fully embraced or supported by colleagues and organizations responsible for making funding and/or budget decisions. Creative strategies designed to engage communities that have traditionally been underrepresented in research are often not valued relative to more traditional strategies, which tended to involve rigid protocols applied within standard working hours (e.g., 9

a.m.–5 p.m.), conducted onsite, and carried out by staff who were not multilingual. These traditional approaches to retention and recruitment may be burdensome for prospective study participants with multiple vulnerabilities, and may result in less participant diversity. Thus, providing a more flexible infrastructure (e.g., more flexible protocols, off-hours participation, offsite participation including by remote or in-home means) may be critical to enhancing participant diversity.

Research teams expressed concern that the current emphasis on recruitment and retention of diverse study participants contrasts with consistent underfunding of disparities researchers despite the additional costs needed to conduct diverse enrollment in all research studies. For example,

It is well documented that scientists from diverse backgrounds are less likely to obtain grant funding, publish as first author, and get promoted (Stevens et al., 2021).

Research teams emphasized that efforts to be intentional and plan ahead to prepare for additional costs related to this work are undermined by budget constraints. Funding agencies, as well as those responsible for approving proposals and distributing budgets, should be required to gain competencies in the challenges and costs associated with nontraditional research approaches to enhance inclusion.

Optimizing the Study Team to Ensure Alignment with Research Goals

All of the research teams that were interviewed described the composition of the study team as an important component of representative research. Research teams interact with potential study participants and are instrumental in the success of recruitment and retention. Diverse study teams were generally described as being helpful to recruitment to enhance congruence between research teams and potential participants, and this congruence was described in different ways depending upon the focus of the study (e.g., age, sex, race, ethnicity). Retaining study staff over time was also emphasized as very important to recruitment and retention success; however, this may be difficult given the competition for skilled study staff. For example, “So having the same staff at our site, we’ve had the same staff for 11 years now and are so thankful and grateful. And we’ve done everything to retain the staff . . . because they’re the face of the study.” It is important to note that cultural and linguistic congruence with the target population was not enough. Gaining engagement and community buy-in for the study goals

and desired outcomes were equally important when working with communities that are underrepresented in clinical trials and research. Several studies show that increasing the diversity of study staff and leadership leads to increased enrollment of diverse populations and improved reporting of results (Khan et al., 2020; Nielsen et al., 2017; Whitelaw et al., 2021). One study found that there was a greater likelihood of reporting sex-stratified results when a woman was either first or last author (Nielsen et al., 2017). Additionally, studies have demonstrated a positive association between the number of women as coauthors and a higher proportion of women participants in the research (Reza et al., 2020).

More can be done to train and develop the next generation of diverse principal investigators. Academic research institutions play a key role in diversifying principal investigators as they train a large percentage of the research workforce, including investigators and research staff. They have the opportunity to diversify the pathway of the students and future clinician-scientists entering health science professions and Ph.D. programs (see Box 5-1). To increase recruitment, retention, and advancement of diverse faculty, institutions can follow and invest in evidence-based practices, as described in Box 5-2.

Academic medical centers also play an important role in investing in and supporting research that designs and tests new strategies that are practical and pragmatic to enhance diverse recruitment of participants representative of the population with a given disease. Academic research institutions can offer training on systemic racism in research, implicit bias, and cultural sensitivities to researchers and research staff. They can also educate researchers on strategies to increase diverse enrollment, including use of broad eligibility criteria and avoiding sex-specific exclusion criteria.

In addition to efforts by academic medical centers, professional societies and federal agencies also have influence by providing training programs for both early- and mid-career women and underrepresented scientists. One example is the American College of Cardiology’s Clinical Trials Research: Upping Your Game program, which is designed to train the next generation of clinical trial team scientists by developing women and underrepresented populations in cardiology. This program includes three 2-day sessions that focus on clinical trials research; networking with other clinical trialists, investigators, industry leaders, and regulatory stakeholders; and developing a personal career action plan (ACC, 2022). Another example is the NIH’s Faculty Institutional Recruitment for Sustainable Transformation (FIRST) program, which aims to enhance and maintain cultures of inclusive excellence in the biomedical research community. These FIRST awards are given to academic institutions to recruit cohorts of early-career faculty who are competitive for assistant professor positions and have demonstrated commitment to inclusive excellence (NIH, 2021c). This is a relatively new program, so evaluation of the program is not available yet. However, the committee feels that these types of initiatives that encourage and promote enhancing diversity and inclusion in institutional contexts are critical for developing our future workforce.

Attaining Resources and Support to Achieve Representativeness

The investment of time and money are necessary to successfully engage in the long-term strategies and relationship building needed to drive inclusion in studies (Green-Harris et al., 2019). According to the research teams that were interviewed, funding for these recruitment efforts was of paramount importance, requiring special funding announcements focused on inclusion of underrepresented groups, expanded budgets for teams attempting to recruit and retain these groups, and flexibility within budgets to allow for deeper engagement of community partners. For example,

In addition to funding, research teams emphasized education of researchers and providing supports such as professional networks and institutional resources with expertise in these areas. Finally, material support for community organizations so that they can build infrastructure to enhance enrollment in clinical studies also emerged as an important long-term necessity to enhance inclusion. In particular, resources that could assist these organizations in building an ongoing foundation for research would create successful long-term partnerships (George et al., 2014). Investments in community-based strategies and partnerships are needed to help minimize the power imbalance between the researcher and participant in ways that build trust in research teams and institutions (BeLue et al., 2006).

The need for greater investments in the people, communities, and institutions engaged in research is echoed in Michos et al. (2021), which outlines several

large- and small-scale interventions by stakeholders for improving enrollment and reflecting the diverse U.S. population in research (see Figure 5-1) (see also Michos and Van Spall, 2021).

Investing in community-based research is critical for developing relationships and involving communities in clinical research. Community-based research takes place where people live, work, and play. Effective community-based research settings create a bridge between the community, scientific institutions, and researchers and build trusting partnerships that are essential for successful research participation. Together researchers and community members engage in the design and conduct of research with the goal of building trust and respect for the values, viewpoints, and interests of the community members. Specific examples of these partnerships are described in the Academic Institutions section, below.

There are many ways to involve community members in ongoing research. UCSF Accelerate (2022) provides a step-by-step guide for practicing community-engaged research, such as the following:

• Assemble a research team that includes community clinicians, clinic staff, and community members who are decision-makers. In addition, set up a patient advisory board that is involved throughout the process.
• In coordination with community clinicians and advisors, identify issues of greatest need and importance to ensure research is relevant and resonates with the community.

• Involve community clinicians and advisors in the writing process and determining study questions to address.
• Communicate the relevance of the study design, but also be prepared to modify the design with more community acceptable approaches, which may involve gathering focus groups or other qualitative measurements.
• Review findings with community members and disseminate results in a way that is appropriate to the community members.
• Include community clinicians and advisors as authors on scientific papers and presenters in community and broader settings.

Investing in the science of engagement and empowerment can also help overcome barriers to equity. As described below, funding agencies, institutions, and researchers all have a role to play in improving community engagement and empowerment.

Funding Agencies

Major funders have a mandate (and/or vested interest) to demonstrate return on investment. For example, the NIH budget is established and renewed by the U.S. Congress, which is responsible for its oversight. Federal research awards are typically funded for a period ranging from 2 to 5 years, a time frame that is meant to encompass all phases of research from project startup to results dissemination. Funding periods and budgets often discourage researchers from more participatory and emancipatory methods. Some funders are moving away from these models, and folding in stakeholder engagement as a major requirement of funding. For example, the Patient-Centered Outcomes Research Institute has invested nearly $3 billion in comparative effectiveness research on health since FY 2010 (PCORI, 2020). The institute engages patients and providers in identifying research priorities, trains patients to review and evaluate applications for funding, and requires that patient engagement be documented in every step of a research project, from the formulation of the research question to the research methods to dissemination of results (see Box 5-3).

Academic Institutions

Academic institutions play a significant—if sometimes obscured—role in community empowerment and engagement (as described in Chapter 4). For example, institutions set expectations for faculty productivity, which have impacts on the extent to which their faculty invest in community-engaged research. As noted above, academic institutions play a critical role in recruiting and retaining diverse faculty and investing in the future workforce.

Institutions and their surrounding communities also have natural ties, but these ties have not always benefited community members. Attention to issues

such as gentrification, local needs, areas of mutual interest, and sustainability can foster engagement and empowerment with community members. Institutions also have the flexibility to leverage internal funds (revenue, endowments) for community engagement and development. For example, in 2015 Indiana University announced it would dedicate $300 million to address health issues important to Indiana communities. The Grand Challenges program funded three major projects with distinct health foci, including precision health, environmental resiliency, and substance use disorders.² While these efforts are currently under way, they have led to an expansion of federal funds. The Grand Challenge on substance use disorder, for example, has helped hundreds of Indiana teens involved in the criminal justice system get screened for substance use issues, and has now expanded to eight additional counties with the help of a recent grant from the National Institute on Drug Abuse.³ The Wisconsin Alzheimer’s Institute, Regional Milwaukee Office, is another example of an institution investing in communities to address issues and build relationships with great success (see Box 5-4).

Many institutions also have affiliated health centers, which can play a key role in community engagement and investment. Many of these health centers partnered with communities to rapidly react to the outbreak of the COVID-19 pandemic, showing that this model is possible and effective for the health of the public. For example, the University of New Mexico partnered with the city of Albuquerque, local health departments, nonprofits, and more to assist seniors and individuals struggling with homelessness during the COVID-19 pandemic.⁴ In another example, the NIH-funded California Community Engagement Alliance (CEAL) consortium of 11 community-academic teams across the state (including academic health centers, community clinics, community-based organizations) developed locally tailored strategies to promote effective communication about COVID-19, improve participation of underrepresented groups in vaccine and therapeutic research, increase vaccine uptake, and enhance clinical and public health equity for the communities hardest hit by the pandemic (AuYoung et al., 2022; Stadnick et al., 2022).

CONCLUSIONS

This chapter provides evidence-based key themes that emerged from a qualitative study of 20 study investigators and staff to promote representation in clinical studies, and it delineates practical and innovative approaches for various stakeholders involved in the clinical research enterprise, including principal investigators, research staff, academic institutions and the broader scientific community, community-based organizations, community clinics, public health

___________________

² See https://grandchallenges.iu.edu/.

³ See https://addictions.iu.edu/news/recovery-month-2020.html.

⁴ A full review of these partnerships can be found at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380298/.

organizations, recruitment centers, pharmaceutical companies, professional organizations, funding agencies, institutional review boards, and journals. Ultimately, efforts to improve representation should involve provision of financial resources for research teams, long-term infrastructure based in communities, material and social support for community advocates and organizations, and education about the relevance of these efforts to scientists, community members, and relevant stakeholders, as well as potential study participants and their caregivers. Dedicated and ongoing funding will be essential to build the infrastructure to achieve representation, and community stakeholders will need to be included and engaged at every step to achieve these goals.

TABLE 5-1 Strategies to Achieve Representation in Clinical Research by Theme