Gina Uhlenbrauck

As patients take more active roles in decision-making about health, healthcare, clinical trials, and regulatory activities, their influence has changed how sponsors and researchers view patient involvement in clinical research. Once regarded as “subjects” who had research performed on them, patients are now contributing across the spectrum of clinical development, including in the design and planning of research protocols, selection of outcomes and endpoints, development of recruitment and retention strategies, and dissemination of research results. The unique perspectives afforded by patients’ lived experiences can inform researchers’ approaches and help identify knowledge gaps. By sharing their experiences of the daily burden of disease and their perspectives regarding unmet needs, therapeutic burdens, the balance of benefit and risk, and the types of research questions most important to them, patient partners can transform the clinical development process from one directed by sponsors and investigators to one driven by the needs of patients and their caregivers.

	While the concept of patients as partners in clinical research is gaining momentum, recent research points to room for improvement.

 The development and validation of partnership models to engage patients in the design and governance of clinical research programs is still in its infancy, and approaches that can ensure meaningful and effective patient participation in research are needed.

 For this reason, the Duke Clinical Research Institute (DCRI) and our research partners are exploring models of patient engagement to determine what works best for patients, their caregivers, research sponsors, and investigators, with the ultimate goal of enhancing the speed and quality of clinical research.

	In this article, we describe three different patient partnership models to help researchers evaluate which method of engagement could work best for their clinical program or study. These models integrate patients and their caregivers into the governance structure of the clinical research program or study to ensure continuous partnership throughout the project life cycle. The models of patient engagement and studies profiled include:

		Patients as advisory board members: the ADAPTABLE aspirin study and CONNECT-HF trial

		Patients as steering committee members: Industry-sponsored Phase II study

		Patients as co-investigators: the PCORnet obesity studies

	We discuss these models, the methods used to implement them, and outcomes to date. We also share lessons learned and explore future possibilities for patient engagement in clinical research. This paper is written from 

the perspective of communication professionals who work alongside research sponsors and study teams-including faculty, operations staff, researchers, clinicians, and patient advisors-to facilitate patients as partners in clinical research. We fully recognize that a commitment from all parties, including our patient partners, is necessary to a successful, lasting engagement.

	PCORnet (the National Patient-Centered Clinical Research Network) is an initiative funded by the Patient-Centered Outcomes Research Institute and is designed to build patient partnerships and harness health data to improve clinical research. PCORnet ensures that patients are directly involved in the development and execution of research by weaving requirements for patient involvement directly into the network’s governance structure. Patient members are represented on each of the overarching 

, where they play an integral role in overseeing decision-making and leadership, stakeholder engagement, PCORnet’s data network, and research partnerships.

	The DCRI serves as the coordinating center for PCORnet and also leads its first demonstration project, ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness; NCT02697916). A pragmatic clinical trial designed to answer an important clinical question in the “real-world” setting of patient care, ADAPTABLE is comparing the effectiveness and safety of two different daily doses of aspirin, both of which are widely used for secondary prevention of heart attack and stroke in persons living with heart disease. However, the study is also implementing a new model of patient engagement in clinical research by integrating patient partners (the 

) into the study team to provide patient voices and perspectives in all aspects of the trial. The Adaptors team is facilitated by 

, a PCORnet Patient-Powered Research Network.

 are involved in the identification and recruitment of study participants. At the onset of the study, each CDRN invited a patient to join the Adaptors team. Some Adaptors have previous clinical research experience through personal or professional experiences; all consider themselves healthcare experts through their lived experiences battling chronic diseases.

	By participating in ongoing study meetings, Adaptors hear firsthand about recruitment challenges and barriers to enrolling up to 15,000 patients in the 

ADAPTABLE study. Working with their local network researchers, Adaptors play a key role in tailoring the recruitment messages. Adaptors help develop and review recruitment materials, anticipating questions and identifying potential points of confusion. They offer input on study materials that facilitates understanding and enhances appeal to a broad audience, such as incorporating graphics and white space, reducing jargon and legalese, and using language that emphasizes the importance of clinical trials, the role of patients in the process, and the value of the patient voice in transforming healthcare. Adaptors have also contributed as authors in peer-reviewed literature.

Better health outcomes for all when patients partner with researchers 

	In addition to spreading awareness of ADAPTABLE, Adaptors are dedicated to educating others on the importance of clinical research. Their motto, 

Better health outcomes for all when patients partner with researchers

conveys how patient participation in research can help answer health questions that matter most to patients and their doctors. This motto is part of the 

, a touring art exhibit developed by Eli Lilly to honor clinical trial participants and raise awareness of clinical research.

	Through the ADAPTABLE patient-research partnership, patient partners have come to appreciate how their experiences can inform research questions, protocol design, and the collection of patient-reported outcomes. Researchers have come to understand that patients may have their own perspectives on what study outcomes or endpoints are most important. For example: an investigator might assume that the most important question to ask during a therapeutic trial is whether the intervention results in an improvement in mortality. However, a patient might be more concerned with quality-of-life issues-if they experience a stroke, will they have to live with a disability, and what will the impact on their family be?

	The Care Optimization Through Patient and Hospital Engagement Clinical Trial for Heart Failure (

; NCT03035474) is a nationwide pragmatic clinical trial funded by Novartis and coordinated by the DCRI. CONNECT-HF employs digital and quality improvement approaches to enhance care for patients with heart failure, with the goal of improving outcomes and reducing the number of hospital readmissions. The CONNECT-HF trial team worked closely with a team of patient advisers while designing the study. To establish the patient advisory group, physicians on the trial steering committee were asked to nominate patients from their practices who they felt would be engaged and interested in giving back to help others with heart failure. Although there were no official requirements for selection, the team aimed to identify advisers who had similar characteristics to the expected trial population, including a similar degree of diversity with regard to age, sex, race/ethnicity, and geographical location.

	The resulting group of eight patient advisers-the “

”-were not professional patient advocates, and most had never participated in a clinical trial. A DCRI patient engagement liaison facilitated interactions between the trial team and the Cardi-Yacks by orienting them to their roles, outlining expectations, answering questions, scheduling meetings, and conveying requests for input from the trial team. The Cardi-Yacks, in turn, offered their experiences and advice on aspects such as eligibility criteria and the follow-up phone call schedule to help researchers design a trial that would be both useful for patients and easy for them to participate in.

	An in-person meeting was organized for the Cardi-Yacks at the trial coordinating center, where they met with the project team and gave feedback on the trial enrollment process and patient-facing educational materials. The meeting included individual mock enrollment sessions with each Cardi-Yack to replicate the patient experience of enrollment. The Cardi-Yacks then participated in a facilitated focus group to provide input on the enrollment process and draft patient-facing materials that would make them more useful and patient-friendly. In addition, the Cardi-Yacks piloted patient-facing mobile applications that are part of the trial interventions and gave input directly to the application designers. The Cardi-Yacks expressed positive feelings about being partners in the trial and helping others with heart failure through their involvement. After trial enrollment began, the Cardi-Yacks continued to work with the trial team on recruitment, adherence, and retention.

	DCRI is spearheading an engagement initiative for a patient to serve as a member of a Phase II study’s steering committee. The selected individual would give input on protocol design, anticipated burden for study participants, recruitment and retention tactics, and other key areas. DCRI would be responsible for the engagement and education of this patient representative, whose views would carry as much weight as those of other steering committee members. 

	The DCRI team, working in close collaboration with the principal investigators and other study stakeholders, has developed a customized internal process according to the therapeutic area, patient population, and protocol (see table below). This customized process enabled us to establish a profile for an “ideal” patient representative, develop selection criteria, identify potentially suitable candidates, and clearly define the role of nominated persons.

	While this patient engagement initiative is still in the early stages of the nomination process, the DCRI is optimistic about the benefits the patient representative could bring to the study. The study team believes this additional layer of patient engagement could strengthen partnerships between patients and study staff, demonstrating the value of patients’ viewpoints in clinical research. It could also facilitate effective communication between the patient representative and the steering committee members. 

	In addition to the ADAPTABLE aspirin study, PCORnet is also conducting a pair of observational studies on obesity. Like many PCORnet demonstration projects, these studies require a patient or caregiver to be included as a co-principal investigator (PI).

, led by Harvard Pilgrim Health Care, examines the relationship between antibiotic use in the first two years of life and weight gain in later childhood. The parent co-PI for the study is a special education teacher and the parent of a teenage son who has experienced childhood obesity for most of his life. As a co-PI, he oversees patient engagement efforts and works to address potential barriers to patient involvement by openly discussing concerns about data security and anonymity and by creating a patient- and family-friendly glossary of acronyms commonly used within the medical community. 

, led by Kaiser Permanente Washington Health Research Institute, is building evidence on which of three different bariatric surgical procedures results in the best outcomes for specific patient communities. A church pastor, community advocate, and bariatric surgery patient herself, the patient co-PI shares her story, “

Why patients need a louder voice in medical research

,” which explores her experience of being part of an underrepresented patient community seeking bariatric surgery, the knowledge gaps that exist in the current medical literature, and the importance of patient partnership in clinical research. 

 have built strong collaborations between patients, clinicians, and healthcare system leaders. One of the unifying messages shared by both co-PIs is how they have learned that these partnerships benefit not just patients but all stakeholders-everybody wins. The model has demonstrated the power of patients’ unique voices when they are thoughtfully integrated into the fabric of decision-making and governance. PCORnet and the DCRI plan to continue to share news on patient engagement strategies, best practices, and lessons learned, highlighting personal stories from throughout the PCORnet partner networks and studies.

The future of patient engagement in research

	The DCRI has been exploring approaches to patient engagement for some time. Large-scale initiatives with DCRI involvement, such as PCORnet, have been characterized by extensive partnerships with communities and individuals to shape, inform, and improve research design and conduct.

	More recently, the DCRI appointed Bray Patrick-Lake, MFS, as director of stakeholder engagement in June 2017. A former trial participant who later became a patient advocate, Patrick-Lake led a multi-stakeholder team of experts from industry, academia, patient groups, the NIH, and the FDA to develop 

Best Practices for Effective Engagement with Patient Groups around Clinical Trials

 for the Clinical Trials Transformation Initiative (CTTI). She also developed successful patient engagement models and strategies for PCORnet studies, co-chaired the Advisory Committee to the NIH Director responsible for authoring the vision of the Precision Medicine Initiative Cohort Program (now called 

), and served as the interim director of engagement during the program’s pilot phase. Under her leadership, DCRI faculty, investigators, and operational teams are working to institutionalize a set of guiding principles for involving patients as partners in clinical research (see table).

	The DCRI is working to catalyze the adoption of a gold standard of partnership with patients in research design, conduct, oversight, and dissemination, while raising the bar on participant experience in research. Although including patients in the governance of clinical studies is just one approach to advancing patient partnerships in clinical research, we have found it to be an effective tool for supporting high-quality, efficient, patient-centered research. Patient input in clinical research has many potential benefits, such as making it possible to achieve higher rates of retention and compliance through enhanced value and improved participant experience; improving data quality by minimizing patient dropout and enhancing participant adherence to protocol; and inspiring scientists to pursue research opportunities and approaches that might not have been obvious. Finally, we anticipate that continuous patient input could drive more rapid research innovation cycles and accelerate the development and appropriate scaling of novel methods and tools. Effectively integrating patient partners into clinical research requires thoughtful approaches and bidirectional learning. Their participation throughout the clinical development life cycle is proving invaluable to improving clinical studies and forging new paths in biomedical research.

Associate Director, Clinical Research Communications; 

Clinical Research Communications Specialist; 

Clinical Research Communications Manager; 

Clinical Research Communications Specialist; and 

Clinical Research Communications Specialist, all with Duke Clinical Research Institute (DCRI)

* The authors would like to acknowledge the following individuals for their leadership in implementing the models of engagement profiled in this paper: Adrian F. Hernandez, MD, MHS; Matthew T. Roe, MD, MHS; William Schuyler Jones, MD; Holly Robertson, PhD; Madelaine Faulkner, MPH; the Adaptors; Jane Anau, BS; David Arterburn, MD, MPH; Jason Block, MD, MPH; Doug Lunsford; Juliane Reynolds, MPH; Neely Williams; Beth Martinez, PMP; Adam DeVore, MD; Linda Davidson-Ray; Tracy Hofmann; Renee Leverty; the Cardi-Yacks; and Susan Landis. 

	1. Calaprice-Whitty D, Byrne J, Gilbert J. Bridging the gap for better patient engagement. 

http://www.appliedclinicaltrialsonline.com/bridging-gap-better-patient-engagement

	2. Domecq JP, Prutsky G, Elraiyah T, et al. Patient engagement in research: a systematic review. 

	3. Hernandez AF, Cruz HP. Engagement, research, and evidence: Leveraging the National Patient-Centered Clinical Research Network for better cardiovascular health. 

Articles

Exploring three distinct patient partnership models to help researchers assess which methods of engagement could work best for their clinical programs.

Models of Engagement: Patients as Partners in Clinical Research

	We discuss these models, the methods used to implement them, and outcomes to date. We also share lessons learned and explore future possibilities for patient engagement in clinical research. This paper is written from the perspective of communication professionals who work alongside research sponsors and study teams-including faculty, operations staff, researchers, clinicians, and patient advisors-to facilitate patients as partners in clinical research. We fully recognize that a commitment from all parties, including our patient partners, is necessary to a successful, lasting engagement.

	By participating in ongoing study meetings, Adaptors hear firsthand about recruitment challenges and barriers to enrolling up to 15,000 patients in the ADAPTABLE study. Working with their local network researchers, Adaptors play a key role in tailoring the recruitment messages. Adaptors help develop and review recruitment

 materials, anticipating questions and identifying potential points of confusion. They offer input on study materials that facilitates understanding and enhances appeal to a broad audience, such as incorporating graphics and white space, reducing jargon and legalese, and using language that emphasizes the importance of clinical trials, the role of patients in the process, and the value of the patient voice in transforming healthcare. Adaptors have also contributed as authors in peer-reviewed literature.

Highlighting three distinct patient partnership models to help researchers evaluate which methods of engagement could work best for their clinical programs.

A staggering number of clinical trials fail to meet recruitment goals, which leads to delays, early trial termination, or inability to draw conclusions at trial completion due to loss of statistical power. A recent analysis found that 19% of registered trials that closed or terminated in 2011 either failed to meet accrual goals (85% of expected enrollment) or were terminated early due to insufficient accrual.

More than 48,000 patients were involved in those 481 trials that were unable to meaningfully answer their primary research question. There can be ethical implications when research participants are exposed to risk but the research does not result in gains in scientific knowledge (even though some participants may have had personal benefit).

Insufficient recruitment also results in missed opportunities for patients who can benefit from clinical trials, wastes time, funds, and other resources. Many potential explanations have been offered, including patient lack of awareness of clinical trials that may be of interest to them and recruitment methods that have not kept pace with advances in communications and other technologies. The Clinical Trials Transformation Initiative (CTTI), a public-private partnership whose mission is to increase the quality and efficiency of clinical trials, launched the Recruitment Project to identify and propose possible solutions to barriers in clinical trial recruitment.

	The Recruitment Project team conducted a systematic literature review to help identify some of the barriers to clinical trial recruitment. After reviewing the available evidence, the project team designed a survey to obtain a deeper understanding of stakeholders’ perceived barriers to recruitment across the clinical research enterprise. Several stakeholder

 groups were targeted: clinical trial sponsors (industry, federal, and academic) and research sites (investigators, coordinators, and executive-level staff), and patient advocacy organizations. The objective of the survey was to gather information for the future development of recommendations and approaches that will improve patient recruitment and enable trials to meet their recruitment goals (click on box at right for full description of the survey methods).

	Data from 90 completed surveys were included in the analysis. Survey completion was defined as reaching the last question and clicking 

 Completed surveys may have some missing data because item nonresponse was permitted. Responses from 58 

partially completed surveys were not included, because most of these surveys were abandoned during early questions about barriers to recruitment. Respondents’ personal and organization characteristics are presented in Figure 1 (click to enlarge).

	Overall, 70% of respondents reported having significant influence in determining recruitment strategies for the trials they manage. Most had more than 10 years of experience with clinical trials and also belonged to organizations that had a long history of involvement in clinical trials. Personal and organizational experience was across a wide variety of therapeutic areas (data not shown). Many respondents were executives or senior staff within their organizations (Figure 2; click to enlarge).

	A key goal of the survey was to collect opinions about the significance of various barriers to clinical trial recruitment. Respondents were asked to rate each named barrier as very significant, somewhat significant, minor, or not a barrier at all. The barrier rated by the most respondents as very or somewhat significant was that of finding or identifying patients who meet eligibility criteria (81%). The next most significant barriers were insufficient staff time for recruitment (67%), length and complexity of consent forms (66%), and protocol requirements other than recruitment criteria (60%). The remaining barriers were rated as significant by less than half of respondents.

	Overall, these results appeared consistent when responses were analyzed according to respondents’ type of organization, though there were limited numbers to draw conclusions from such a sub-analysis. Transportation to trial visits and out-of-pocket expenses were more often rated as significant barriers by respondents from patient advocacy groups (56% and 67%, respectively) than sponsors, contract research organizations (CROs), and research sites (21%-47%). Respondents from sponsors and CROs more commonly rated finding patients who meet eligibility criteria a significant barrier (92%-95%) than did respondents from research sites and patient advocacy groups (78% each).

	For each barrier that was rated as “very significant” or” somewhat significant,” an open-ended follow-up question was asked: “From your perspective, tell us briefly how this barrier can be overcome or what steps have been taken by your organization to overcome this barrier.” Several themes were noted in the proposed solutions. Increased education of patients, physicians, and research staff regarding various aspects of research appeared as a theme for eight of the 12 barriers to recruitment. Respondents proposed technology (i.e., use of electronic health records) as an important solution for seven of the 12 barriers. Other themes included obtaining patient and community input in research design, proper planning and budgeting, and increased flexibility and streamlining of various aspects of the study (e.g., study visits, consent process).

	The survey collected feedback on the most frequent recommendations for overcoming the named recruitment barriers. The most frequent recommendation for identifying eligible patients was to engage in effective study planning, which centers on careful site selection. Respondents noted 

that it is important for sites to undergo feasibility studies, to be in a convenient location for participants, and to have documented availability of potential participants (i.e., through pre-screening activities, review of electronic medical records, or electronic data mining). Another recommendation related to this barrier was broadening of eligibility criteria. One respondent commented, “the inclusion/inclusion criteria are needlessly narrow to the point of making few subjects eligible, even if we have many subjects with the disease available.”

	Respondents suggested either eliminating eligibility criteria that are not necessary for participant safety or not directly related to answering the research question, or designing studies with broad eligibility requirements to enroll individuals more representative of the actual population, including those with multiple comorbidities. As part of developing recruitment strategies, establishing realistic timelines and communicating expectations to sites were mentioned as important.

	Many respondents recognized that sites seem to be understaffed, with available staff fragmented by multiple responsibilities. Beyond hiring more staff, recommendations included flexible staffing models (e.g., as-needed, job sharing, or part-time positions), increased coordinator support, and dedicated staff for specific projects. Responses emphasized that planning should include “carefully assessing site workload and resources and making the commitment to not take on trials if there is not sufficient staff to implement them.” Several respondents mentioned that increasing site financial resources was important to hiring and adequately training staff. Although most comments related to increased financial support for research were nonspecific, sponsors, sites, and the government were all suggested or implied as potential sources of funding.

	While many of the recommendations could be implemented by researchers or site staff, respondents recognized that some would require change at a higher level. Simplifying informed consent was identified as requiring change in sponsor and regulatory requirements. Additionally, several respondents felt that sponsor or regulatory requirements were behind the collection of excess data or unnecessary trial procedures, which lead to more frequent study visits and may prevent streamlining of study design.

	While some respondents seemed to believe that out-of-pocket costs were a significant issue for patients, some also suggested that compensation was a difficult issue to determine. One respondent stated, “There is a fine balance between ensuring the subject does not incur out-of-pocket costs to participate in the research study versus overpayment that can be construed as enticement.” Thus, the majority of the recommendations proposing financial assistance for trial participants used terms such as “reasonable” and “adequate” or “as deemed necessary.” Proposed strategies for reimbursement or coverage of out-of-pocket expenses included writing participant costs into study budgets, using institutional financial assistance plans, applying for small grants to cover participant expenses, or negotiating coverage with managed care plans.

	Another component of the survey assessed respondents’ perceptions of, and experience with, specific methods to improve recruitment (Figures 1 and 2, respectively). Recruitment by means of medical records and hospital-based registries or databases were methods that respondents felt were most effective and had been most often employed successfully by their organizations. Sending electronic alerts to physicians about clinical trials available to specific patients was reportedly being planned by 20% of respondents’ organizations, the highest of all of the methods. The least favorable recruiting method in both the opinion and experience polls was recruitment through public events such as farmers’ markets or health fairs.

	When prompted to describe any other methods to increase recruitment, the majority of suggestions addressed either researchers’ relationships with other clinicians or researchers’ relationships with patients. Many respondents felt that building relationships and establishing referral programs with trusted clinicians are crucial. Respondents also suggested that a research presence could be established in clinics through a person such as a research coordinator, via research advertisements and informational leaflets in the waiting room, or using computerized systems like electronic alerts.

	Outreach via community champions and patient advocacy groups were described as ways to build relationships with patients. Respondents noted that patients could also be contacted directly using technology such as social media, webinars, trial-matching websites, and patient registries. Additional suggestions included making protocols more patient friendly and inclusion of patient input in study design. As one respondent noted, “the bottom line is ‘one size does not fit all’ and there needs to be a site-specific recruitment action plan to strategically apply tactics to the site’s own institution, community, and patient population.”

	Responses to a question about emerging recruitment methods for national trials largely emphasized the use of technology. Respondents indicated that technology has the power to create efficiencies in several stages of research, including trial planning, advertising, recruitment, guiding potential participants through the informed consent process, and keeping in touch with participants. Nearly half of the comments concerned electronic health records, which enable researchers to work with clinicians to quickly pre-screen patients. The use of registries and national networks, such as the National Patient-Centered Clinical Research Network (PCORnet), along with inclusion of patient input in study design, were also seen as important emerging recruitment strategies.

	When asked to identify what combinations of sectors would be most effective in partnership to increase clinical trial recruitment nationally, patient advocates (82%), sponsors (71%), and researchers (68%) were named most often. Professional societies and government regulators were named by 44% and 38% of respondents, respectively. Trade organizations (8%) and “other” sectors (4%) were named least often. The two most frequently mentioned sector combinations were (1) patient advocates and researchers, and (2) broader coalitions between patient advocates, government regulators, researchers, sponsors, and professional societies.

	The survey assessed respondents’ outlook on increasing national clinical trial recruitment rates in the next five and 10 years. More than half of respondents reported a more optimistic than pessimistic outlook for both the five- and 10-year marks (see Figure 3). When results were examined by organization type, patient advocates were the most optimistic group, with 70% and 74% reporting more optimism than pessimism for the next five and 10 years, respectively.

	Results of the stakeholder survey indicate that there are significant protocol-related, patient-related, and clinician-related barriers to clinical trial recruitment, and there is no single solution for overcoming them. Respondents offered a variety of recommendations for improving recruitment that could be implemented at various stages of the research process, including during planning, recruitment, or throughout a trial, as well as some actions that could occur independent of any specific trial.

	Finding or identifying eligible patients was identified as the most significant recruitment barrier, and various technologic methods were believed by respondents to be effective for this purpose. Although technology-assisted recruitment methods are increasingly being employed,

thorough evaluations of their performance remain needed.

While most organizations had experience with identifying patients through medical records, registries, or databases, markedly fewer had tried electronic alerts to physicians. Physician alerts were rated highest in the “plan to try” survey category, and several studies support their effectiveness in increasing clinical trial recruitment.

	Importantly, our findings suggest that technologic solutions alone will not address all causes for insufficient recruitment, a sentiment that has been echoed by others.

Respondents stressed the importance of thoughtful site selection, feasibility testing, and development of recruitment strategies with realistic timelines and goals. Inclusiveness of trial eligibility criteria can also be a significant predictor of recruitment

and was frequently mentioned by respondents.

	According to a conceptual model of factors that lead to clinical trial enrollment, “an individual must be 

 that the study is being conducted and must have an 

Promotion through education and advertising was suggested for increasing awareness in many of the open-ended survey responses. However, recruitment via social media, mobile health units, or public events were rated as somewhat or not effective by the majority of respondents, signaling that other methods may be preferred. In one systematic review analyzing recruitment of vulnerable groups, community outreach was the most effective recruitment intervention in only two of 16 studies (13%) in which it was attempted, and marketing (e.g., mass mailings, telephone calls, media campaigns) was most successful in eight of 18 studies (44%).

Additional well-designed research, including examinations of cost effectiveness, will be important to inform the future use of such methods. Respondents further proposed that educational strategies could improve recruitment by increasing knowledge about clinical research in general, including its importance to society and its processes and safeguards. However, it may be difficult to obtain support for educational efforts that may not have a direct impact on enrollment for a specific trial.

	Another theme evident throughout the survey results was that patients offer a valuable perspective to overcoming recruitment barriers. Patient advocates were rated by respondents as the most effective partners for increasing recruitment. Their involvement was suggested as a solution to overcoming research mistrust, as well as for addressing patient-specific 

concerns related to study design. This is supported by the survey findings in which logistical and cost concerns were rated as more significant barriers by patient advocates. The Patient-Centered Outcomes Research Institute (PCORI) is one sponsor that requires in its funding applications a plan for engagement of patient partners and other stakeholders throughout the entire research process, from planning to dissemination of results.

	Clinician-related barriers included insufficient staff support for recruitment and negative attitudes about trial referral. Others have observed a relationship between clinician time and resource issues, including adequate staff support, and clinical trial recruitment.

In addition, clinician attitude and communication with patients can play an important role.

Communications training, increased staff support, adequate planning, and clinician engagement were among the variety of suggestions for addressing these barriers.

	Not all of the respondent suggestions will be feasible, such as completely eliminating wait times. For example, use of nonrandomized or open designs may increase recruitment,

but it is important to consider potential tradeoffs in scientific validity. Although social stigma associated with research was not rated as a significant barrier in the survey, this issue may be more relevant in specific populations or areas of research (e.g., AIDS, substance abuse).

The problems with informed consent described in the survey responses are well recognized and are being addressed by several other efforts,

	Limitations of the survey included that the design prevented calculation of response rate, and there was limited sample size to allow analysis by subgroups. The survey was also limited by the number of barriers and strategies that could be included in the multiple-choice options while keeping the survey at a reasonable length. However, respondents were given the opportunity to provide open-ended responses. It was not always clear whether respondents’ open-ended recommendations described actions that have already been taken and proved effective, or whether they were simply predicting that a given course of action could be useful. Finally, with many respondents being senior staff and executives, there is a potential that they may have been too far removed from day-to-day operations to have an accurate understanding of recruitment barriers.

	The positive outlook on increasing clinical trial recruitment over the next five to 10 years among respondents is encouraging of the potential for progress to be made. It is apparent that a comprehensive recruitment strategy, rather than a single tool or solution, will be required to address the range of significant recruitment barriers identified. These data have informed the work of the CTTI Recruitment Project, which will continue to engage stakeholders in understanding barriers to clinical trial recruitment and developing practical tools to address them.

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is Associate Director, TCSM Oncology, Janssen Research & Development, LLC;

Senior Clinical Project Manager, Clinical Trials Transformation Initiative, email: 

President and CEO, Parent Project Muscular Dystrophy;

Senior Science Writer, Duke Clinical Research Institute;

 Director, Office of Minority Health, Office of the Commissioner, US Food and Drug Administration

* To whom all correspondence should be addressed 

Survey takes deep dive into enrollment hurdles, aims to inform future recommendations for improvement.

Barriers to Trial Recruitment and Possible Solutions

	The Recruitment Project team conducted a systematic literature review to help identify some of the barriers to clinical trial recruitment. After reviewing the available evidence, the project team designed a survey to obtain a deeper understanding of stakeholders’ perceived barriers to recruitment across the clinical research enterprise. Several stakeholder groups were targeted: clinical trial sponsors (industry, federal, and academic) and research sites (investigators, coordinators, and executive-level staff), and patient advocacy organizations. The objective of the survey was to gather information for the future development of recommendations and approaches that will improve patient recruitment and enable trials to meet their recruitment goals.

 Completed surveys may have some missing data because item nonresponse was permitted. Responses from 58 partially completed surveys were not included, because most of these surveys were abandoned during early questions about barriers to recruitment. Respondents’ personal and organization characteristics are presented in Figure 1.

	Overall, 70% of respondents reported having significant influence in determining recruitment strategies for the trials they manage. Most had more than 10 years of experience with clinical trials and also belonged to organizations that had a long history of involvement in clinical trials. Personal and organizational experience was across a wide variety of therapeutic areas (data not shown). Many respondents were executives or senior staff within their organizations (Figure 2).

	A key goal of the survey was to collect opinions about the significance of various barriers to clinical trial recruitment. Respondents were asked to rate each named barrier as very significant, somewhat significant, minor, or not a barrier at all. The barrier rated by the most respondents as very or somewhat significant was that of finding or identifying patients who meet eligibility criteria (81%). The next most significant barriers were insufficient staff time for recruitment (67%), length and complexity of consent forms (66%), and protocol requirements other than recruitment criteria (60%). The remaining barriers were rated as significant by less than half of respondents (Figure 3).

	Table 4 shows a summary of the most frequent recommendations for overcoming each of the named recruitment barriers. The most frequent recommendation for identifying eligible patients was to engage in effective study planning, which centers on careful site selection. Respondents noted that it is important for sites to undergo feasibility studies, to be in a convenient location for participants, and to have documented availability of potential participants (i.e., through pre-screening activities, review of electronic medical records, or electronic data mining). Another recommendation related to this barrier was broadening of eligibility criteria. One respondent commented, “the inclusion/inclusion criteria are needlessly narrow to the point of making few subjects eligible, even if we have many subjects with the disease available.” Respondents suggested either eliminating eligibility criteria that are not necessary for participant safety or not directly related to answering the research question, or designing studies with broad eligibility requirements to enroll individuals more representative of the actual population, including those with multiple comorbidities. As part of developing recruitment strategies, establishing realistic timelines and communicating expectations to sites were mentioned as important.

	When prompted to describe any other methods to increase recruitment, the majority of suggestions addressed either researchers’ relationships with other clinicians or researchers’ relationships with patients. Many respondents felt that building relationships and establishing referral programs with trusted clinicians are crucial. Respondents also suggested that a research presence could be established in clinics through a person such as a research coordinator, via research advertisements and informational leaflets in the waiting room, or using computerized systems like electronic alerts. Outreach via community champions and patient advocacy groups were described as ways to build relationships with patients. Respondents noted that patients could also be contacted directly using technology such as social media, webinars, trial-matching websites, and patient registries. Additional suggestions included making protocols more patient friendly and inclusion of patient input in study design. As one respondent noted, “the bottom line is ‘one size does not fit all’ and there needs to be a site-specific recruitment action plan to strategically apply tactics to the site’s own institution, community, and patient population.”

	The survey assessed respondents’ outlook on increasing national clinical trial recruitment rates in the next five and 10 years. More than half of respondents reported a more optimistic than pessimistic outlook for both the five- and 10-year marks (Figure 3). When results were examined by organization type, patient advocates were the most optimistic group, with 70% and 74% reporting more optimism than pessimism for the next 5 and 10 years, respectively.

	Another theme evident throughout the survey results was that patients offer a valuable perspective to overcoming recruitment barriers. Patient advocates were rated by respondents as the most effective partners for increasing recruitment. Their involvement was suggested as a solution to overcoming research mistrust, as well as for addressing patient-specific concerns related to study design. This is supported by the survey findings in which logistical and cost concerns were rated as more significant barriers by patient advocates. The Patient-Centered Outcomes Research Institute (PCORI) is one sponsor that requires in its funding applications a plan for engagement of patient partners and other stakeholders throughout the entire research process, from planning to dissemination of results.

Senior Clinical Project Manager, Clinical Trials Transformation Initiative; 

 Director, Office of Minority Health, Office of the Commissioner, US Food and Drug Administration

Financial support was provided by cooperative agreement U19 FD003800 from the US Food and Drug Administration awarded to Duke University for the Clinical Trials Transformation Initiative (

). Views expressed in this article do not necessarily reflect the official policies of the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.

The authors wish to thank and acknowledge members of the CTTI Recruitment Project team for their help in developing the survey and interpreting the results, including Melinda Bomar, Lilly Cappelletti, David Ciavarella, Grant Huang, Jeffrey Jamer, Jane Kolimaga, Puja Mehta, Claire Meunier, Margo Michaels, Ashish Oza, Bray Patrick-Lake, Elizabeth Pinnow, Kelli Potter, Anuja Rastogi, and John Reites, as well as Carrie Dombeck, Emily Gao (survey results interpretation), and Project Assistant, Kimberley Smith.

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A staggering number of clinical trials fail to meet recruitment goals, which leads to delays, early trial termination, or inability to draw conclusions at trial completion due to loss of statistical power.

Gina Uhlenbrauck

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