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Survey takes deep dive into enrollment hurdles, aims to inform future recommendations for improvement.
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.1More 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).2Insufficient 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 Submit. 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).
Barriers to recruitment
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.
Methods to improve recruitment
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,3thorough evaluations of their performance remain needed.3,4While 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.5-9
Importantly, our findings suggest that technologic solutions alone will not address all causes for insufficient recruitment, a sentiment that has been echoed by others.3Respondents 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 recruitment1,10and was frequently mentioned by respondents.
According to a conceptual model of factors that lead to clinical trial enrollment, “an individual must be aware that the study is being conducted and must have an opportunity to participate.”11 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%).12Additional 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.13-15
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.16,17In addition, clinician attitude and communication with patients can play an important role.16Communications 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,18-20but 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).21,22The problems with informed consent described in the survey responses are well recognized and are being addressed by several other efforts,23-27including another CTTI project.28
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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Elizabeth Mahon, JD, BS, is Associate Director, TCSM Oncology, Janssen Research & Development, LLC; *Jamie Roberts, MA, CCRP, is Senior Clinical Project Manager, Clinical Trials Transformation Initiative, email: email@example.com; Pat Furlong, RN, BSN, is President and CEO, Parent Project Muscular Dystrophy; Gina Uhlenbrauck, is Senior Science Writer, Duke Clinical Research Institute; Jonca Bull, MD, is Director, Office of Minority Health, Office of the Commissioner, US Food and Drug Administration
* To whom all correspondence should be addressed