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Study findings identify various factors affecting subject enrollment in today?s clinical trial world.
Study findings identify various factors affecting subject enrollment in todays clinical trial world.
A key determinant of the success of a clinical trial is the recruitment and retention of a study population of an adequate sample size. Low rates of recruitment and retention have a number of negative implications, such as longer durations of the clinical trial, which may lower staff and participant morale; a costlier clinical trial, since extra resources may need to be dedicated to the recruitment effort; and less statistical power for both the study and the validity of the results. In some cases, inadequate accrual of subjects may result in the termination of the trial.
Poor clinical trial recruitment and retention is therefore likely to impede the successful evaluation of new and existing interventions, and prevent greater efficiency in clinical development.
To improve subject accrual to clinical trials, the barriers to recruitment and retention need to be identified, so appropriate strategies to overcome them can be implemented. These barriers are already well recognized in the literature. The aim of this article is to examine if the identified barriers are in reality what is encountered by those involved in clinical trials today.
Qualitative data collection
Data was obtained on the barriers to recruitment and retention by carrying out in-depth semistructured interviews with a variety of professionals, employed in the United Kingdom, involved in recruitment to clinical trials, both nationally and internationally. A total of 16 professionals were interviewed, including investigators, representatives from pharmaceutical companies, and representatives from contract research organizations. (For practical reasons, the qualitative data collection for this study was limited to data collection from professionals in the United Kingdom who are involved in subject recruitment. Seeking the opinion of study subjects was beyond the scope of this study and would necessitate a further study.) Despite the small sample size used and the limited range of professionals interviewed, this study yielded some interesting observations.
According to a recent CenterWatch report, dropout rates of 15-40% in clinical trials are not uncommon, and 86% of all U.S. clinical studies fail to recruit the required number of subjects on time.5 Participant recruitment to clinical trials has been called the most difficult and challenging aspect of clinical trials, with flaws in recruitment identified as one of the main reasons for the failure of clinical studies.3,6
The four barriers
The barriers to recruitment and retention as identified in the literature may be classified in four broad groups: 1) subject-related barriers, 2) investigator-related barriers, 3) protocol-related barriers, and 4) other barriers. The sidebar below lists the barriers found in the literature.While this research showed a strong consistency between the literature and the practical experience of those professionals interviewed, a number of enlightening differences between the accepted barriers and the actual barriers encountered in practice today were identified. Interview respondents identified the same four broad categories of barrier to recruitment and retention as identified in the literature. Each of the key areas identified is discussed below.
Subject-related barriers. Interviewees identified many similar subject-related barriers to recruitment and retention as has been noted in the literature. However, some important differences were also noted.
According to the literature, long waiting times associated with clinic visits and inconvenient scheduling of appointments are barriers to recruitment and retention.7,8 Interviewees did not view these as barriers. This may imply that greater consideration is being given to subjects other commitments, and that subjects are being offered more flexible and reliable appointment times to encourage their participation.
Secondly, the literature reports that subjects often fail to enter or complete clinical trials as they dislike the uncertainty associated with the trial, and in many cases prefer the doctor to make the decision about their treatment.9,10 This was not noted by interviewees as a barrier, and may reflect the fact that those interviewed are not at the trial site to hear of such concerns. It may also reflect the growing knowledge among the public of medical-related matters (perhaps as a result of people having greater access to information available on the Internet) coupled with their concerns about risk. However, public concerns about risk do not appear to conform to scientific or technical measures of risk, with an extensive body of literature having been written on this topic. A useful overview is provided by Slovic.11
Some factors were also noted by those interviewed that are not widely reported in the literature. Interviewees reported that subjects who have unrealistic expectations of the clinical trial may be reluctant to complete the study protocol. Such expectations could imply a problem with the informed consent process, with details of the requirements associated with trial participation being poorly communicated to subjects. This may result in reduced retention, with subjects dropping out prior to trial completion.
Interviewees also reported subjects disease status (the more symptomatic the subject the less likely they are to participate), age (parents of children who are ill are often reluctant to provide consent for their child to enter a clinical trial, and the elderly may be reluctant to participate in a clinical trial due to family objections), level of education (the more highly educated sectors of society are more likely to consent), and social circumstances (subjects who lack time to attend extra trial-related appointments due to family commitments are less likely to consent to participate), as well as language (if a potential subjects first language is other than English this may discourage participation) and cultural issues (minority populations may be reluctant to participate in clinical trials due to distrust of existing systems) as barriers to recruitment and retention. These have not been conclusively recognized as barriers in the literature.
Interviewees also noted that people are tending to change jobs more frequently and are moving to new locations to take up these jobs. Moving out of the area is an increasing potential barrier to subjects completing trial protocols. This has not been widely reported in the literature, but is likely to become an issue if such trends continue within the work force.
Investigator-related barriers. Despite investigators agreeing to recruit subjects to a clinical trial, many factors related to the trial investigator may prevent them recruiting adequate subject numbers. The main barriers identified in the literature may be divided into logistical factors and personal factors. The recruitment and retention barriers identified in the literature review and by those interviewed were broadly consistent, but as with the subject-related barriers, some revealing differences were also noted.An inability of the recruiting physicians to integrate their roles as caregivers with that of scientists is identified in the literature as a barrier to recruitment and retention.12,13 Interestingly, interviewees did not note this conflict of roles as a barrier to recruitment and retention, which may reflect that it is not an issue for research investigators today. This may also be a reflection of todays climate of evidence-based medicine, with the widely acknowledged importance of undertaking quality research.
Many factors reported by those interviewed as being investigator-related barriers to recruitment and retention were not widely cited in the literature. The literature relates a lack of time to recruit to the investigators normal clinical workload and management duties.1 Interviewees related this lack of time to the investigators involvement in other clinical trials, which may reflect the growing importance of the investigators involvement in clinical research, as previously mentioned. It may also be a reflection of research-focused clinicians becoming involved in too many clinical trials.
An interesting comment by one respondent was that an investigators underestimation of the workload involved in a clinical trial may act as a barrier to recruitment and retention. This could reflect a poor choice of investigator to undertake the study, and could also imply poor communication between the sponsor company and the investigator as to the amount of work actually involved in the trial. It could also imply that proper feasibility surveys are not being undertaken prior to study commencement. (The correct choice of study site by those organizing a clinical trial is critical to the success of the clinical trial. A proper feasibility survey must be undertaken at an early stage in the study site selection process to ensure that the clinical trial can be conducted at the site of choice. This survey will gather data on the availability of potential study subjects who meet the study entry criteria and the likely recruitment rate, as well as data on competitor studies on-going at the site and any regulatory or ethical issues. A good feasibility survey will help to ensure the success of recruiting a study population of an adequate sample size.14 However, 11 of those interviewed did mention the importance of carrying out a full feasibility survey as a strategy to enhance recruitment and retention.
One personal barrier not cited in the literature is a lack of motivation on the part of the investigator. A lack of time and resources to undertake the study may cause investigators to lose their motivation to recruit. Those interviewed noted that inadequate financial incentives being provided to the investigators may have a negative effect on the amount of effort they are prepared to commit to the recruitment effort. Poor motivation on the part of the investigator may also be a result of competing trials being undertaken at the study site that are of greater interest and offer more attractive incentives.
One interviewee cited the country the investigator is situated in as an investigator-related barrier. Each country will have distinct rules and an ethos that will determine the level of contact that is feasible between the investigator and the sponsor company, as well as the ease of setting up and running the study. Difficulties with these may negatively affect recruitment and retention. The identification of this barrier may reflect the globalization of clinical trials today.
Protocol-related barriers. The interviewees and the literature both identified many similar protocol-related barriers to recruitment and retention, and as with the first two group, there were some differences of opinion as well.
First, although the literature identifies a lack of full support and enthusiasm for the design or aims of the study protocol on behalf of the investigator as a cause of poor recruitment at the study center,15 interviewees did not mention this as a barrier. However, respondents noted a lack of referrals from colleagues to the clinical trial, a lack of interest on the part of the investigator in the research question, and a lack of motivation to recruit as investigator-related recruitment and retention barriers. These findings may indicate that investigators may agree to be involved in clinical trials despite a degree of disagreement with an aspect of the study.
Second, the literature identifies as recruitment and retention barriers protocol designs with eligibility criteria that are so tight that potential study subjects do not qualify for entry, and protocols that are too difficult for investigators to follow due to overly complex study designs.16-18 However, even though these factors were not identified as issues by interviewees, they did identify several barriers: lengthy study periods, being expected to comply with excessive visit schedules, and demanding product dosage schedules, as well as too great a degree of change being expected of study subjects. This may imply that some clinical trial protocols being designed today are unrealistic, difficult to implement in reality, and difficult for subjects to comply with.
Interview respondents noted that protocol procedures that are too costly also may be a barrier: this was not identified in the literature review. Costly clinical trials due to expensive protocol procedures may be difficult to obtain funding for. Delay in the commencement of the clinical trial may affect recruitment, since the subjects originally identified as suitable to participate may no longer be eligible or available when the trial commences.
Other barriers. The main other barrier to recruitment and retention identified in the literature is the negative influence of the media.19,20 This was also identified by those interviewed. However, a number of other other barriers to recruitment and retention were identified by interviewees, which were not identified in the literature review.
Respondents commented that the lengthy U.K. ethical approval process may delay subject recruitment and trial commencement. Changes are currently being implemented to the U.K. ethical approval process in response to the EU Clinical Trials Directive (2001/20/EC), and the resultant system when established should be more efficient and help to speed up the commencement of clinical trials.
Another barrier cited was a poor choice of study site by the sponsor. This may reflect the globalization of clinical trials, and the fact that new countries are being considered regarding clinical trials. Investigators largely unknown to a pharmaceutical company, in fact, may be responsible for the subject recruitment aspects of a trial. The fact that this was reported as a barrier by respondents is interesting, particularly in light of the fact that more than 50% of this group mentioned the importance of carrying out a full feasibility survey as a strategy to enhance recruitment and retention.
One interviewee mentioned the importance of involving key opinion leaders in clinical trials as a strategy to help endorse products. However, this respondent acknowledged that despite the importance of their support for particular products, these leaders are not necessarily the best investigators to involve in clinical trials, as they often lack the necessary time to devote to subject recruitment or to enhance retention.
The citing of a poor choice of study site, poor timing of study commencement, and unrealistic timelines as barriers to recruitment by interviewees may reflect an inappropriate choice of investigators in terms of their ability to recruit within the planned timelines. This feedback also indicates that they may have been chosen instead for their status and reputation. Nevertheless, this finding is again interesting in view of the emphasis placed on the importance of carrying out a full feasibility study prior to trial commencement.
The way forward
The barriers to recruitment and retention are well documented in the literature. However, this study also shows the emergence of other barriers that have not yet been widely reported, but which nonetheless may be potential issues for clinical trials of pharmaceutical products today. Sponsors need to be aware of site and investigator needs, and be clear about their demands. Investigators need to assess their time available to invest in the study, their concerns regarding the study, and their motivation to participate.All those involved in clinical trials need to be aware of these potentially emerging new barriers, but more importantly need to discuss appropriate strategies to overcome these and other barriers prior to trial commencement.
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The full title of this research project is Barriers to Recruitment and Retention in Clinical Trials of Medical Foods and Medicinal Products. This study was part of a Masters in Clinical Research undertaken at the Welsh School of Pharmacy, University of Cardiff, Wales, which was funded by SHS International. The views expressed in this article are those of the author and not those of SHS International. The results presented in this article refer to clinical trials of medicinal products only. In view of the concise nature of this article, full details of the interview schedule and methodology used are not provided.
Jean Sullivan,MSc, is senior project leader with SHS International Ltd., 100 Wavetree Boulevard, Liverpool L7 9PT, United Kingdom, +44 (0)151 228 8161, fax +44(0) 151 228 2650, email: email@example.com.
Table 1. Previously reported barriers to recruitment and retention