Martin Lee

	More than half of all clinical trials experience delays in completion, with one in six taking more than twice as long to enroll as originally planned.

 It is well documented that lengthy start-up at individual trial sites related to contracting and committee reviews contributes significantly to these delays. Of equal or greater significance, however, is slower than planned enrollment of subjects at individual trial sites, a factor that has led to the increasing global nature of clinical trials.

 Because most trials that experience slow enrollment are conducted for the treatment of medical conditions (as opposed to healthy normal volunteer studies), the field of patient recruitment has evolved to develop strategies to optimally recruit patients into clinical trials.

 With the development of this field, a large number of tactics and strategies aimed at improving enrollment have been implemented with varying degrees of success across countless clinical trials. Somewhat surprisingly, though, we still lack solid information on the relative effectiveness of many of the individual recruitment tactics, even those that are commonly used.

 There are many reasons for this, the most important of which is that individual recruitment tactics are rarely employed in isolation, making it difficult to determine which are successful and which are of little value. Beyond this, the trials that use patient recruitment programs often have unique eligibility criteria and interventions, making it difficult to generalize the results of a program used in one study to any future study.

	Despite the overall lack of information on the effectiveness of individual tactics, there is no denying that patient recruitment programs can be effective in reducing or eliminating delays in trial completion.

 Understanding whether a program is likely to be effective, and what the components of that program should consist of, requires a thorough understanding of the intervention being studied, the design of the trial, and the patient population being studied. More specifically, it’s necessary to 

understand how the study intervention fits into current patterns of care

 that participating in the trial will require of its subjects.

	Clearly, not all clinical trials benefit from patient recruitment programs. For those that are well designed and that are being conducted at specialist centers with a strong research infrastructure and a major emphasis on enrolling patients in clinical trials, there may be relatively little to be gained from extensive efforts focused on patient recruitment. The one significant exception to this is the case in which the study has enrolled well but has essentially exhausted the patient population at the investigational site. In these cases, recruitment strategies focused on directing patients to the site via advertising techniques and/or increasing referrals from other healthcare providers may be of benefit. It should be noted that even in cases when external referrals are not needed, strategies to maintain awareness of the trial at the site, provide patient and caregiver education, and  facilitate the informed consent process are likely to be helpful in optimizing recruitment.

	For other studies in which there may be a significant opportunity to impact patient recruitment, the decision on which specific tactics to employ requires careful consideration of two specific questions:

		Is the patient population accessible to direct-to-patient recruitment approaches?

		Can the benefit of trial participation be easily communicated to potential subjects?

	In determining the accessibility of the patient population to direct-to-patient approaches, it is important not to equate accessibility to the incidence or prevalence of the condition. In fact, many rare diseases have patient populations that are well organized and that are actively searching for information on the treatment of the disease. This is especially true in more serious diseases that have a major impact on quality and/or length of life. It is also important not to confuse accessibility with the ease of accessing the patient group under study. In some cases, outreach efforts to a community may be successful in raising awareness of a disease or its seriousness, which in turn can increase  accessibility of potential subjects for a clinical trial. 

	The ease of communicating the benefits of trial participation is also an important factor to consider. For some clinical trials, there may be no direct benefit to potential subjects. One example of this is a trial that tests therapies head to head where previously conducted clinical trials of the therapies being compared have produced conflicting results. Other common examples are epidemiologic studies in which the goal is not treatment, but better understanding of the incidence, prevalence, or risk factors for a disease. In other cases there may be a potential benefit to participation, but clearly understanding what the benefit is requires considerable explanation by the patient’s physician and/or trial investigator. This is often the case where there may be benefit to individual participants, but where there is a significant trade-off with respect to side effects of the treatment.

	As illustrated in Figure 1 below, the answers to these questions can help define whether a site-focused approach, a patient-focused approach or a combination of the two is most likely to be effective. 

	Site-focused strategies are often employed alone or as part of a mixed approach to recruitment when accessibility to subjects (including the ability to obtain trial-specific referrals), is limited or when the benefits of participation are not immediately obvious and require detailed discussion with potential subjects.   

	As previously mentioned, trials conducted at expert centers that receive sufficient referrals as part of routine clinical care often require little assistance in recruiting patients. Larger clinical trials, however, often extend to sites that do not fit the mold of expert centers that focus on clinical research as part of their core mission. For these sites, assistance with recruitment can be critical. To maximize effectiveness, this assistance should focus primarily on the site’s prescreening practices. For small sites, in which all prospective trial subjects are seen by a principal investigator who is actively engaged and knowledgeable concerning the study, simply maintaining education and awareness of the trial with the investigator may be sufficient to ensure optimal recruitment. At many sites, however, clinical care is scattered among many different providers who may have varying levels of interest in and knowledge of clinical research. For these sites to function optimally, a systematic method of prescreening for potential subjects is needed. This duty often falls on research staff, who themselves have varying levels of knowledge concerning the trial and/or the disease under study. Educating research staff on the specifics of trial eligibility and on the clinical scenarios where patients present, coupled with maintaining awareness of the trial with care providers at the site other than the principal investigator, are very important for these centers. Formal site-specific recruitment plans that clearly delineate the expected patient pathways within the site and responsibilities for maintaining trial awareness among all providers are necessary to ensure that these sites perform to their fullest potential.

	The following are typical components of an effective site-specific recruitment plan:

		Materials to maintain awareness of the trial in areas of the site where patients who are candidates are likely to be encountered

		Tools to help site staff in pre-screening patients and/or conducting various study procedures that may be complicated

		Detailed maps of patient pathways to assist site staff in understanding patient flow and optimal prescreening strategies which can differ from site to site

		Development of specific prescreening criteria, which can include using web-based or mobile technology to assist the site in implementing effective prescreening

		Periodic one-to-one discussions of the trial with all care providers focused on the scientific rationale for the study and its design

		Educational activities at the site focused on awareness of the condition under study and its treatment

		Informed consent aids to assist providers and research staff with educating patients on the study in a balanced manner

	Studies in which patient populations are accessible and where the benefit of trial participation can be effectively communicated lend themselves well to strategies focused on direct engagement of potential trial subjects. The most effective of these direct-to-patient strategies employ a tailored message to notify and energize potential subjects using the media outlet(s) best suited to that audience.

	Traditional media, such as newspaper, radio, and television have long been used for recruiting patients into clinical trials, especially for highly prevalent indications . Of these, television remains the most effective, although it is also the most costly and requires considerable expertise to implement effectively. With more people “cutting the cord” with respect to cable and satellite television service and the advent of online streaming, the effectiveness of traditional media for recruitment is likely to decline progressively, especially for younger patients.

	Direct-to-patient mailings via “snail mail” or email are another approach that can be successful assuming an appropriate mailing list is available. There are extensive databases available for certain indications that can yield many potential patients, especially in North America. These mailings are typically sent to potential patients who have opted in to a larger database that offers extensive information about the conditions that may affect them or their family. These mailings contain pertinent information about the study and direct the recipient to a phone number or a website for further information.

	As global internet access and use has increased, attention is increasingly turning to web-based and mobile technologies as platforms for patient recruitment. Social media and search engine advertising allow for precise targeting of individuals who are a part of a patient community or who have searched online for information on a given condition. The ability to restrict messaging geographically adds the additional ability to target potential subjects who live and work in proximity to participating clinical trial sites.

	Once contact is made, regardless of the platform used, it is important to ensure that an effective approach is in place to ensure that each potential subject is appropriately evaluated for trial participation. This is often done through a prescreening questionnaire that is administered electronically or by telephone screening. Patients who are interested in and potentially eligible for the trial are then referred to a study site for further evaluation. Study sites are pivotal in this process, and should be involved in determining how they will receive referrals that result from this process. Some sites may prefer a “warm transfer” or a live call to ensure that the referral is handled promptly. Other sites may prefer to receive email notifying them that a patient is potentially eligible based on the prescreening process and is interested in being evaluated for participation.    

	Establishing an effective overall referral management process helps to ensure the effectiveness of direct-to-patient approaches. The process should define the various media through which patients may be contacted; how initial prescreening is managed; and how each site prefers to handle the referrals generated. An online platform to track patients from initial contact to presentation at the site can help to ensure that all interested and potentially eligible patients are evaluated. Proper management of this process increases the return on investment of the approaches used and increases site satisfaction by decreasing the volume of unqualified referrals.  
	 

Case Study – Developing a Recruitment Strategy

	A small biotech company is developing a new drug for the treatment of type 2 diabetes. Early studies have indicated that the new drug has the potential to lower blood sugar, particularly after meals when the blood sugar tends to be higher. Those same studies have demonstrated that the drug can lead to night-time hypoglycemia in a very small percentage of cases, a dangerous condition that can be associated with seizures or even death. The company has recently changed the formulation of the drug as well as the dosing schedule in an attempt to reduce the risk of this complication, and preliminary testing of the new dose and schedule appear promising. Several hundred patients will need to be recruited into the study. A patient recruitment group was consulted to assist with developing an effective recruitment strategy.
	 

	In the US, there are 30 million people with type 2 diabetes, and there are at any given time a large number of individuals who are searching online for information on its management. For this reason, making contact with potential subjects through the internet is feasible and likely to be cost-effective. Thoroughly explaining the potential risks and benefits of study participation, however, requires more direct interaction with potential subjects for several reasons. First, there are a variety of effective treatments available and there are numerous other clinical trials available. More important, even though the sponsor has changed the formulation and the dosing schedule, there remain possible risks associated with participating in the study that must be carefully discussed with potential subjects.

	In this situation, the patient recruitment group recommended a mixed approach utilizing both site-focused and patient-focused approaches. The site-focused approach is designed to ensure that the site has effective prescreening practices in place. In addition, a comprehensive education program was recommended to help ensure that sufficient knowledge is present among the site staff and investigators, with the focus on providing them with the ability to effectively communicate both the risks and benefits of study participation.

	A patient-focused approach also was needed to contact potential subjects. A strategy was recommended to target  online patient communities and individuals who may be searching online for new treatment options. This tactic was combined with a study website that included both an online prescreening function and an option to speak directly with someone who can administer the prescreening questions. For potential trial candidates who “pass” the prescreening questions and are interested in participating, a referral management plan was developed so that each potential subject was referred to a study site for evaluation. This process was carefully tracked to ensure that no potentially eligible patients were missed through lack of coordinated follow-up.

	While it widely acknowledged that clinical trial enrollment is often delayed, in many cases insufficient attention is paid during the initial planning of the trial on strategies to assist with optimizing enrollment at individual sites. The effective evaluation process begins by focusing on a thorough understanding of the clinical setting in which the trial is being conducted, the design of the trial, and the patient population under study. Based on this understanding, the next steps are to determine the accessibility of the patient population to direct-to-patient strategies as well as the ease with which the benefits of study participation can be communicated, followed by effective implementation of site-focused strategies, direct-to-patient strategies or both. When implemented in the planning stages of the trial, this planning process will reliably lead to identifying the most effective recruitment strategies for the trial and increase the chances of meeting the planned timeline for the study.

		Getz KA. Enrollment Performance: Weighing the Facts. Applied Clinical Trials, May1, 2012. Accessed at 

http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/article/articleDetail.jsp?id=772226&sk=&date=&pageID=2

		Butler et al. Relationship Between Clinical Trial Site Enrollment With Participant Characteristics, Protocol Completion, and Outcomes. J Am Coll Cardiol. 2013;61(5):571-579	

		Glickman  SW., McHutchison  JG., Peterson  ED.  Ethical and scientific implications of the globalization of clinical research. N Engl J Med. 2009;360:816-823	

		Anderson DL. A Guide to Patient Recruitment and Retention. Boston: CenterWatch, 2004	

		Lamberti MJ et al. Evaluating the Impact of Patient Recruitment and Retention Practices. Drug Inf J. 2012; 46: 573-580	

		Bhatnagar s et al. Development and impact of an intervention to boost recruitment in a multicenter pediatric randomized clinical trial. Clin Pediatr (Phila) 2014; 53(2):151-7

		Madsen LT et al. Impact of a clinical trial initiative on clinical trial enrollment in a multidisciplinary prostate cancer clinic. J Natl Compr Canc Netw. 2014;12(7):993-8

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