Successful Subject Recruitment: One Size Does Not Fit All

Effective clinical research requires attracting the attention of individuals with treatable medical conditions, then screening them and enrolling them into a clinical study. Subject recruitment has turned into an industry in which the environment is tumultuous and the competition is stiff. Sponsors are continuously developing and refining their techniques to reach out to appropriate patient groups and are becoming more sophisticated consumers of recruitment services; vendors continue to refine their service offerings; and site personnel are dedicating increased resources to recruiting and enrolling subjects. Although the subject recruitment sector is maturing, it is far from delivering predictable and successful outcomes.

Three elements influence the recruitment process: the protocol, the investigative site, and the patient population. We believe the reason that most recruitment programs fall short of expectations is that they do not address these factors and the relationships between them. Understanding and avoiding common mismatches between the protocol design, site infrastructure, and prospective subjects interests and needs will make recruitment easier.

When the fit is bad
Just as you would not purchase an expensive wedding gown or suit off the rack and expect it to fit without going through the painstaking fitting and alterations process, you should not expect a recruitment program to be successful without undertaking similar measures to ensure a good fit between the study protocol, the participating sites, and the target patient population. Mismatches between these three core elements can result in an ill-fitting and ineffective recruitment program.

Site versus subjects. For example, the team responsible for subject recruitment may have created a very effective media awareness campaign that results in a high response rate from interested candidates. Yet if the site has insufficient staff to screen prospective subjects via the telephone or doesnt promptly respond to patients referred by a centralized call center, this may result in a low yield of subjects. In such cases, it is common to blame the recruitment team for not delivering successful results. The media campaign was likely very successful in attracting the attention of interested participants, but the site didnt have sufficient resources to respond to the high volume of calls.

Protocol versus subjects. Another common mismatch relates to the strictness of the subject eligibility criteria. Failure to secure input from the sites on the inclusion and exclusion criteria often leads to enrollment delays and protocol amendments. Recruitment of subjects into a study is a shared responsibility between sponsors and sites. Sponsors should validate the number of potential subjects available, and sites should not accept studies without doing a thorough feasibility assessment of their access to the appropriate patient population.

Site versus protocol. A further illustration pertains to the site selection process. Investigators are often selected based on medical expertise and past experience, which may or may not relate directly to the ability of the research site (as an entire entity) to implement the protocol. A thorough evaluation of the site capabilities, resources, and facilities for a specific protocol, in addition to validation of the sites access to the appropriate patient population, are critical steps. Interviewing several staff memberssuch as the investigator, clinical research coordinator, and site administratorto confirm subject availability estimates and site capabilities is an often overlooked but essential activity to ensure recruitment success.

The box, Fitting Together the Components of a Clinical Trial, highlights elements that should be addressed during the protocol design, site selection, and recruitment planning phases of study implementation. Early assessment of these variables is essential to understanding the recruitment challenges of each study and identifying the most suitable interventions.

Ensuring a good fit
Recruitment issues can be assessed as part of the routine site selection and subject recruitment planning processes.

Feasibility of a study for a site. Sites should conduct a thorough feasibility assessment of the protocol, including retrospective and prospective analyses of their patient population. This may be done by conducting database searches and reviewing medical records over a period of time to identify subjects who meet the eligibility criteria. This should be accompanied by a careful review of past enrollment performance metrics for the disease in question to evaluate what the most successful strategies were for recruiting subjects in past and similar studies. In the United States, sponsors and CROs have access to more sophisticated informatics vendors, such as Acurian (www.acurian.com), the MedStat Group (www.medstat.com), Quintiles (www.quintiles.com), and others, who use prescription and medical claims databases to validate site enrollment projections and model the disease prevalence rates in given geographic regions. These evidence-based techniques provide an aggregate view of disease prevalence by geographic area and practitioner/prescriber, preserving patients confidentiality while validating that the sites selected truly have access to the patient population of interest.

Availability of potential subjects. Sites should then undertake detailed subject source mapping and recruitment planning, outlining all possible sources of subjects (for example, existing medical practices, referral physicians, and the public at large) and estimating the percentage of subjects likely to be drawn from each source. The table above provides an example of a subject source map. Such a map can be used to identify which sources are most likely to yield the most subjects and help prioritize the types of outreach and awareness programs most likely to reach each source.

The subject source mapping and recruitment planning exercise is also extremely valuable for resource planning and allocation. For example, if the primary source of subjects will be the investigators own pool of patients, additional staff resources may be required to conduct chart reviews to identify potential candidates. If the primary source of subjects will be referring physicians, the site will need to define the resources and materials required to identify and educate potential referring physicians and assess their access to suitable subjects for a given study. Up-front planning such as this will ensure that adequate funds are secured to implement the strategies and that sufficient time is allowed for development and ethical review of clinical trial awareness materials.

Advertising to potential subjects. If the primary source of subjects will be the general public, all stakeholders (sponsors, CROs, recruitment vendors, and sites) should consider investing in some type of market research activity. Market research techniques (including focus groups and the profiling of population subsets by demographic, socioeconomic, and lifestyle interests) can shed further light on unique characteristics of the patient population, such as their hobbies, interests, and media use habits. This information can be used to create the most effective eye and ear catchers and help sites target their media placements more strategically. Such techniques may reveal, for example, that senior citizens in central Florida who suffer from type 2 diabetes are 10 times more likely to listen to light jazz radio stations than all other stations, whereas the same population in Seattle is more likely to listen to talk radio programs or is more effectively reached through another medium such as a home magazine. Members of a target patient group start to react to an advertisement when it appears before them three or more times, and market research can help ensure that advertisements are placed with the right message in the right media so that members of the target group are exposed to the message repeatedly. A combination of various outreach methods may yield the best response of interested subjects for a study.

Market research can provide further insight into the motivation of potential subjects for participating in clinical research. For some subjects, the prospect of relief of symptoms is the key motivation, whereas other subjects reasons may be altruistic. Understanding potential subjects concerns can have a significant impact on the protocol design itself, in addition to awareness of the study. For example, if the target patient population is of working age, then it will be important to consider the number and duration of study visits to minimize the overall burden to the subject. Otherwise, all the efforts to attract the appropriate patient population will be wasted if the subjects arent able to comply with protocol visits.

These are but simple illustrations of the type and depth of information that can be uncovered through market research techniques. All too often sites or media vendors may have the proper message, but it is placed in the wrong medium, or vice versa. Sophisticated information about potential subjects lifestyles and media techniques will ensure that recruitment budgets are spent wisely.

Other ways of recruiting subjects. Beyond designing clinical trial awareness programs that are media-focused, it is also important to consider other channels for recruiting subjects. Not only is it important to understand what potential subjects read, watch, and listen to, it is also important to understand where and how they live, what activities they participate in, and so forth. Religious-, work-, and school-oriented disease educational programs; health fairs; and other activities can be just as effective as advertising, if not more effective, in raising awareness about a potential study, particularly in countries and communities where direct-to-patient advertising may not be allowed or considered appropriate. Several minority organizations and patient advocacy groups in the United States and around the world are getting involved in developing patient education materials to help raise awareness about the value of participating in clinical trials, in addition to including information about clinical trials in their newsletters, posting information on their Web sites, and sponsoring community-based awareness programs.

Bringing treatment to patients is increasingly possible through the use of mobile mammogram and blood donation units and visiting nurse services. Similarly, mobile research units can be used to bring research to the subjects and provide the opportunity for potential subjects in remote and underserved areas to participate. Telemedicine interfaces, such as those developed by Frontier Medical research (www.frontiermedicalresearch.com) are also being applied in the clinical research environment to reach previously untapped patient populations.

One size does not fit all
Selecting the most appropriate and cost-effective approach to reaching potential subject populations is complex and multifaceted. What works for a private practice physician investigator in New York City will be quite different from what works for a professional research center based in the midwestern United States, and different further still from what works at an academic medical center in Seattle. Techniques that are appropriate in France may not be transferable to Thailand, and so on. While it goes without saying that any recruitment program must adhere to all levels of regulatory and ethical compliance, it is important to recognize that international regulations and guidelines dont begin to address the site- and protocol-specific needs and issues that affect recruitment for a given study.

Gaining an appreciation for the fact that each site is structured differently and operates in different environments, and that every potential subject has different needs, will go a long way toward developing more effective subject recruitment programs. Although the protocol and subject definition criteria for a given study are consistent, the study is being implemented at many different sites, all of which have different and unique infrastructures, environments, personnel, and needs. Although the patient population in general may be the same age and be suffering from the same conditions as required by the study, each potential subject is unique in terms of his or her interests, needs, motivations, and media use habits. Outreach programs that use the wrong media, or clinical trial awareness messages that fail to target different lifestyle segments and cultural sensitivities, will miss the opportunity to reach the largest audience possible. Successful recruitment requires sensitivity to site, geographic, cultural, and community differences and a willingness to tailor the recruitment program, where possible, to accommodate these differences.

SIDEBAR: Fitting together the components of a clinical trial

Ensuring a good fit between sites, protocol, and patient population requires careful assessment of many factors.

Between the protocol and the sites

• Site experience. Past experience conducting trials in a similar patient population and assessment of past enrollment performance metrics.
  
• Site resources. Personnel resources including the number and type of personnel available, their functional responsibilities, and their relationships to other institutional departments, referring physicians, and community organizations. Financial resources to support hiring and training of additional staff if needed
  
• Site personnel skills and abilities. Appropriate delegation of responsibilities among personnel with sufficient qualifications to perform the protocol procedures involved.
  
• Ethical review committee policies and procedures. Ethical review committee attitudes toward patient outreach programs (for example, restrictions on media messages), subject reimbursement, and so on.

Between the sites and the patient population

Disease prevalence in the geographic region of the site.Access to the appropriate patient population. Is the investigator a treating physician who can draw on patients from his or her existing practice, or a dedicated clinical trialist who sees only research subjects?

• Competing studies. Existence of any competing trials and their expected dates of completion of enrollment.
  
• Site facilities and procedures. Subject-friendly facilities (comfortable waiting room); efficient scheduling; extended clinic hours to accommodate subjects work schedules; transportation support, subject reimbursement, and compensation amount and procedures. Type of screening procedures (clinical chart review, phone, mail, face to face).
  Communication skills. Are the individuals who will be screening and interviewing potential subjects and obtaining informed consent skilled at verbal communications (and in which languages) and responding to subjects questions and concerns? Are site staff focused on creating a pleasant customer service experience for the subject?

Between the patient population and the protocol

• Subject definition criteria. How restrictive are the criteria relative to the existence of patients with the disease or condition being studied? How closely do protocol procedures and treatments resemble standard medical practice?
  
• Protocol procedures. How invasive and burdensome are the procedures? How demanding is the visit schedule in terms of visit frequency and duration?