Risk Response: Constructing a Plan

Embarking on a multimillion dollar project without first identifying and assessing the risks involved and then creating a risk–response strategy would be like sending a blindfolded person out into a foreign city with no seeing eye dog, no cane, and no prior training on what to expect.

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A risk–response planning strategy encompasses those efforts necessary to identify risks, lower the likelihood of those risks occurring, and minimize their potential impact on the project if they do occur. Although risks can never be totally eliminated, they can be managed to lessen the likelihood of occurrence and/or impact on the project. In the clinical research industry, although study enrollment is only a piece of the overall clinical R&D process, it is one of the most pivotal projects and deserves the same rigorous protection.

Taking responsibility

Historically, when it comes to subject enrollment, sponsors have practiced what risk management experts would call risk "transfer"—giving the entire responsibility and accountability for enrollment solely to the sites. As subject recruitment knowledge and practices have developed and become more sophisticated, sponsors practiced transferring the risk to CROs and subject recruitment companies.

Today, however, sponsors are realizing that financial accountability remains squarely in their camp. If enrollment numbers aren't materializing fast enough, or at all, it is their company's potential profit that may suffer. Consequently, top executives are choosing to take more control of subject enrollment internally. With that decision comes a daunting challenge for sponsors.

First they need to understand the complexities of subject recruitment well enough to spot the unique risks or threats to enrollment, and then they need to be capable of carefully weighing their impact and making sound decisions about the actions they will take to respond most effectively. After all, subject recruitment has now become a full discipline—a field of study worthy of specialized expertise that may or may not exist in its entirety within sponsor organizations.

This article provides a framework that sponsors can use for recognizing and addressing the common threats to recruitment success through six universal risk areas of patient enrollment and illustrates how they can be analyzed and managed in a clinical study environment.

Six risk areas

The field of subject recruitment recognizes that every study faces its own unique challenges, and there is no single solution for ensuring that every clinical trial enrolls on time and on budget. It is critical to have methodologies in place that hone in on how to develop the ideal approach in any given recruitment situation.

Experts that have originated the development of subject recruitment as a field have identified and articulated six distinct threats to on-time enrollment:

• Poor study community communications or infrastructure

• Inadequate planning, monitoring or redeployment of enrollment efforts

• Poor site selection or performance

• Ineffective materials or inefficient approval of materials

• Ineffective recruitment of subjects from site panels and the general public

• Subject attrition or noncompliance with the protocol.¹

The definition of subject recruitment as a field goes far beyond generating interest in a trial through outreach. The discipline has expanded to include early assessment of the protocol from a recruitment perspective, site and country selection, outreach strategies and implementation, and retention programs, among other activities (see Figure 1).

Figure 1

Identifying the risk area of most concern for a particular study is the first step in a risk assessment and risk–response strategy plan. Once prioritized, each of the six risk areas may be addressed effectively with one or more of an arsenal of recruitment tools, tactics, and processes; however, it is neither strategically necessary nor financially prudent to apply every intervention to each of the risks. This is where the details of a risk–response plan are formulated, supported by a keen understanding of subject recruitment.

That ability to scrutinize every angle of the study through a subject recruitment lens and the expertise to apply only those resources with the highest potential for success are the most effective skills to enroll studies not only on time but also cost effectively.

Risk 1: Study infrastructure

Because effective enrollment depends on a variety of individuals and organizations, often in multiple countries, a communications plan and infrastructure are critical tools to share recruitment status, plans, and materials. To make timely assessments and to be able to respond to changes in the environment, stakeholders require access to data and information. Without shared knowledge, the sites, monitors, and global teams are less able to identify barriers to recruitment and act quickly to rectify them.

Case study. One Type II diabetes study's goal was to enroll 750 subjects across 65 sites in six months, and the clinical team called in recruitment professionals to help them increase the company-wide average of 0.5 enrolled subjects per site, per week in this therapeutic area.A miscommunication between managers and monitors relegated recruitment tasks to the bottom of the to-do lists, leaving investigative sites without the proper materials and support to conduct enrollment.

After identifying the risk, recruitment professionals acted as facilitators to open up communication between the managers, monitors, and sites, paving the way for recruitment activities to flourish. They achieved this by introducing an online portal to deliver tools and training to sites, share best practices, and communicate real-time enrollment progress reports to the sponsor.

Along with interventions addressing other risk areas, the program employed by recruitment professionals raised the average to .67 enrolled subjects per site per week, and enrolled the study slightly ahead of schedule. Lesson learned: Proactive risk assessment can identify recruitment barriers such as communication gaps between key players before they happen.

Risk 2: Study planning

It is common practice to create recruitment strategies and plans at the sponsor and even the monitor and site level. What is less well-recognized is the importance of continually assessing the performance of these plans in real life and knowing how to adjust strategies and tactics to keep enrollment on course. A systematic approach is required to collect the data that will allow study leaders to track recruitment performance results and make effective decisions in allocating resources.

Four Ways to Respond to Risk

Case study. In a Phase III study for an overactive bladder (OAB) treatment, recruitment professionals were charged with recruiting 722 subjects within three months. Challenges included a highly competitive environment with numerous other OAB studies being conducted and a variety of approved treatments available. Additionally, many subjects, due to embarrassment, were afraid to inquire about treatment so they didn't know treatments were available.

The subject recruitment campaign included a 30-second television spot at key broadcast times, and although caller responses flooded call center phone lines, monitoring of the data showed that site enrollment numbers had barely shifted. With careful analysis, recruitment professionals were able to quickly identify the bottleneck: Sites were overwhelmed and unable to follow up on referrals in a timely manner, losing potential participants.

By immediately shifting the plan to include a triage system for feeding screened subjects to sites with the capacity to handle them, enrollment began to shoot up.

Sites supported by the recruitment campaign randomized an average of 1.4 more subjects per site than those that chose not to participate. Also, the majority of sites stated that referrals received through the call center were well-qualified. The screen failure rate for referrals received through the call center was comparable to that of referrals that came directly from the sites' databases.

Risk 3: Site performance

Choosing sites for a clinical study should not be about relying on past relationships or taking a leap of faith based on an investigative site's reputation. And once sites are selected, they should be monitored as they initiate and begin enrolling subjects, and even supported in their recruitment efforts along the way.

However, many clinical studies suffer because investigative sites were not selected using strategic criteria related to recruitment capacity, nor were they assessed for strengths and weaknesses or supported and trained to fill in skill and knowledge gaps to recruit the study at hand. To ensure enrollment success, sites should be measured against a range of macro and micro variables, including access to subjects, staffing characteristics, and openness to new recruitment techniques, and then ranked by likely performance.

Case study. In one Phase III anemia study that was lagging far behind schedule, the study enrollment goal was to recruit 1300 subjects in an intensive care unit (ICU) setting across just over 100 sites. The challenge for subject recruitment experts, who were called in to get the study on track, seemed daunting. But a thorough risk assessment drew them to lackluster site performance—particularly in conducting informed consent.

Based on the rates of approach and consent for each of the sites, they found that there were several points during the complex process of approach and consent where sites could have difficulties. For example, most of the potential study participants were in trauma or unconscious, and so were unable to undergo the informed consent process themselves. Thus, site staff members had the extra challenge of approaching and consenting legally acceptable representatives (LARs) on behalf of the subjects, in a particularly stressful environment.

Recruitment professionals grouped sites according to their strengths and identified gaps in performance, enabling them to customize training programs and tools to address each group's core difficulty. The sites were grouped into the following categories:

• Introducers: approached most eligible LARs, but did not get them to consent

• Closers: consented most of the LARs approached, but had a low approach rate

• Performers: good at both approaching and consenting

• Nonperformers: low rates for both approach and consent

• Low Subject Yield: small ICU population of potentially eligible subjects.

Training for the Introducers, for example, included role-playing activities that would help study coordinators feel more confident and comfortable discussing study participation with LARs, while the training for the Low Subject-Yield sites focused on brainstorming ways in which these sites could conduct outreach activities to include other ICUs within their own institutions or nearby institutions.

Grouping sites according to strengths and customizing training to fill in knowledge gaps was a success. Sites were able to raise the randomized subjects per site, per month from .21 to .97, putting the study back on schedule. If study leaders had identified and planned to reduce the risk of site underperformance through training at the outset, the study would likely have enrolled ahead of schedule.

Risk 4: Recruitment materials

Effective recruitment materials (from subject-facing brochures to referring physician letters and advertising) are created using the principles of marketing, one of the core competencies of recruitment experts. Careful attention to the protocol requirements and the subjects targeted by the study provide them with clues to the correct messaging and tactics that will engage potential study participants.

In addition to resonating with subjects, those materials must get through the submission and approval process of ethics committees and institutional review boards as swiftly as possible. Time is of the essence in a clinical study, but precious time is often lost due to lack of control over the materials, development and editing process, and regulatory approval process.

Case study. In developing materials for a Phase III, global rheumatoid arthritis (RA) study involving three separate protocols spread across 29 countries and 30 different languages, recruitment professionals met with several challenges. Chief among these was the need to localize recruitment materials to meet the cultural acceptances and educational needs of audiences in each country. In addition to this, they faced immovable parameters such as tight recruitment time frames, multiple layers of sponsor reviews and sign-offs, and lengthy and varying ethics committee approval periods.

Aware of these risks because they were brought in to the study at the outset, the experts answered the challenges with an optimal, culturally malleable campaign design. Clear, simple language and a multicultural creative concept that was carefully constructed to resonate with RA patients across cultures helped facilitate the cultural adaptation process. Pre-existing arrangements with communications partners in several countries allowed for fast and high-quality cultural adaptation of materials.

To preempt time crunches caused by materials editing and regulatory submissions and approvals, recruitment professionals introduced an online subject recruitment management system to track, approve, and deploy the study's 1000+ culturally adapted communications pieces. Because the online system allowed study community members a secure means to access, share, and track these large documents throughout every stage of development, version control problems were eliminated. The system's efficient tracking capabilities also facilitated a more streamlined regulatory edit and approvals process.

The results proved successful. Recruitment materials garnered a 95% success rate with local ethics committees, allowing for a timely deployment to sites and on-time study enrollment.

Risk 5: Patient recruitment

Locating the right subjects who fit all of the criteria for a specific protocol can be like trying to find a needle in a haystack. But there is more to recruitment than generating subjects through advertising. It requires a thorough situation analysis to design the best mix of communication tactics. These could come from subject panels, physician referrals or the public. A risk assessment helps recruitment professionals determine the best mix of the three.

In some cases, recruitment could be a matter of maximizing subject "in-reach" through tools to help sites identify subjects in their panel or reach out to referring physicians. An example of this would be a study investigating a second-line treatment for metastatic breast cancer, where oncologists focus on their patient base. On the other hand, a research site with no patient base studying a treatment for newly diagnosed diabetes patients would likely require patient outreach—using advertising or public relations to recruit subjects from the public.

Case study. Achieving enrollment for a clinical study of a treatment for immune thrombocytopenic purpura (ITP) relied heavily on locating the right subjects. And although incidence of the condition was low, there was a high number of competing ITP studies. Recruitment professionals recognized that recruitment would have to come largely from in-reach and that hiring sites with the best subject access would greatly enhance on-time recruitment.

After conducting both primary and secondary research, the recruitment professionals were able to pinpoint the ideal investigator: a hematologist specializing in ITP whose treatment philosophy aligned with the novel scientific approach of the investigational drug. Next, using state-of-the-art technology that synthesizes a variety of data to zero in on geographic locations most likely to contain subjects who fit the protocol criteria, recruitment experts were able to map new investigative sites. As the final piece in this risk assessment plan, recruitment materials were developed to maximize the investigators' ability to mine their own databases and communicate to referring physicians the opportunity the study offered their subjects.

Risk 6: Patient retention and compliance

Study leaders can often overlook subject retention and compliance when planning for recruitment. A retention strategy should be devised early in study planning, beginning with a rigorous protocol assessment identifying the challenges and strengths that might affect retention. The retention barriers are weighed alongside strengths to determine the number, type, and quality of retention tactics.

Underlying all retention activities is the principle that active relationship building keeps subjects engaged in a study. The greater a site's ability to provide information and regular contact with a subject throughout study participation, the more likely that subject is to complete the study requirements. Sponsors and monitors can contribute greatly to providing tools and supporting sites in this effort.

Case study. Recruitment experts enrolling a two-year, Phase III study of an investigational treatment for slowing the progression of diabetic neuropathy were also challenged with subject retention for the same period of time. For this study, subjects needed to visit their study center once every two or three months. Additionally, at the end of both the first and second years, participants had to make four visits to the study center within one month. While the regular visits consisted of basic testing, the annual visits were all day visits and tests were significantly more involved.

Recruitment professionals knew that retention would have to begin as early as recruitment efforts. The key was to create a relationship to the study. Using the same strong study identity created for recruitment, they devised a retention support system, the keystone of which was a participant Web site that featured regularly updated information about living with diabetic neuropathy. Employing a series of birthday, holiday, greeting, and appointment reminder cards, study coordinators were able to maintain relationships with the study participants during the year between scheduled study visits.

By providing repeated opportunities for contact between study staff and study participants that were relationship building (rather than merely study completing), participants became invested in the basic caring contact they received through participation. Moreover, because this contact minimized attrition, the study was completed on time with sufficient data to allow for submission to the FDA.

Applying the six risk areas

Considering the infinite number of protocols possible and the potential recruitment conundrums they will create, it may seem an insurmountable task to gain a full understanding of every threat to subject recruitment and enrollment. The six enrollment risk areas have proven to be the most comprehensive method for identifying typical study downfalls. At the very least, these areas can help sponsors structure an internal mechanism for managing enrollment. Considered at the outset of every study, the risk areas offer a framework upon which to build a risk–response planning strategy.

Sponsors that have taken back the accountability for subject enrollment are advised to assess the robust subject recruitment expertise available within their ranks. Using their findings, they can determine a strategy for gaining the institutional knowledge they lack by investing in the formal study of the subject recruitment discipline. Where necessary, it may still make strategic sense to transfer certain identified risks to or share them with experts who have the capabilities and expertise to obtain results.

Joan F. Bachenheimer is chief executive officer of BBK Healthcare, Inc., 320 Needham Street, Newton, MA 02464, email: jbachenheimer@bbkworldwide.com

Reference

1. Six Risk Areas of Clinical Trial Patient Enrollment, BBK Healthcare, Inc. (d/b/a BBK Worldwide) 2007.