Paul Bishop is CEO, Atlantic Research Group (ARG), and can be reached at pbishop@atlanticresearchgroup.comÂ Lyle Camblos is Managing Partner, Atlantic Research Group (ARG) and can be reached atÂ lcamblos@atlanticresearchgroup.com

Paul Bishop and Lyle Camblos

	As floods engulfed suburbs across northern Illinois in 1986, two freelance writers were working furiously to meet a publisher’s deadline before being forced to evacuate. Their phone rang. It was FedEx. “I have a package. Do you need it?” asked the delivery man. Yes, urgently. Those materials were necessary to complete their project.

	“OK, I’ll walk it over,” said the young man. And so he did-through chest-high water, holding the package above his head as neighbors cheered him on.

	FedEx’s tagline at the time, “When it absolutely, positively has to be there overnight,” captured this extraordinary commitment to customer service-and put a small courier on the map as a specialized option when high-volume competitors were notoriously slow.

 The delivery man's actions were not a result of a lone employee’s enthusiasm for his job, but rather a company-wide policy that encouraged employees-especially delivery drivers-to use their expertise, initiative, and insights into unique customer needs to do whatever it took to get the job done.

	Rare disease clinical trials also require extraordinary customer service-sometimes even including package delivery. In one case, each treatment dose cost more than $3,500, required constant refrigeration within a narrow temperature range, and had to be checked in and out to document protocol compliance and chain of custody-requirements beyond even FedEx’s legendary capabilities. Often, the task fell to the trial’s clinical research associates (CRAs), who went well beyond their job description to ensure the trial succeeded.

	And like package delivery, clinical trial performance can be improved by empowering frontline employees-most especially CRAs. Since CRAs spend the most time with study site staff and patients’ charts, they are a rich source of detailed, real-world knowledge needed to identify and solve unanticipated problems. While valuable in any trial, harnessing these insights is especially important in the growing rare diseases segment, where small populations often mean trial designs must be tweaked mid-study, and retaining all the patients can be critical for trial success.

	Too often, however, valuable CRA resources are lost. The worldwide CRA turnover rate remained above 25% through 2015, and lack of internal career development opportunities was a significant factor, according to a long-running annual survey.

 Such high CRA attrition often undermines continuity, which is imperative to the success of complex clinical trials.

	The example set by FedEx’s management approach presents a valuable opportunity to improve clinical trial operational efficiency and success rates not only for rare diseases, but also for all types of clinical studies. It might even help transform a clinical trial industry mired for years in a downward spiral of higher costs and ever more tenuous returns.

	Rare disease and orphan drugs is among the fastest growing patent drug market segments. In 2016, the FDA Office of Orphan Product Development received an astonishing 582 requests for orphan drug designation and granted 333, both more than double a decade earlier. In the same year, 39 orphan drugs were approved, down from the 49 and 48 in 2014 and 2015, but 50% more than any year before 2013.

 Over the next five years the orphan drug market is projected to grow 11% annually, about double the overall prescription drug market growth. Moreover, it will likely reach 21% of total patent drug sales and an even higher share of net revenues by 2022.

	Because rare diseases affect so few people-defined in the U.S. as less than 200,000 individuals or about 6.3 per 10,000; less than five in 10,000 in the EU; and less than four in 10,000 in Japan-study populations are also small. In 2013, the average number of patients enrolled in Phase III clinical trials was 731 for orphan drugs, or about one-fifth the 3,540 for non-orphan drugs.

 However, these averages don’t capture how truly small many orphan drug trials actually are.

	For example, a 2009 study of 32 successful orphan drug pivotal trials for neurological indications identified 10 with 50 or fewer participants-including four enrolling just seven, 10, 17, and 18 patients.

 Similarly, a 2014 study of 24,088 interventional clinical trials of all stages found that 72% of orphan trials enrolled 50 or fewer patients compared with 43% of non-orphan trials.

	Clearly, rare disease is a market segment sponsors cannot afford to ignore. More importantly, rare diseases require a different approach to clinical trials, as well as highly motivated and skilled CRAs to carry it out.

	Small study populations present unique challenges that may include:

		Incompletely understood disease pathophysiology

		Unknown phenotypic and/or genomic variability

		Inconsistent or lack of a standard of care

	As a result, the standard approaches to executing a clinical study that may work for well understood, more common conditions with large patient populations are less likely to succeed for rare diseases. Due to the complexities rare disease trials present, it is crucial that the trial’s frontline managers-CRAs-play a more creative, proactive role.

	Often, rare disease trials are a journey of discovery-not just about the treatment, but also about the disease for clinicians and researchers alike. Close coordination among research sites and central trial monitors, including uniformly introducing protocol changes, such as dosing or outcome measure adjustments, is essential. As the primary liaison to research sites, CRAs are responsible not only for implementing any changes, but also for monitoring their effectiveness and collaborating on further changes as active members of a quality improvement team.

	The importance of flexibility is illustrated by a study of a rare eye disease, in which blinding fibrous membranes grow under children’s eye lids. The initial protocol called for clinicians to visually estimate lesions size, but this produced inconsistent data from visit to visit. Observers troubleshooting in the clinic saw the problem was squirming children. A solution was devised: substituting a central scorer to grade lesions using electronic analysis of digital photographs. This ensured the trial’s success.

	Site and patient recruiting also may be very different for rare disease trials. For example, the usual large trial model of selecting experienced research sites and waiting for patients to accrue may need to be reversed. With patients widely and remotely spread, it can make more sense to find them first, and then work with an accessible clinic to set up a research site. Close support from onsite CRAs is required to bring up and support inexperienced sites.

	In addition, CRAs may need to address patient needs, from clinical issues to arranging transportation and housing for patients who must travel, and even help manage their schedules to ensure they can stay on protocol. For example, in a trial of a drug for hereditary angioedema, CRAs supported sites by flying across the U.S. immediately when any patient had acute attack and needed to then rapidly enroll in the trial. Moreover, they had to closely monitor infusion supplies, providing a range of needle sizes to ensure that smaller veins could be used for patients undergoing dozens of infusions over the course of the trial. This same trial nearly failed early due to high turnover among CRAs provided by a large clinical research organization, and was salvaged when a smaller organization took over and assembled a motivated CRA team.

Cultivating a “founder’s mentality” in CRAs

	For success in rare disease trials, the range and technical complexity of the services CRAs must deliver, and the interpersonal skills needed to deliver them effectively, require that CRAs be highly trained, experienced, and motivated. Their ability to assess site performance and needs, and willingness to act independently to address them are especially important for supporting sites with limited clinical trial experience. The value of trained, competent, committed, and team-oriented CRAs can hardly be overstated.

	But how do you recruit and retain the necessary talent? Our experience suggests that recruiting experienced and ambitious CRAs, and consistently providing them with the support they need to do whatever it takes to keep site staff and patients engaged, is similar to the way FedEx supports its drivers.

	Empowerment of frontline employees to improve organizational performance is hardly a new idea. Indeed, top management support for doing whatever it takes to improve quality and service is a central tenet of quality improvement theory as formulated and applied by W Edwards Deming and others to rebuild Japan’s devastated industrial base into a world leader following World War II.

 More recently, consultants Bain & Company have characterized it as harnessing the “founder’s mentality,” which includes:

		A sense of mission to change the status quo on behalf of customers

		An obsession with the front line, characterized by an intellectual curiosity about every detail of the customer experience and of how everything in the business works, with decisions driven by instincts formed at the ground level, and empowerment of frontline employees

		An owner’s mindset, characterized by a powerful sense of responsibility for employees, customers, products and decisions; an antipathy to bureaucracy; and a bias toward speed in decisions and actions

	Bain’s analysis found that as companies grow, many end up losing this “founder’s mentality.” This process starts in well-intentioned attempts to scale success, such as when an organization’s original entrepreneurial heroes are asked to codify their success in SOPs, and professional managers are hired to enforce them. This leads to meetings at which no one at the conference table has contact with customers, and decision-making becomes increasingly less agile and customer-friendly. As this bureaucracy emerges, the talent attracted to the company is less interested in an insurgent mission, and more interested in the stability offered by carrying out a prescribed role in an established organization. In this way, growth can unwittingly dilute a firm’s original edge, breed complacency, and generate an environment that no longer values the entrepreneurial problem solving that once made the company great.

	The lesson for all organizations involved in clinical trials-whether sponsors or CROs-is quite simple: The role of the CRA is pivotal to corporate success. Specifically, empowering CRAs and instilling in them an owner’s mindset could improve corporate performance.

	Interestingly, our changing technological landscape could end up playing a major role in the continuing evolution of the CRA as a key player in clinical trial development. According to a recent survey of industry research experts, sponsored by SCORR Marketing and 

, the role of the CRA has changed more than any other job over the past 10 years, and will likely change the most over the next five. Increased availability of technology, including electronic medical records and risk-based site monitoring, were seen as the most important change drivers.

	These changes may bode well for better engaging CRAs in improving clinical trial performance. In particular, risk-based management, which shifts CRAs’ focus from mechanically reviewing 100% of source documents to a more proactive troubleshooting and advisory capacity for sites, will help make better use of the high skills most CRAs bring to their jobs.

	As we alluded to throughout this piece, CRA engagement is essential to the success of rare disease trials. Maybe it is a judgment call to extend a visit by a day to provide extra training to site nurses on a new procedure. Maybe it is buying a site a better stethoscope for cardiac monitoring when inaccurate readings impede patient screening. Such solutions are born of a trusting, face-to-face working relationship, which may be difficult to develop from a remote call center. Recruiting CRAs with exceptional experience and commitment to customer service is a big factor, candidates who internalize the “founder’s mentality” if you will. And adopting a CRA-first culture can pay off-doing so has driven our turnover rate to between one to four percent annually for the last 10 years.

	The challenge for our industry is overcoming organizational inertia that makes it difficult to institute a new culture that elevates the value of CRAs. FedEx proves this is possible for large organizations. Indeed, high CRA turnover is not a law of clinical development, it’s simply a problem that can be resolved by adopting a new mindset towards management.

 is CEO, Atlantic Research Group (ARG), and can be reached at 

 is Managing Partner, Atlantic Research Group (ARG) and can be reached at 

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