Entering the Realm of Flexible Clinical Trials

The business community has long held that performance can only really be managed when it can be measured. Clinical research sponsors have been embracing this concept for decades. But during the past five years, research sponsors have significantly increased the sophistication of--and their usage of--metrics.

More is being routinely measured than ever before. And the metrics being gathered are measuring more targeted and distinct tasks. In a survey of 30 major pharmaceutical companies in 1999, for example, only 17% reported that they systematically gathered and reviewed contract research organization (CRO) and investigative site performance metrics on each clinical project. In 2004, 93% of companies reported doing so.¹

Performance metrics are also being gathered and managed more rapidly. As a result, benchmark and performance metrics have shifted from being retrospective to being diagnostic, and even predictive. Key factors driving this shift include sponsors' growing focus on finding new ways to optimize resources and ensure that capital invested in drug development activity is maximized. Sponsors have improved their definitions of key benchmarks, and they have implemented better systems and mechanisms to collect and track these metrics.

eClinical technologies have been essential to the establishment of measurement systems and mechanisms that assisted this shift from retrospective to diagnostic clinical study management. Although technology adoption rates are still relatively low, a recent survey conducted among 100 biopharmaceutical companies estimates that in 2004 16% of all North American-based clinical trials now utilize electronic data capture and patient-reported outcomes solutions and clinical trial management systems. This compares to only 1 out of 20 clinical trials doing so in 2002.² Sponsor performance measurement focus and practice is further reinforced by the growing use of proprietary internal and commercial databases to enable CRO and site selection, patient recruitment planning and execution, and the monitoring of recruitment promotion effectiveness.

Since early 2000, a growing number of sponsors have instilled an enterprise-wide commitment to better ensure that performance metrics are actively collected and shared. The rising complexity of project team membership involves multidisciplinary personnel along with multiple contract service providers from CROs and investigative sites to contract employees and contract niche service providers. It has required sponsors to adopt more sophisticated project management tools and placed increasing burden on contract service providers to better measure, monitor, and report on their own performance.

Continuing on this course, FDA-regulated clinical research is entering the realm of truly flexible clinical trials, those that can be rapidly modified and adjusted in real-time, on an ongoing basis. Sponsor company efforts to further streamline processes, maintain relationship and resource flexibility, and drive ever more demanding metrics-based performance have profound scientific and regulatory implications and will dramatically impact the utilization of contract service providers. With regards to the latter, sponsors will look to minimize project risks and maximize their adaptability by:

• streamlining initiation activities in order to place sites in a start-up queue prior to beginning a clinical project
  
• modifying payment structures and schedules to limit risk exposure and to provide tie-in performance incentives
  
• entering into shorter-term contract commitments with minimal to no penalties for early termination
  
• establishing predictive metrics that act as reliable performance indicators.
  Research sponsors are clearly making moves to support flexible clinical trials. At a recent CRO management conference, for example, a top five pharmaceutical company executive said that his company had re-engineered its clinical research processes end to end in order to establish cross-functional roles and processes to better support clinical trial flexibility. He said that whereas the organization had historically "operated under a craft model where each clinical area did everything; now the company had moved to a specialty model where organization-wide, all roles and processes have been redefined around performance measurement."

To support this change, the company utilizes an expedited study initiation process and seeks master service agreements with all investigative sites that it uses for three or more trials. Study contract length has been significantly reduced, and sites have been offered a much shorter period of time within which to accept or reject a study. The executive reports that the company is more deeply committed to rapidly terminate a site that fails to meet enrollment requirements on an ongoing basis.

A growing proportion of outsourcing and contract management departments now report that they are tracking provider performance themselves instead of relying on reports from the clinical teams. In a 2005 Tufts Center study of outsourcing department managers from 31 pharmaceutical companies, 61% report that they routinely track supplier performance. This is substantially up from 38% in 2003.³ And whereas their traditional responsibility has been to save costs and expedite contract negotiations and approval, a majority of outsourcing departments now report that one of their primary responsibilities is to increase supplier productivity.

Since 2001, investigative sites have seen sponsors provide smaller payments at the outset of a clinical study and withhold larger portions of the grant payment until the study has been closed out. Sites report that sponsors are taking considerably longer to pay for clinical trial work already completed. In 2001 for example, it took a sponsor 78.5 days, on average, to pay its investigative sites for work already performed. In 2003, it took 139.2 days--a 77% increase.⁴

An executive from another top 10 pharmaceutical company recently told me that he is now looking closely at the concept of using real-time operational benchmarks to predict and anticipate performance, and to support making rapid remedial changes during the trials. These benchmarks would come from historical data on high-performing sites.

"Investigative sites," he stated, "behave rather predictably over time despite the multitude of variables that can impact performance." His company recently found that 70% of the time high-enrolling sites were consistently high enrollers. Moreover, the enrollment pattern of average and low-performing sites was also consistent and predictable. "We found in a recent pivotal trial that sites enrolling a certain number of study volunteers within the first 35 days had a 95% chance of completing the study on time. This compares to an 80% chance of failure for sites that are unable to enroll that number of patients within that time frame," he said.

In the coming 18 months, investigative sites and other contract service providers need to consider the full ramifications of the flexible clinical trial as it increases their risk exposure and requires changes in their operating environments to support this shift. For research sponsors, the dangers of entering the realm of flexible clinical trials need to be fully and carefully understood and managed.

The focus on metrics-driven per-formance, cross-functionally supported and managed centrally, runs the risk of diminishing the benefits of an effective relationship, and promotes the perception that contract providers offer inter-changeable commodity services. Flexible clinical trials by their nature lower the sponsor's tolerance for performance deviation and recovery. This "unforgiving" stance denies contract service partners the opportunity to make adjustments mid-stream. And, if not managed carefully, the abrupt termination of underperforming investigative sites may place their study volunteers at risk--particularly those participants responding favorably to the study drug.

Sponsor demand for higher levels of metrics-driven performance will likely drive consolidation within CRO and investigative site market segments, particularly among novice and less-experienced players. Whereas some consolidation and the elevation of overall performance standards are welcome, over time it may be more difficult for new professionals to enter clinical research.

Clinical research insiders readily admit that the clinical research enterprise is as much about "relationships" as it is about gathering scientific and operating evidence and metrics. It is well documented that the stronger the relationship, the more effective and efficient performance will be. As research sponsors drive the shift to truly flexible clinical trials, they will need to strike and manage a delicate balance between rapid adaptability and the benefits of long-term partnership.

References
1. K. Getz, "7th Annual ACT EuroSummit, Technology Use and Investigative Site Efficiency," Geneva, Switzerland, 2000; TCSDD 2005.
2. R. Kush et al., CDISC 2004 Research Project on Attitudes, Adoption, and Usage of Data Collection Technologies and Data Interchange Standards, DIA EuroMeeting, Lisbon, March 2005.
3. TCSDD, 2005; Thomson CenterWatch 2002.
4. Clinical Financial Services, 2004.