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The next 18 to 24 months may bring profound changes for investigative sites.
Despite the premium that sponsors and CROs now place on driving higher levels of study conduct efficiency and performance, the odds are greatly stacked against them given the structure and characteristics of today's global investigative site community.
Recent research on the global study conduct service provider market paints a picture of a landscape that has been spinning its wheels for 30 years, unable to mature or achieve scale efficiency and operating sophistication (e.g., standardized procedures, financial and management controls). The site landscape has been in a perpetually nascent and fragmented state.
Stakeholders across the enterprise are looking to change the situation by focusing on a range of initiatives to transform the study conduct landscape. Which approaches will achieve lasting and substantive improvement? A look at the current state of the landscape and how it is managed may hold some insight.
In 2013 the total number of active principal investigators (PIs) participating in FDA-regulated studies worldwide reached its highest level in history. There are now nearly 28,000 unique investigators each conducting fewer trials on average than in prior years. Annual growth in the number of active principal investigators between 2002 and 2012 has been modest (0.8%) compared with rapid growth (9.7% CAGR) between 1992 and 2002.
Emerging regions, including Asia and Eastern Europe, have seen the highest relative growth in the number of FDA-regulated investigators since the late 1990s due to the small bases from which they started. The proportion of investigators based in North America has been declining steadily from 84% of the total international community of FDA-regulated investigators in 1998 down to 61% in 2012.
Less than a third of all investigative sites around the world are part of a network. The vast majority are stand-alone sites, with limited infrastructure, operating autonomously. The typical investigative site has only one principal investigator and two staff members involved either on a full or part-time basis as study coordinators.
For more than a decade, the United States was the only geographic area where independent investigators comprised the majority of FDA-regulated sites. This is no longer the case as sponsors and CROs have looked to place more of their trials in emerging regions. The majority (53%) of all FDA-regulated investigative sites operate as for-profit, independent, community-based entities unaffiliated with academic systems. University, hospitals, and government clinics have been gradually losing their share of industry-funded clinical trials. Two-thirds of all global FDA-regulated investigators in 2006 were based in academic settings compared to 47% of the total in 2012.
Investigative site performance on any given clinical trial varies widely and underscores the inherent and high risk associated with study conduct activity. Sponsors and CROs widely recognize that success is directly tied to patient enrollment and every clinical trial has its share of poor performers.
A 2012 Tufts Center for the Study of Drug Development study of several hundred global clinical trials found that sponsors are forced to double the planned enrollment period on average in order to give investigative sites enough time to recruit study volunteers and complete a given clinical trial. Even with long cycle-time extensions, one out of every 10 (11%) sites, on average, in any multi-center clinical trial will fail to enroll a single patient and one-out-of-four (39%) will under enroll. The other half of sites in a given multicenter study will either eventually meet the enrollment target or will exceed it.
The migration of industry funded clinical research into the private sector has been largely driven by performance and economics. Overhead rates have been lower, and performance quality higher, among independent investigators. Study start-up cycle time and enrollment performance among independent investigators is faster than that experienced in university centers, hospitals, and government clinics. Independent PIs tend to negotiate and approve study contracts and budgets nearly twice as fast as their academic counterparts. For-profit sites have higher activation rates with 9% failing to enroll at least one patient per clinical trial compared with 13% of sites in academic settings. Independent sites also have higher enrollment achievement rates with nearly all (96%) eventually meeting patient enrollment targets. Less than 75% of academic centers eventually meet their patient enrollment targets.
Wide regional performance differences are also common. The Tufts CSDD study found that North American investigators have the fastest study start-up times and higher than average enrollment performance. European and Asia Pacific investigators have relatively slow start-up times and average enrollment performance. Latin American investigators tend to have relatively high enrollment performance following slow start-up cycle times.
Turnover rates among the global pool of FDA-regulated investigators are also high and vary by region. Overall, approximately 40% of PIs choose to never conduct another clinical trial after a given 1572 submission year. Turnover rates are particularly high in Asia Pacific, Europe, and Latin America where more than half of all investigators submitting a form 1572 never return to the research enterprise. High turnover rates—in part a function of challenging regulatory compliance requirements and a difficult operating environment—drive site selection and management costs and inefficiencies, and contribute to an unstable and fragmented site landscape.
Since 2005, an average of 257 complaints for PI non-compliance and fraud has been filed with the FDA each year. Protocol non-compliance, data falsification, and poor drug accountability are the top areas of noncompliance cited. The number of complaints filed with the FDA for investigator non-compliance and fraud is nearly 10 times higher than the level of complaints observed in the 1990s due in part to increased reporting from ethical review boards, institutions, and study monitors.
Although most markets mature and consolidate to drive scale economies and efficiencies, during the past three decades the investigative site landscape has failed to do so. Community-based investigative sites eager to participate in clinical trials have largely avoided the risks associated with mergers and consolidation.
Traditional site management practices have contributed greatly to current landscape conditions and have unintentionally facilitated instability and harmed the viability of site operations. Until recently, most sponsors and CROs have largely treated investigative sites as commodity service providers, where the lowest cost prevails; contracts and budgets are offered on a take-it-or-leave-it basis; and payment for work performed is delayed. These practices have invited lower cost, and inexperienced, novice investigators lacking training and infrastructure.
Sponsors and CROs have hedged patient recruitment risk by enrolling larger numbers of sites; each site enrolls smaller numbers of patients rendering study grants less attractive to those sites that have established infrastructure and require a fixed number of patients to recoup their initial study start-up investment.
A recent CenterWatch study found that investigative site operating costs have been rising by 5% annually during the past five years at the same time that average study grant amounts have declined by 3% each year. Nearly 40% of sponsor payments are greater than 90 days overdue and 5% to 7% of study grant payments invoiced are written off by sites as bad debt each year.
There have been many ideas and much speculation recently about ways to improve this fragmented and immature landscape. Some approaches are more passive than others:
Policymakers and educators—including the Clinical Trials Transformation Initiative, the Association of Clinical Research Professionals, and the Alliance for Clinical Research Excellence and Safety—have set their sights on training, certification, and accreditation to elevate and set minimum standards of site experience. The Society of Clinical Research Sites seeks to unify the investigative site community and, in doing so, inform practice improvements and collaborative effectiveness.
TranCelerate BioPharma and commercial database providers see the enhancement of site selection practice as a critical step required to improve site performance prediction. The Metrics Champion Consortium is eyeing standardized site performance metrics as a critical management resource.
Several sponsor and CRO companies—including Sanofi, Roche, Quintiles, and Parexel—have been implementing new relationship models and establishing site partnerships to streamline study start up timelines, nurture longer-term collaborations, lock in preferred pricing, and guarantee repeat study activity. And with the backing of private equity, select CROs and large global and national site networks appear poised to acquire premier investigative sites and drive consolidation.
Although the jury is out on which initiatives will have the greatest impact, a growing number of stakeholders acknowledge the limitations of a fragmented and immature landscape. It's clear that investigative sites can expect a lot of attention and change during the next 18 to 24 months.
Kenneth A. Getz MBA, is the Director of Sponsored Research at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, e-mail: [email protected]