The Elusive Sponsor-Site Relationship

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Arguably, drug development sponsors consider improvements in site selection and management one of their top priorities. Tackling this problem has been very difficult. Investigative site performance is both highly variable and unpredictable.

Kenneth A. Getz

According to several independent studies: Less than one-third of investigative sites in any multicenter program are outstanding performers; 20% will meet expectations; and approximately half will underperform or fail to enroll a single patient. At the same time, sponsors concede that for any given study they do not know which sites will deliver and which will not due to numerous factors, including the motivation of the investigators and study staff; complexity and demands of the protocol; and competition for study volunteers.

My colleagues and I at the Tufts Center for the Study of Drug Development (Tufts CSDD) have been monitoring several trends in the investigative site landscape that threaten to make improvements in sponsor–site collaborative effectiveness even more elusive. What follows is a brief discussion of these trends based on data maintained and provided by the FDA. It's important to note that although this data captures a majority percentage of the global investigative site landscape, it does not include all of it. Comparable and comprehensive data on investigative sites regulated by other agencies around the world is not available.

Globalization

The number of investigators conducting FDA-regulated studies is increasing. At the same time, a large and growing percentage of investigators are no longer based in North America and Western Europe. This trend highlights the rising, and costly, logistical complexity of finding, building, managing, and monitoring relationships with investigative sites dispersed around the world.

Worldwide, more than 26,000 unique investigators conducted FDA-regulated clinical trials in 2007. Globally, the number of investigators grew at an annual rate of 8.7% from 1990 to 2000. Since 2001, however, growth in the absolute number of investigators has been slower, at 2.1% annually.

The proportion of investigators based in North America has steadily declined from 96% of the total global pool of FDA-regulated investigators in 1990 to 54% in 2007. Western Europe has held a share of approximately 12% to 14% of all FDA-regulated investigators for the past five years.

Latin America, Eastern Europe, and Asia have seen rapid growth in the number of FDA-regulated investigators, mostly for confirmatory, later stage clinical studies. Steady growth in the proportion of investigators in emerging regions is due to many factors, including lower relative study conduct costs, harmonization of good clinical practice guidelines, well-positioned CROs, and the availability of large numbers of well-trained professionals and treatment-naïve patients.

At the end of 2008, 8.5% of active FDA-regulated investigators were based in Central and Eastern Europe. Asia and Latin America each hosted 5.5% of all investigators.

Interestingly, we've observed a decline in the number of active FDA-regulated investigators conducting Phase II and III trials in North America, while the opposite has occurred in Phase I studies. Growth in North America-based FDA-regulated investigators in early, first-in-man clinical studies has been substantially faster than that observed in Western Europe and in emerging regions. This is due to a number of factors, including sponsors' belief that Phase I studies are more economical and can be initiated faster in North America.

Privatization

Since the early 1990s in the United States, drug development sponsors have facilitated the privatization of clinical trial conduct in their search for lower cost, higher performing investigative sites. Today, the U.S. investigative site market is comprised of three primary segments.

The Part-time segment is made up of physicians in private, community settings that derive the majority (85% or more) of their annual revenue from clinical practice. In 2007, this highly fragmented and transient group has surpassed Academic Medical Centers (AMCs) as the largest market segment, with a 38% share of total clinical trial grants.

Nearly two-thirds of the 9000 investigative sites conducting clinical trials in the United States annually fall into the Part-time segment. Select sites in this segment may conduct as many as 25 or 30 clinical trials each year, although approximately 85% conduct only one clinical trial annually. Turnover rates among sites in this segment are extremely high. And financial controls and clinical research infrastructure are highly variable.

The Dedicated investigative site segment captures 26% of the market. Private, community-based Dedicated sites derive nearly 100% of their annual revenue from clinical trial grants. Sites in this segment operate independently or have formed managed networks. They have considerable clinical research expertise, experience conducting trials, and good infrastructure. As such, Dedicated sites tend to have higher relative operating costs. A conservatively estimated 350 investigative sites fell in this segment in 2008.

AMCs capture approximately 36% of all clinical trial grants from pharmaceutical, biotechnology, and medical device companies. Since 1998, AMCs have lost nearly 40 percentage points in market share of total industry sponsored clinical trial grants.

Whereas the mid-1990s saw a flurry of academic institutions establish clinical trial offices to handle industry relationships, the late 1990s through mid-2000s saw a reversal of that trend. AMCs cite a number of explanations for this shift, including poor returns on infrastructure investment, lack of institutional support, and renewed emphasis on the more prestigious government-funded research programs.

Size and scope changes

Although it is too early to quantify the impact of the current global economic crisis on clinical trial volume, it will no doubt decelerate. As a result, investigative sites can expect to see competition for clinical trials intensifying over the next 18 months. Still, my Tufts CSDD colleagues and I have our eyes on an even more alarming trend that challenges the long-term viability of experienced investigative sites.

The number of investigators per active IND has nearly doubled during the past decade. At the same time, the average number of patients per NDA is less than half that observed 10 years ago. Put another way: Sponsors are engaging more investigators to recruit fewer patients per IND. In 1997, on average, sponsors recruited six investigators per active IND. In 2007, sponsors recruited an average of 11 investigators per active IND. During that same 10-year period, the average number of patients per new drug approval declined from 5600 to 2200.

Many factors may be driving this trend. Sponsors are looking to hedge their study conduct risk by engaging a larger number of investigators. In addition, clinical trials are increasingly seeking more targeted, smaller patient subgroups in part due to the diseases under investigation, newer study design strategies, and cost considerations.

This trend does not bode well for investigative sites that cannot justify participating in future clinical trials because the compensation based on the volume of patients per study does not cover their operating costs.

At the present time, global investigative site landscape trends present unprecedented challenges for sponsors looking to improve the effectiveness of their relationships with investigative sites. Yet these challenges must be addressed with creative solutions and the necessary investment of personnel and resources in order to establish viable and successful sponsor–site collaborations.

Acknowledgement

The author wishes to thank Rachael Zuckerman and Stephanie Roshon for their assistance in gathering and analyzing investigative site data.

Kenneth A. Getz, MBA, is a senior research fellow at the Tufts CSDD and chairman of CISCRP, both in Boston, MA, email: kenneth.getz@tufts.edu