New survey from Tufts CSDD and Applied Clinical Trials provides an inside look at global sites.
The investigative site landscape has passed through two notable phases during the past 15 years: Between 1995 and 2002, the landscape—primarily concentrated in North America and Western Europe—saw the emergence of new investigative site operating models (e.g., Site Management Organizations, Investigative Site Networks, Trial Management Organizations) and consolidation by well-capitalized companies. The years 2003 through 2010 can be best characterized as a period of intense globalization and the emergence and growth of investigative sites based in more remote regions of the globe.
A Tufts Center for the Study of Drug Development (Tufts CSDD) analysis of the FDA's Bioresearch Monitoring Information System (BMIS) database indicates that more than half of all FDA-regulated clinical investigators are now located outside the United States. Research by Opperheimer, based on a review of industry sponsored studies listed on www.clinicaltrials.gov, indicates that nearly one-third of all active late stage (Phase III) clinical trials are conducted outside of North America and Western Europe. Late stage clinical trials are the most conducive to economic and patient recruitment advantages found in emerging regions where large numbers of well-trained clinical research professionals and treatment-naïve patients reside. The majority of early stage (Phase I and Phase II) clinical trials, however, are conducted in North America where study initiation times are generally faster and where better oversight and study conduct infrastructure can be found (see Figure 1).
Simultaneous, globally dispersed clinical trials are a common occurrence. The typical late stage clinical study—sponsored by small, mid-size, and large companies—is conducted in an average of 34 countries today, more than 70 countries on average for the top 20 sponsor companies.
Despite such a broad global scope, most sponsor companies think about investigative sites as region-specific entities. Investigative sites are rarely thought of comprehensively as part of a global portfolio of study conduct assets at the outset of a clinical program. Certainly once a trial is underway sponsors compare sites' performance across regions. But sponsor companies do not commonly assess the aggregate operating characteristics of a global collection of investigative sites. Such an analysis would allow them to identify and anticipate which sites may require additional support in order to succeed.
Earlier this year, Applied Clinical Trials (ACT) and Tufts CSDD collaborated on a survey of the global investigative site landscape. Our goal was to gather baseline site operating characteristics to establish an initial set of comparators when evaluating a portfolio of globally dispersed sites.
In December and January, email invitations were sent to 2700 sites around the world. This convenience sample was drawn from ACT's readership and was likely more experienced than the typical investigative site. Invitations contained a link to an online, 40 question survey. Active clinical investigators who participated in industry sponsored trials were asked to complete the survey. In total, 157 respondents completed the survey representing a 6% response rate. Although the total sample size is lower than what we hoped, the response rate is consistent with those achieved by other online surveys among professionals.
One-third (32%) of survey respondents are operating in ascending regions (e.g., Central and Eastern Europe, Latin America, India, and China), 16% in Western Europe, and 52% in North America. This distribution is consistent with findings published by Tufts CSDD and others. Thirty percent of respondents are principal and sub-investigators, 45% are clinical research coordinators, and 25% are administrative personnel (e.g., directors, business development, and office managers).
Nearly half of all investigative sites aggregated globally are based in an academic and hospital setting; 22% are part of a community clinical practice (see Figure 2). Approximately 30% are investigative sites that derive the majority of their revenue from study grants. A large proportion of sites in this latter segment operate within North America, although a growing number operate in parts of Central and Eastern Europe, Latin America, and India. Of all investigative sites operating within community settings, the majority (67%) is led by a group of physicians. One-third has a single physician investigator.
Survey respondents report having an average of 11.6 years conducting clinical research—and more than 10 years specifically conducting industry sponsored trials. Respondents also report having broad multispecialty therapeutic area expertise. The most common specialty areas among investigative site respondents include cardiovascular illnesses (51%), endocrine disorders (45%), CNS (32%), and oncology (31%).
Globally, in the aggregate, the typical site has a median of four active principal investigators (PIs), three full time study coordinators, and two full-time administrative personnel (see Figure 3). Respondents also report a median of one active part-time study coordinator and one part-time administrative resource. In addition, overall, site personnel are highly experienced. PIs reportedly have 13.5 years of experience conducting clinical research on average. Research coordinators have an average of eight years of experience.
Investigative sites operating in the European Union have been conducting industry sponsored trials the longest, on average 13.4 years. This compares with approximately nine years on average for North American sites and those operating in ascending regions (see Figure 4). These differences may be due to sampling bias, as respondents were self-selected from among regular readers of Applied Clinical Trials magazine.
Three out of four clinical trials managed by the typical investigative site are industry sponsored, as expected, given that pharmaceutical and biotechnology companies fund the lion's share of all clinical research activity worldwide. The typical investigative site in this survey conducted a mean of 21 industry sponsored clinical trials, and a median of 10, in 2008 (see Figure 5). The coefficient of variation on this measure was relatively high, suggesting wide variability between respondents. One out of 10 clinical trials at the typical site are investigator initiated. Phases II and III studies are the most common (51%) industry funded clinical trials conducted annually by investigative sites in the survey. And 43% of the total clinical trials conducted annually are Phase IIIb/IV studies. This distribution may also reflect sampling bias.
Globally, investigative sites report flat annual growth in the number of industry funded clinical trials between 2006 and 2008, and robust annual growth (20%+) in government funded and investigator initiated clinical trials. And while investigative sites in the European Union and North America reported flat annual growth in industry sponsored clinical trials during 2006 to 2008, sites in ascending regions reported a 17% annual increase in industry sponsored clinical trial volumes during that same period.
Overall, investigative sites aggregated globally screened an average of 1245 patients in 2008, up 8% over the number screened in 2006. Of those screened, a reported 424 patients were enrolled on average per investigative site, one-third of the total screened (see Figure 6). Between 2006 and 2008, patients enrolled as a percentage of total patients screened declined from nearly 40% to 34%. Sites involved with investigator initiated clinical trials screened and enrolled 58 and 50 patients respectively for these types of trials. Sites participating in government funded clinical trials screened an average of 28 patients in 2008 for government sponsored trials, and enrolled 21 patients that year.
Survey respondents report a substantial number of formal interactions each year with study sponsors. Aggregated globally, the typical investigative site had 5.5 study monitor visits each month with half handled by CROs, and received three site audits from sponsors or CROs in 2008. Sites also report having been inspected by a regulatory agency once on average during the past five years.
The majority (nearly 58%) of investigative sites, overall, report that it has become more difficult to operate profitably compared to three years ago (see Figure 7). A higher percentage (65%) of independent practicing physicians report having difficulty maintaining profitable site operations compared with university and hospital based PIs. Seventy percent of all investigative sites report a high reliance on clinical trial grants as a source of funding to support their operations.
Interestingly, 97% of investigative sites report high patient willingness globally to participate in clinical trials. The primary challenges, according to sites, is that protocol eligibility criteria have gotten too restrictive, and that increasingly demanding and complicated protocols make recruitment and retention more difficult.
Aggregated globally, investigative sites convey frustration with the onerous burden of regulatory compliance. A large percentage of sites note the high cost and delays associated with having to complete regulatory documentation, to prepare and file duplicative paperwork, to obtain ethical committee review and approval, and to endure excessive bureaucracy when dealing with local authorities.
Survey respondents offer a wide range of suggestions for ways that sponsors and CROs can improve the global study conduct process and assist investigative sites in performing more successfully. Many sites convey frustration in not receiving timely compensation from sponsors for work performed. By far, the largest collection of suggestions from sites relates to protocol design improvements. Common themes include:
This survey is an initial effort to capture baseline measures of the global investigative site landscape. Respondents were drawn from the ACT readership and, as a result, our sample is biased and the results should be read with some caution.
Nevertheless, the survey findings capture an experienced collection of investigative sites and personnel who are managing a substantial amount of clinical research. Survey findings also indicate financial pressures and pressing operating challenges such as complex protocol designs and a heavy regulatory compliance burden.
Although the structure of the global investigative site landscape reflects historically North American and Western European market characteristics, it is clear that the landscape is changing as new sites in ascending regions mature. Looking ahead, it is our hope to periodically update and improve these baseline measures to aid general understanding as well as the management of globally dispersed investigative sites.
Kenneth A. Getz,* MBA, is a Senior Research Fellow at the Tufts Center for the Study of Drug Development and Chairman of CISCRP, both in Boston, MA, email: firstname.lastname@example.org. Rachel Zuckerman is a research analyst at the Tufts CSDD.
*To whom all correspondence should be addressed.