The European Union lurches into another difficult year, with—for the first time ever—the Czech Republic holding the rotating chairmanship for the next six months, and consequently largely responsible for setting the agenda. In addition to coping with the challenges of energy security, climate change, the credit crunch, and constitutional reform, the Czech government has also listed its priorities in relation to health. 

The Czech health program includes efforts to provide patients with new rights to high-quality health care across all 27 member states, increased provision for health care workers to move around within the EU, tighter controls on quality and safety in organ transport and storage, stricter measures for infection control in European hospitals, reassessment of the financial sustainability of health care funding, and interoperability of health care information systems. 

"What has all this to do with clinical trials?" one might ask. The answer to that question is, "A lot." And for two reasons. 

One reason is that the Czech health program also includes some elements directly related to the development and use of pharmaceuticals in Europe—notably, additional support for research into rare diseases; tighter pharmacovigilance systems; and what are officially described as measures to "improve and guarantee the high quality and safety of pharmaceuticals, while maintaining cost-effectiveness."

How far it gets with these proposals will depend heavily on how far it gets with its overall program—not just in health care but in its overall objectives. Because in the EU, hardly anything is dealt with in isolation. Most decisions are made as compromises among many conflicting currents of national opinion and priorities in 27 national capitals. 

So if the Czech presidency runs into difficulties in winning support for its measures to overcome the economic crisis or loses face in diplomatic debacles in the Middle East or with Moscow, it will be less able to pursue other elements of its program effectively. 

The other reason is related not so much to the Czech presidency's program as to the clearly expressed concerns of the clinical trials community in Europe. 

Any hopes that Europe's much-maligned clinical trials directive is likely to be amended and improved received another blow just at the end of 2008. The principal conclusion of many leading European clinical trials professionals is that now the deficiencies in the directive are going to be completely neglected by the EU authorities for years unless there is a major push to bring in the improvements many are calling for. 

It was at a major conference in Brussels in December on EU legislation and clinical trials that the evidence of official indifference was exposed. The conference, on the Impact on Clinical Research of European Legislation, was the culmination of the "ICREL" project, funded by the EU itself to provide objective data and arguments about the need for adaptations to current legislation so as to make European clinical research more competitive. 

The background is well known. Concerns have been raised by investigators and sponsors ever since the adoption in 2001 of the EU's Clinical Trials Directive (2001/20/EC). Many stakeholders believe that the directive has largely failed in its objective of simplifying and harmonizing the conduct of trials, and has imposed unnecessary administrative burdens and costs. 

As the ICREL study confirms, part of the problem is divergent implementation across the EU member states—giving rise to a total of 122 legislative or guidance measures. The result has been inconsistent interpretation of the rules, duplicative demands for information, longer procedures, and differences even over which languages may be used. 

The introduction of the directive has been especially problematic for investigator-initiated clinical research, whose advocates insist on the value of independent clinical research for patients, for science, and for more efficient use of health care budgets. 

Respected academic researchers told the meeting that the new framework provides little or no visible improved protection for trial patients, has failed to harmonize regulation, and has certainly not improved competitiveness. Instead, it has made international trials more difficult to conduct and has decreased or delayed access for patient to innovative meds. 

But the commercial sector is equally concerned, and industry executives have reported recent trends toward more questions, requests for additional data, and increasingly divergent decisions. Sponsors have had to invest heavily in developing new systems to cope with the requirements and have then had to devote resources to much more paperwork related to GCP, contracts with investigators, hospitals and CROs, more complicated insurance issues, and expedited reports. 

More guidelines are not the answer, say industry executives. Nor is mutual recognition the solution for clinical trial authorizations. That approach is incapable of supplying the high degree of reactivity, quick decisions, and rapid information flow needed in clinical trial decision-making. As things stand, bioequivalence studies have already moved substantially outside Europe, largely to Canada and Asia, say industry executives. 

For ethics committees too, differences in the structure and function are a problem throughout the EU.  

Regulatory authorities acknowledge some of the continuing areas of difficulty—notably persistent nonharmonization of requirements on clinical trial authorization dossiers, definitions, safety reporting, and the concept of investigational medicinal products. National assessments of applications for clinical trial authorizations still differ, and there are problems over transparency of decision-making and adequately factoring risk into decisions. 

Contrary to the EU intention of attracting clinical trials, there appears to be stagnation, even a slight decline, authorities suggest, pointing also to an increase in rejections of applications for clinical trial authorizations. 

Weaknesses identified by the ICREL report itself were similar. The key failings observed in EU clinical trial regulations were the lack of harmonization of procedures, the lack of transparency, unclear definitions, increased workloads (particularly for assessing annual safety reports), and the need to simplify reporting to ethics committees. Initial ICREL findings were that negative outcomes of clinical trial authorization applications had increased, as had protocol amendments. Meanwhile, the scientific and administrative workload rose, with a corresponding rise in costs. 

Faced with such an overwhelming body of criticism—much of it echoing criticisms raised a year earlier at the European Commission–European Medicines Agency conference on the impact of the directive—it might have been expected that the EU authorities have some concrete proposals to offer to remedy the defects. 

At least two clear lines of potential relief emerged during the discussions at the ICREL meeting. One was angled toward giving the EU measures greater force and consistency by making them binding in detail on all member states, thus eliminating much of the confusion and delay currently experienced. Another possible improvement, it was argued, could come from focusing more on the real risks linked to any trial, rather than following a standard tick-every-box approach for every trial. This would permit more proportionate controls on trials and allow more efficient use of resources. 

But no such relief was offered by EU officials at the conference. In fact, not only was there no offer of relief, the message as it came across to many was that there was very little officials could do about it. The directive had been adopted and was in force, and apart from some minor tinkering around the edges with more guidelines, there was little prospect of any improvement in the foreseeable future. 

Political considerations have conspired to leave the clinical trials community a victim of circumstance. The five-year term of office of the current European Commission—the EU's civil service—comes to an end later in 2009, so there is virtually no chance of any new initiative emerging from what is increasingly a lame-duck administration. 

Similarly, the five-year term of the European Parliament comes to an end in the spring, so the current crop of the EU's directly elected legislators have no time to examine the matter afresh—and their successors will not be in a position to begin to do much before the end of 2009, even if they can be persuaded of the need. 

The only other major EU organ—the Council, consisting of member state ministers—will act only in light of promptings from the Commission or Parliament, or, in extremis, of the member state holding the rotating EU presidency. And as already suggested, the nascent Czech presidency has its hands full already, So little can be expected from the Council either. 

The net result is that European clinical trials legislation is in a position akin to that of a disease for which diagnosis is now possible but for which no treatment has yet been found. On that basis, the new year may be happy but it is unlikely to be healthy.  

is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

Articles

View from Brussels

What to expect from the new leadership and why there's not much hope for an improved directive.

A Healthy 2009 for the European Union

It's true. What many have pitted as perennial foes in the battle for industry-sponsored drug trials—with the Academic Medical Centers (AMCs) as underdog—is changing. What history may show in regard to the use of AMCs in industry-sponsored drug trials remains to be seen. But in just the past few years, there has been a recent upswing among CROs and AMCs that are collaborating. This requires an adaptation to business relationships on both sides of the fence, but is occurring to meet the needs of the evolving drug development market. 

And what are the drivers of collaboration? For the CRO, drivers of collaboration with AMCs may include greater access to specialized expertise for specific therapeutic areas, the ability to take advantage of certain AMC-developed tools, or the opportunity to provide sponsors with additional benefits through expanded access to investigator sites and patients. For the AMC, the ability to be on the cutting edge of drug development remains paramount. For the industry at large, most have recognized that the blockbuster drug is becoming a business model of the past. "The world is realizing it is very expensive to get drugs to market," Josef von Rickenbach, chairman and chief executive officer of Parexel told 

"In order to develop drugs more effectively, the industry needs to identify where more efficiencies can be gained." He said that the trend toward targeted treatments combined with the constricting health care dollar, means that more fragmented markets don't have the resources to absorb development costs. 

In early December, Parexel announced its alliance with the Safe Implementation of Treatments in Stroke (SITS) International, a network of clinical sites specializing in stroke. In a release, the CRO included the following benefits of the alliance to its clients: accelerated study start-up, patient recruitment, and specialized capabilities to execute stroke-related studies on a global basis. "In joining forces with Parexel, SITS looks forward to furthering the growing field of stroke research and speeding the introduction of important treatments to patients," said Nils Wahlgren, MD, PhD, and Chairman of SITS in the release. 

Von Rickenbach, commenting prior to the announcement of the alliance, told us that the CRO intended to continue its relationships with AMCs in many forms. Specifically of the SITS alliance, von Rickenbach noted that it "highlights an approach we are applying, a more constructive way we have developed to work with academia." Parexel has had numerous successful relationships with AMCs over its 25 plus years. "The collaborations between CROs and academic medical centers  have waxed and waned over the past couple decades," von Rickenbach noted. "But the number of these relationships has grown in the past few years." The company will continue to identify strategic opportunities to create alliances with effective AMCs. 

"In order for us to keep our edge as a tertiary medical center, we have to do research," said Janis M. Orlowski, MD, senior vice president and chief medical officer, Washington Hospital Center (WHC) located in Washington, DC, and part of the MedStar Health System. 

"We are looking to partner into higher impact, high quality trials," Dr. Orlowski told 

. "Our investigators have done a study here, one study there. With Quintiles, they bring us a portfolio of studies they are working on, and let us choose from that portfolio." Orlowski maintains this is different from the investigator-initiated or industry-initiated trials where "you're either in or you're out." Orlowski was impressed with both the quality of investigators that would be involved as well as the quality of the clinical research Quintiles was doing.  

Oren Cohen, MD, senior vice president of clinical strategies at Quintiles, and consulting professor of medicine at Duke University School of Medicine, believes the benefits of collaboration for the AMCs with which Quintiles partners—such as the MedStar Health System—do have a different value, as Orlowski mentioned. "Clinical research can raise the profile of the institution, and a lot of partners tend to find attractiveness in the steady stream of cutting edge clinical studies we can provide."  

In regard to the types of trials CROs and AMCs are currently involved with, Cohen noted that as early as five years ago, CROs were getting knocked for just being contracted  by pharma for the "me-too" drugs. "Now, that's changed dramatically," said Cohen. "We are involved in biologics, immunology, cutting-edge cancer treatments...and that is attractive to the AMC as well." 

Orlowski is looking forward to using the connections that Quintiles has to get the studies the hospital needs to support its community, as well as its internal research desires. "We ask them to keep their eye out for a certain type of study (WHC has a high interest in cardiology) and they have the ability to look for these studies."  

Although its partnership with Quintiles is only a little over six months old, Orlowski reports she is very happy. "We have other relationships with pharmaceutical companies, and we have worked with other CROs, but not as a primary research site," she said. "It will be interesting to see how it develops." 

"I call us a 'megasite' but I don't think Quintiles uses that term," said Neil J. Weissman, MD, president, MedStar Research Institute and professor of medicine, Georgetown University. MedStar Research Institute is the centralized clinical trials and medical research services function of MedStar Health. MedStar Health includes WHC, as well as Georgetown University Hospital, National Rehabilitation Hospital also in DC, Franklin Square Hospital Center, Good Samaritan Hospital, Harbor Hospital, and Union Memorial Hospital in Baltimore. As such, they could be considered a megasite in the case of subject recruitment, where as Weissman explained, Quintiles could go to 50 sites and enroll 10 people, or go to five sites and enroll 100.  

MedStar Research Institute (MRI) was initially formed in the 1960s under a different name and was the research division of the WHC. According to Weissman, 10 years ago when the MedStar Health System was formed from the merger of two previous systems, MRI grew fast. "Academic medicine and community medicine came together in our diverse hospital system," says Weissman. "It gives us the potential to tie together translational research from lab bench to bedside to community." Like other AMCs who noticed the need to centralize certain aspects of the clinical trial initiation, MRI provides one IRB, one place for contracts, investigator support in terms of personnel, training, budgets, and more. Specific to the success of the Quintiles alliance, MRI is providing a medical scientific director and project manager dedicated to Quintiles' studies. 

The ties to community that exist with the AMCs can't be overemphasized in the new model CRO–AMC collaborations. Cohen cites a March 2008 

 article titled "Better Outcomes for Patients Treated at Hospitals That Participate in Clinical Trials" (Vol. 168, No. 6, March 24, 2008, pp. 657-662; 

http://archinte.ama-assn.org/cgi/content/abstract/168/6/657

 links to the abstract, you need to purchase one time, full-text access), which presented its supported hypothesis that hospitals that perform clinical trials have certain elements that carry over into better overall care (i.e., patient outcomes) in the community. Cohen called it the "halo" effect in the community.  

"We are using our strength as a multisite hospital system to look at novel and innovative ways to develop research. We can bring the clinical investigator and community-based research together," said Weissman. The issue is that what works in the isolated academic hospital setting doesn't necessarily work in the community. Weissman envisions a Primary Care Based Research Model with community researchers bridging the gap on an outpatient basis. As Weissman says, "Clinical research is changing and we need to stay ahead of those changes to be successful." 

is editor-in-chief of Applied Clinical Trials. She can be reached at 

Feature Article

A look into the evolving relationship and what motivates the two to work together.

CRO and AMC Collaboration

Alot can change in 15 years. Consider how Edwin C. Cadman, MD, described the scene at Academic Medical Centers (AMCs) in a 1994 article: "[There's a] prevailing attitude that patient-related research is easy and can be accomplished at night or on the weekends after spending 60 hours caring for patients and teaching."

Cadman, whose long career included serving as chief of staff and senior vice president for medical affairs at Yale New Haven Hospital, displays a deep concern—echoed by others—for the lack of investigator training in the methods of patient-oriented research. An absence of which, he attests, often leaves faculty "ill prepared to conduct scientifically credible research."

Fast forward to a new century, and Cadman's remark about how many in the early 90s viewed patient-related research elicits responses like "that's crazy" from some who now call AMCs their work place. Apparently, there's a new prevailing attitude not only in regard to research but also to training.  

Conversations with those in academia today portray AMCs as institutions well aware of the need for trained investigators as well as staff—from nurses to administrative personnel. And many of these institutions are taking it beyond the nuts and bolts of safety and good clinical practice to the A, B, Cs of clinical and translational research via a degree. 

But degree programs aren't new. "There were programs designed for physicians, but it's evolving into a much more structured program," said Erin Haynes, DrPH, assistant professor and director of the clinical and translational research program at the University of Cincinnati (UC). "For instance, AMCs may have had programs in epidemiology, but [they're] changing into a more tailored program." 

Haynes' own university, an AMC, is one example of the kind of change she's talking about. UC only recently started offering a master's program in clinical and translational research (it's still awaiting approval by the Ohio Board of Regents). Previously, UC physicians would earn an MS in epidemiology. With the advent of the master's program, however, they can receive comprehensive training in clinical trials, molecular epidemiology, translational research, and clinical effectiveness. 

Another AMC that's tailoring their research training for physicians is Robert Wood Johnson, one of the hospitals that make up the University of Medicine and Dentistry in New Jersey (UMDNJ). Next fall RWJ, as its known, will launch a masters of science in clinical and translational science. The program will include classes on clinical trial design, biostatistics, ethics, regulations, and grant writing and funding. 

The impetus behind the creation of RWJ's new program is the National Institutes of Health (NIH) and its Clinical Trials and Science Awards (CTSA), says Diane Ambrose, PhD, Director of special projects in the office of research and sponsored programs at UMDNJ-RWJ Medical School. 

"We want to submit a proposal [for] the award and to do that we have to build training programs, that's a requirement [of the grant]," she explained, adding that "it's been pretty clear this is the way academic medicine is going, that the NIH wants to see more therapies and more diagnostics produced for their dollar." 

Although NIH training grants for academic physicians date back to the 50s, it was the institute's 1997 Nathan Panel—which recommended establishing training and career development programs—that Stephen Heinig of the American Association of Medical Colleges (AAMC) calls a "landmark." 

The result was the Mentored Patient-Oriented Research Career Development Awards (K23), the Midcareer Investigator Award in Patient-Oriented Research (K24), and the Clinical Research Curriculum Awards (K30). [All three have since been merged into the CTSA to form a more cohesive and larger clinical research training program.] 

Patient-oriented research received another boost in the early 2000s with the development of NIH's Roadmap for Medical Research. Among its goals: reengineer the clinical research enterprise by attracting more investigators, protecting their time, providing mentoring, and breaking long-standing barriers between the laboratory and the bedside. Soon after NIH launched the CTSA. 

From the looks of things, all signs—and almost all interviewees—point to NIH for the recent push to strengthen training for academic investigators. But to give them all the credit would be telling only part of the story. That's according to both 

 Columnist Ken Getz and AAMC's Heinig. In fact Getz, who is also a research fellow at Tufts CSDD and chairman of CISCRP, says crediting NIH for the push for better training is putting the cart before the horse. 

"I think it came more as a result of some of the very highly publicized and tragic patient deaths in the late 90s that led to a whole host of reform at IRBs and efforts to create a higher level of accountability," said Getz. "If anything, it was some of those initiatives that prompted the creation of the Roadmap and the Critical Path." 

And while Heinig, lead science policy analyst at AAMC, credits the NIH's support and commitment for "creating a lot of the impetus for the new training," he points out that a number of schools—like Pitt, Duke, and the University of North Carolina—had already begun implementing stronger training for physicians. 

These institutions foresaw what NIH would eventually describe in their Roadmap: the need to improve pathways for training physicians in patient-oriented research since none existed—most investigators learned on the job—and the need to catch up with laboratory science. "There were all these new advances out of the lab that seemed to be begging for investigation in human subjects," explained Heinig. 

So, where does pharma stand on all this? George Betts, MBA, head of U.S. medical operations at Novartis, says pharmaceutical companies prefer to work with trained investigators. It's their ability to properly execute the clinical study and keep patients safe that pharma finds most appealing. 

As for whether training is one of their selection criteria, Getz doesn't think so. "It's going to be an additional credential," he says, "after they've established the experience level and whether they have a prior relationship with the investigator." 

At least two drug companies, however, are participating in training. A grant from Pfizer and Merck is funding the Clinical Investigator Training Program, a cooperative effort between Boston's Beth Israel Deaconess Medical Center and the Harvard–MIT Division of Health Sciences and Technology. The program's Web site describes its goal as "to train physicians in the techniques and processes in patient-oriented research." 

The idea that physicians need tailored training in clinical research is actually spreading outside the walls of AMCs. The AAMC's Clinical Research Task Force II (CRTF II), which Heinig worked on, recommends that "every future physician should receive a thorough education in the basic principles of translational and clinical research, both in medical school and during residency training."

This, concludes the CRTF II, would among other things equip all physicians—including those who eventually work in private practice—with the ability to effectively communicate with patients about clinical research and, thus, participation in trials. With data showing that most study volunteers find out about clinical trials from their doctor, one can argue that if all physicians receive solid training in clinical research then every patient will truly represent a potential trial participant. 

 is managing editor of Applied Clinical Trials, email: 

1. E. Cadman, "The Academic Physician-Investigator: A Crisis Not to be Ignored," 

2. H.B. Dickler, D. Korn, S.G. Gabbe, "Promoting Translational and Clinical Science: The Critical Role of Medical Schools and Teaching Hospitals," 

Concerns are being put into action with the trend toward better investigator training.

Higher Education

Act cover

Graham Belgrave• As an active member of 

 (Bourne End, UK) for more than 20 years and a clinical research consultant for Ipsen Ltd (Slough, UK), 

 has been recognized as the 100th ICR Chartered Scientist.

 to its staff as the new business development manager, where she will oversee the company's activities in its Northeast United States and Southern California areas.

• With more than 10 years of conference and exhibition management experience, 

 (Bourne End, UK) new conference project manager.

 (Princeton, NJ) has made several executive appointments, including 

, MD, as vice president for medical affairs; 

, PharmD, as director for product safety services; and 

 as vice president for regulatory affairs. 

 (Boston, MA) new chief medical officer. He will bring with him over 20 years of management experience in preclinical and clinical development for therapeutics and diagnostics. 

, MD, senior medical officer for the EMEA, has become the first non-U.S. regulatory liaison to the 

Clinical Trials Transformation Initiative Executive Committee

. Dr. Eichler will fill the recently created nonvoting position. 

 (Boston, MA) clients now have access to more than 800 investigator sites in 40 countries that are dedicated to acute stroke treatment and Phase II–IV stroke-related clinical studies as a result of its recent alliance with 

Safe Implementation of Treatments in Stroke (SITS) International

 has entered into a three-year contract with 

 (Baltimore, MD) that requires the company to provide data management software and services, including the implementation of its StudyCTMS clinical trials management software.

(Fremont, CA) that allows the University to implement Velos eResearch over a two-year period. The intent is to provide medical researchers with a support system for regulatory, administrative, financial, and clinical information needs.

 (Essex, UK) text messaging technology, ATLAS, to better maintain patient communication across Belgium, Singapore, and the United States throughout the lifetime of a clinical trial.

 (Essex, UK) is engaging in its full mobile phone EDC study utilizing the Western Ontario and McMaster Osteoarthritis (WOMAC) NRS 3.1 index. The goal is to further comparisons between the effectiveness of patient self-reported outcome questionnaires on paper and those completed with a mobile phone.

After completing a brand and identity audit, 

 (Camborne, Cornwall) is unveiling its new identity with changes ranging from the company's signage and letterheads to its new Web site and exhibition stands.

 (Yardley, PA) is celebrating reaching its 20th year, in which it now employs 1100 individuals across three locations, including the UK, Pennsylvania, and North Carolina. The company has also recently expanded its U.S. headquarters.

 (Alexandria, VA) has launched several new services to expand its online community, including an interactive member directory, a resource library, an interactive online encyclopedia and glossary, and eGroups.

Marking the first time a major pharmaceutical company has agreed to publicly share anonymous data from a drug safety trial, 

 (New York, NY) will contribute electrocardiographic data to the 

 in an attempt to help researchers develop new methods to ensure safety of experimental drugs.

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and People Update February 2009

Projections "made by various industry analysts and market research companies...vary" on clinical trial growth in the Asia-Pacific region, but "estimates project growth of clinical research in China and Korea to be 25% and 30% per year, respectively," observed Stanford S. Jhee, PharmD, senior director of research, early phase development, for Parexel. "China, in particular, is expected to become the sixth largest pharmaceutical market by 2010."  

Though the tremendous growth in the Asia-Pacific region undoubtedly attracts sponsors abroad, when penetrating foreign borders the applicability of clinical data becomes questionable. This has led some countries to require that sponsors provide data specific to the ethnicity of its population. 

The challenges of conducting global trials along with the requirements that emerge when working with a different ethnic population have led to the birth of a relatively new market of studies. That is, bridging studies. 

A "bridging study...is a pharmacokinetic study conducted in early clinical development," explained Jhee. It "evaluates drug responses in the areas of pharmacokinetics, safety/tolerability, and pharmacodynamics in target ethnic populations." 

These particular studies are generally intended for early phase trials as "the populations available are too limited for it to be useful for Phase II or Phase III programs," explained Stewart Geary, 

 Editorial Advisory Board member and vice president and global safety officer for Eisai (Tokyo, Japan). 

Parexel (Waltham, MA) has placed itself among the first to complete a bridging study outside of China. This global reaching CRO has also completed Korean bridging studies and over 40 Japanese bridging studies. 

These studies are becoming more common because they allow sponsors to pursue global programs without encountering the usual adversarial factors that can often lead to excessive timelines and costs. 

"There are multiple challenges, especially in terms of the regulatory environment. While ICH-GCP guidelines have been in place in many Asia-Pacific countries for more than 10 years, currently, particularly in China and Korea, the IND process can still be long and challenging," Jhee observed. 

 that product registration for Japan and China requires ethnic Phase I data for new drug registration, and that the inclusion of Asian countries in global trials for Japan requires Japanese Phase I data; however, Korea does not require such data but China is beginning to. 

Not all countries require Phase I bridging data in order to initiate a Phase II trial, but sponsors often still conduct such studies because by collecting ethnic-specific data while simultaneously collecting Western Phase I data, time and inevitably funds can be saved. 

As Western countries see bridging studies as a cost conscious way to expand business globally, Asia-Pacific countries see an opportunity to enhance clinical development. 

"On a regional basis, Asian countries want to accelerate drug development," noted Jhee. "This is particularly true in Japan, which has a 'drug lag' of five years." 

The "bridging study should be faster," Geary explains. And, "one hopes the quality is more consistent when you are doing a bridging study with both populations in the United States managed by the same procedures." 

By accepting foreign clinical data countries that typically have a lagging clinical trial process are able to make more drugs, more available to its population. 

"Japan, China, and Korea have joined forces to acknowledge data from each of the other countries to expedite drug development in Asia," Jhee noted. "However, supplemental PK data showing similarities among each population must be established before such extrapolation is made." 

Global News

Bridging studies help pave the way for more efficient global drug development in the Asia-Pacific region.

Ethnic Trials Bridge Global Gaps

Industry Trials Poised to Win Back Academia (April 2007)

Challenging Times for Non-Commercial Researchers (May 2006)

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. 

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. 

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. 

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. 

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. 

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

 MBA, is a senior research fellow at the Tufts CSDD and chairman of CISCRP, both in Boston, MA, email: 

Global clinical trial landscape changes pose new challenges for all sites-even AMCs.

The Elusive Sponsor-Site Relationship

Within the last 10 years, eight University Medical Centers (UMCs) were created in the Netherlands. In a UMC, the faculty of medicine, with its responsibility for the initial training of physicians and for scientific research, is merged with the academic hospital, with its responsibility for tertiary care and clinical research and innovation. All medical faculties and academic hospitals in the Netherlands are now a UMC. 

Each UMC is a private, nonprofit enterprise with strong links to the University and with an executive board, including a dean of medicine. The finances come from the Department of Education and Science and the Department of Health, as well as health insurance companies that operate the mandatory health insurance in the country. The eight UMCs have a special position in the health care system, because although they are legally private entities, they have a distinct public mission. This mission can be divided into three core responsibilities: teaching and training, basic and clinical research, and (tertiary) patient care. 

The added value of UMCs is that they integrate these three core functions—patient care, biomedical research, and biomedical education. Medical students are exposed to patients as well as to basic research from day one of their curriculum and they become part of the UMC community. 

Many of them will participate in research projects during their studies and many will opt for a MD/PhD program. Almost every doctor and nurse is involved in the teaching process. And as students enter their clinical rotations they will be an important driver for quality of care, as their supervision requires doctors and nurses to provide a good role model. Increasingly the modern curriculum will include a mix of clinical and basic science around a specific disease, and so both clinicians and scientists often lecture together. 

As the science labs are often located within the same building as the hospital, interaction between clinicians and scientists is frequent, but also many doctors continue to work in a lab as well. Good clinical epidemiology in most UMCs has supported many clinical researchers (doctors and nurses) and the close vicinity of patients has proven immensely important in the recent developments in the area of genomics, proteomics, and other fields of translational medicine. This is visible in the position of Dutch biomedical research in the international scientific community. 

Increasingly, results of research are taken further, either as direct innovations in patient care after thorough evaluation studies or through patents, spin out companies, or other forms of "valorization" of science. Innovation in clinical therapeutics and diagnostics has always been important in academic hospitals. 

UMCs also are becoming more responsible for innovations in the process of care delivery, not only in the hospital setting but also for their departments of family practice in primary care or nursing home care. Innovations can be thoroughly evaluated before becoming standard practice and their value in improving outcomes for patients or in reducing costs can be critically assessed. In that way the whole health care system profits from academic medicine. 

Finally, UMCs have an important responsibility in tertiary care. Patients with rare diseases, difficult to manage complications, or who are in need of very complex interventions are often referred to a UMC. Transplantations, neonatal intensive care, genetic diseases, rare metabolic disorders, and complex cancers are examples of patient groups that are concentrated in some or all UMCs so that sufficient volume guarantees expertise. However, despite the unique responsibility for tertiary care, all of the UMCs provide a certain amount of regular hospital care, if only for training purposes. For those patient services, the UMCs compete in the health care market just as general hospitals do. 

Since 1992, the Netherlands has increased the number of first year medical students from 1485 to 2850 a year. Each UMC has an average of 315 to 410 new first year students. 

After six years of training, two of which on average are spent in clinical rotations (50% in a UMC and 50% in another health care institution), physicians can enter specialty training. UMCs offer all specialties including family practice and public health; but during most specialty training the physician will spend approximately 50% of his training in a general hospital. Around 60% of the Dutch hospitals participate in specialty training in regional networks around each UMC. The UMC plays an important role in providing courses and lab skills for students and teachers. 

All UMCs also have at least one degree program in biomedical sciences (around 500 students a year) and all participate actively in the training of nurses and nurse specialists. 

The UMCs together are responsible for one-third of the scientific output in the Netherlands in terms of publications, and on average they have a citation score of almost 40% above the international average, with variations by field in the different UMCs. Together, the UMCs award 800 doctoral degrees a year, which means that on average each UMC has 400 PhD students.  

UMCs have both clinical and basic science research groups. Increasingly, the combination of the two creates powerful groups specialized in translational medicine. Although UMCs have a certain amount of funding for research through the medical faculty, most get a much larger amount of funding from the research councils at the national or international level, from charities, and from projects together with industry. Both other faculties of the university and biotech companies collaborate with UMCs in solving biomedical mechanisms, developing new methods for diagnostics or therapeutic interventions, and evaluating the results in clinical trials. 

The tradition of sound clinical evaluation studies has proven to be a very successful field in medical research, not only in large industry driven trials but also in the much smaller investigator driven trials, which have helped practitioners decide the best course of action when there is doubt and have formed the basis for many clinical guidelines. These papers are often among the most cited publications. 

Each UMC has a research infrastructure and in certain cases close collaboration between them provides a unique scientific environment. An example of this is the Pearl String Initiative (PSI) in which eight UMCs are jointly building prospective patient cohorts for which both clinical data and biomaterials are collected in a standardized fashion. For some diagnoses this means that all patients with that diagnosis in the Dutch population are included in one database. This PSI bio-bank will provide unique material for research on the interaction between genotype and phenotype.  

Another example of the strength of cooperation in research is the recently established MCRN, the Medicines for Children Research Network. UMCs feel children deserve evidence-based medicine and thus a critical evaluation of the medications they take. That will require careful assessment using randomized controlled trials. 

Recent European legislation has emphasized the necessity of trials for children. UMCs feel it is part of their public mission to provide a methodologically sound environment to do so. It is always difficult to explain to the public that the essence of a successful randomized controlled trial is that one of the two study groups will prove to have a worse outcome, thereby helping to decide what treatment is best. They often find it extra hard to understand when it concerns children. However, parents are often appalled to discover that there has not been an adequate evaluation of the treatment proposed for their sick child. With the MCRN, the UMCs propose a safe environment for parents to allow their children to participate in so needed clinical studies. 

Together the UMCs have taken responsibility for technology assessment studies, partly financed through the Medical Research Council (ZON-MW). Outcomes of such studies have been instrumental in deciding which new treatments are included in the basic benefit package and in disseminating innovation to other hospitals. Many of the researchers in UMCs are involved in advisory bodies to the government, such as the National Health Council. 

UMCs have a long tradition of close collaboration with private partners as well. Many of the new medical devices have first been tested and refined with physicians from UMCs. Pharmaceutical companies have traditionally worked together closely with UMCs for the required evaluation of new drugs. But in the future, one can expect a new kind of collaboration. 

As the importance of patient material for the understanding of biomedical mechanisms that will lead to new products becomes apparent, the interest in working together closely with the basic scientists at UMCs will grow. The Netherlands has invested in that public–private partnership in a number of large innovation programs in the field of translational medicine. The Dutch UMCs are convinced that these new partnerships will prove very productive, but they also require a good understanding of each partners' interests. 

The Valorization Code of the joint UMCs provides a good start to avoid a conflict of interest while allowing for the joint effort to improve patient care through research. 

Although all UMCs provide basic hospital services, their public function is primarily determined by the top clinical services they provide together with their last resort function for referrals from other hospitals. Such tertiary care should build on the knowledge infrastructure that the UMC provides, their clinical research, innovation, and multidisciplinary approach, which provides continuity of expertise, 24 hours a day, seven days a week. Such continuity is important for patients and also for preserving centers of excellence so that tertiary care is not dependent on one person. 

Increasingly as the market for care evolves, more complex or more costly patients will be referred to a UMC. That is why the financing of UMCs requires special measures; otherwise, academic medicine would be in danger.  

"Part of the health care market where possible, separately financed when necessary." This credo, explained then Minister of Health Hans Hogervorst to parliament, is why UMCs needed a special position in his reforms of the Dutch health care system. As he transformed the health insurance system to achieve universal coverage with risk and income solidarity, executed by private insurance companies, he introduced a special financing scheme for UMCs. 

Of course, UMCs are financed in many different ways. Part of their budget comes from the Ministry of Education and Science, through the universities, both for the faculty and the academic hospital to provide the infrastructure for teaching and research. A major part of the research money for UMCs is secured in the fierce competition for grants at a national or international level. 

For their patient care budget, however, a distinction is made by the insurer and the UMC between the negotiated budget for regular services and the lump sum provided as a so called "academic budget" for the excess costs of tertiary care patients. This last budget is strictly limited to UMCs.  

With the creation of UMCs, academic medicine in the Netherlands has entered a new phase. While the International Campaign to Revitalize Academic Medicine worries about the position and the power of academic medicine in the future, the eight UMCs have shown that merging two traditional institutions—a medical faculty and an academic hospital—provides a good environment in which innovation and quality of care can be developed, assessed, and passed on to the next generation of doctors and nurses. 

The three core responsibilities of education, research, and patient care are intertwined and as such can no longer be evaluated in separation. Together they are the essence of academic medicine and the R&D of any health care system.  

Part of this text has been used in a short brochure by The Netherlands Federation of UMCs. 

 is chairman of the executive board of the academic medical center of the University of Amsterdam and dean of the medical faculty of the University of Amsterdam, both in Amsterdam, The Netherlands, email: 

How the merging of medical faculty and academic hospitals in The Netherlands is improving the country's research infrastructure.

A New Phase in Medicine

The growth of the global pharmaceutical market, estimated by PricewaterhouseCoopers to reach $1.3 trillion by 2020, is by necessity propelling the progress of enabling technologies. Whether due to deep development pipelines or industry wide initiatives effecting clinical trials such as the Critical Path, it's becoming increasingly imperative for research organizations to manage extremely large volumes of data in real time. In fact, the PricewaterhouseCoopers analysts predict that the pharma industry will not be in a position to capitalize on opportunities unless R&D productivity improves. Yet despite technological progress, it's been well documented that at least three out of four clinical trials today experience costly delays. 

There aren't the same statistics available for measuring a hot topic in the world of ongoing clinical trials: the rescue study. It's a term applied to the transfer of study responsibilities from an existing vendor (EDC or otherwise) to a new vendor midway through a clinical trial. 

While it is always the goal to choose a compatible vendor from the start, sometimes problems occur that necessitate a change in vendor before study completion. This is usually a costly and timely proposition, but there are valid reasons why a sponsor may need to prematurely sever the relationship, such as: unresponsiveness to the sponsor or the needs of its study sites; lack of support desk assistance; the platform is not as robust or user friendly as originally thought; the system is unstable, with significant downtime or data crashes. 

Should the sponsor and research team decide that a vendor change is warranted, there are ways to mitigate problems that might occur when inserting a new technology into an existing study. 

Any EDC or Web-based services vendor will require two things to determine the best methodology for switching data from a current vendor to a new one: the existing database specifications and screen shots. These should be offered during the discussion process; it will help determine whether the vendor is a good fit. 

The specifications will give the new vendor a roadmap for determining how to best convert existing data into a format compatible with the new vendor's software. The screen shots of the existing EDC system will illustrate to the new vendor how the sponsor and sites currently view the data and will help them create forms and datasets that closely match the existing ones in look and feel. 

Next, set a hard stop date for entering data into an old database and for blocking access to it. Give sites the target date and work with them to get all data current and in the system by this time. If a site is behind in data entry, maybe have its staff just enter the data into the new database once it is up and running. This can be determined on a case-by-case basis. 

Once the old database has been turned off, the old vendor should forward the final SAS extract to the new vendor so that data may be loaded into the new system. In the interim, instruct sites to hold off entering any data. Once the process of loading data into the new system is complete, the system will be opened up to the sites and access will be given to study personnel and the sponsor. The goal is to make the transition between vendors as seamless as possible for site personnel and the project team.  

A Closing Thought

Ways to ensure the transition between vendors is as smooth as possible for everyone involved.

Applied Clinical Trials-02-01-2009

A Healthy 2009 for the European Union

CRO and AMC Collaboration

Higher Education

Act cover

Business and People Update February 2009

Ethnic Trials Bridge Global Gaps

The Elusive Sponsor-Site Relationship

A New Phase in Medicine

Switching Vendors Midstudy

Letting Investigators Lead

eClinical Software: February 2009

Is Two a Crowd?

Applying the Supply Chain Model

Health Reform Targets Costs and Coverage