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A Drop in Numbers

A CenterWatch analysis of its site operations survey, conducted online earlier in 2012 and reported here, showed that the number of active investigators in western Europe has dropped 9.1 per cent during the past five years. Possible causes for this include sites struggling with regulatory burdens and the unprecedented economic challenges of the European financial crisis.

According to a new analysis, the number of active investigators declined steadily between 2007 and 2010, from 4,511 to 2,999, before increasing 2.7 per cent to 3,079 in 2011. The new analysis estimates the size of the western European clinical grants market at $1.34 billion in 2011, a 3.2 per cent increase from the previous year.

The analysis was based on partial metrics about western European sites, since more comprehensive figures are not maintained by regulatory agencies in the EU. Industry experts, however, confirm that the number of active sites in western Europe has declined in recent years. “Intuitively, I would say that the number of quality, committed investigators has to be falling,” said Ian Smith, founder and global medical director of Synexus, a UK based site management organisation that runs 25 dedicated research sites in nine countries. “Conducting clinical trials is getting more difficult every year. Trials are getting more complex regulatorily, ethical requirements are getting more demanding and the part-time investigator must be finding it tough.”

Despite this downward trend, western European sites saw encouraging signs of financial recovery the past year. New analysis identified a rebound in western European clinical activity from 2010 to 2011, with the average site reporting growth in site staff, patient volume and the size of individual grants from industry-sponsored trials.

Western European sites, however, expressed caution about the stability of the recovery, largely due to uncertainty about Europe’s ongoing financial crisis. Sites say profitability has suffered during the past year, and 45 per cent believe economic conditions for sites will deteriorate this year. Investigators also expect the size of individual grants for industry-sponsored trials to decrease, and more than 50 per cent have no plans to hire new employees this year. “The poor economy is a real cause,” said Oliver Joannes-Boyau, a clinician and principal investigator at University Hospital of Bordeaux, France. “I think economic conditions will probably get worse due to the duration of the crisis.”

Challenges in Sizing the Market

Despite the fact that the clinical grants and investigative site market has been monitored in North America for two decades, initial attempts to model this market in western Europe – which traditionally has been a key region for conducting international, multicentre trials – proved difficult. It was difficult to determine the size of the market as the European Medicines Agency’s (EMA) clinical trials database, which was opened to the public only last year, provides statistics on the number of clinical trials and the number of sites involved per trial, but does not isolate data about active investigators. Given the challenges in acquiring specific metrics about sites, the analysis represents the best effort to characterise this market quantitatively.

This new analysis used two primary data sources to calculate the western European clinical grants market: the Bioresearch Monitoring Information System (BMIS) operated by the FDA’s Center for Drug Evaluation and Research (CDER); and data from a global 2012 Site Operations Survey.

In general, data used to analyse industry trends in the number of active investigators or clinical trials conducted in western Europe largely come from US-based government databases, including the BMIS and the National Institutes of Health’s, both of which include information about a large percentage of studies conducted outside the US. The BMIS database tracks the number of active investigators through a 1572 form, which sponsors must collect from each clinical investigator in a trial conducted under the FDA’s investigational new drug (IND) regulations. The EMA’s European Union (EU) Clinical Trials Register database lacks any similar way to track investigators in western Europe.

Data for the analysis was downloaded from the BMIS website in March and cleaned to remove duplicate investigator submissions, and then sorted by country. In 2011, a total of 13.3 per cent of FDA-regulated investigators were from western Europe; that proportion dropped slightly from 13.8 per cent in 2010.

The total number of active investigators identified in the BMIS database were adjusted to account for two limitations. First, the CDER database does not yet accept electronic submissions of 1572 forms. In addition, the agency requires sponsors to collect a 1572 form from each investigator, but the form itself doesn’t need to be submitted to the FDA. A majority of sponsors do submit 1572 forms, however, since it includes other information required under IND regulations. The adjustments were for 33 per cent in the past two years and five per cent in 2009; no adjustments were made in 2007 and 2008. These revised totals were then multiplied by the percentage of filings originating from western Europe (13.8 per cent in 2010 and 13.3 per cent in 2011) to determine the adjusted number of unique 1572 filings from the region.

That adjusted number was further revised based on an assumption that FDA 1572 filings represent 70 per cent of the western European active investigator site market. Finally, the total estimated number of active sites was multiplied by the average number of trials and the average revenue per trial data sourced from the 2012 Site Operations Survey to calculate the estimated western European market size.

A Decline in Investigators

While many factors make it difficult for investigators to support site operations in western Europe, investigators point to the ongoing financial crisis, which has led to loan defaults and austerity measures in EU member states, as a current dominant challenge. Public funding for research has been cut at academic institutions, where almost 50 per cent of clinical research is conducted in western Europe, and the crisis has created an unstable financial environment, with 58 per cent of sites reporting that they won’t hire new personnel in the coming year.

Rising costs for conducting clinical research in western Europe also has helped drive the clinical trials market toward emerging regions such as Latin America, India, China, and central and eastern Europe; these regions have high volumes of treatment-naïve patients and physicians willing to conduct clinical studies at half the cost of their counterparts in western Europe. A recent EMA report revealed that 61 per cent of patients enrolled in pivotal trials submitted to the agency between 2005 and 2009 received treatment in countries outside the EU.

“This has been a clear development,” said Gerd Brunner, medical advisor and project leader at PPH plus, a speciality CRO based in Germany. “Pharma companies are going to emerging countries not only to get patient numbers, but for cost reasons. Many sites, particularly in eastern Europe, are much more motivated due to financial interests. It’s very attractive to them. If they are earning €500 a month for their normal work and they have the possibility of doubling it or tripling it, this is high motivation. If you tell a German investigator that he will get €500 a month for participating in a clinical trial, he will laugh.”

Regulatory pressures in western Europe also have contributed to a difficult operating environment for sites. The EU Clinical Trials Directive, which took effect in 2004, was meant to raise the standards of clinical research by simplifying the trial application process and providing a common set of regulations for member states. But instead, critics charge the Directive has been interpreted inconsistently throughout Europe and that requirements have caused unnecessary complexity and bureaucracy, which have increased the time and cost needed to get clinical studies underway. In the UK, for example, where the Directive has been implemented more restrictively, the Academy of Medical Sciences issued a report saying regulations have resulted in the UK’s global market share of patients in trials dropping from six per cent in 2004 to three per cent in 2008. Among all EU member states, the number of new clinical trials recorded in the EU clinical trial register, called EudraCT, dropped from 5,030 in 2007 to 4,130 in 2011 – an 18 per cent decrease.

“I had a very experienced site and the principal investigator rejected by an ethics committee because in their opinion, he didn’t have enough experience to be an investigator,” said PPH’s Brunner. “The investigator had 20 years of experience as a physician and had participated in several clinical trials that were approved by this same ethics committee, but nevertheless, they stated that he did not meet requirements and was not allowed to participate.”

The western European site landscape also has changed as drug sponsors invest in new therapeutic areas in which physician investigators or governmentfunded centers might lack expertise. Two of the fastest growing areas in clinical research are central nervous system (CNS) and endocrinology, but none of the respondents to the 2012

Site Operations Survey conducted trials in these areas. Top therapeutic areas in western Europe were cardiology (27 per cent) and oncology (21 per cent); clinical trials in these areas typically are run at hospitals or academic medical centres. In addition, as drug sponsors focus on more targeted products and smaller patient segments, sites with specific therapeutic expertise are needed.

Western European sites report the instability in the investigative site landscape as also being a direct result of drug development practices implemented by sponsors during the past decade. Increasingly complex protocols, flat study budgets, more demanding workloads, and constant pressure on cycle times have created a difficult operating environment for experienced investigators and made it hard for new ones to join the research enterprise. The analysis found about half of investigators who conducted an FDA-regulated clinical trial in western Europe in 2006 have not conducted a study since then, compared to a 35 per cent turnover rate in the US.

“The conditions are getting more and more difficult, especially for new sites that want to enter clinical research, due to the rising complexity of requirements both from the authorities and from sponsors,” said PPH’s Brunner. “The pharmaceutical companies themselves are responsible for a big part of this problem. They are very inflexible and the only target is to reduce cycle time metrics; they say time saved equals more dollars earned. But this is absolutely wrong. If you are not preparing for a trial in a sophisticated and well-constructed manner, you will have delays and problems at the end.”

Unique Characteristics

The 2012 Site Operations Survey, which was used to help size the western European site market, also offers a look at the unique characteristics of sites operating in this region. The survey, with responses from 257 global investigative sites, including respondents from 10 western European countries, provided detailed information about staffing levels, volume of research activity, financial operations and outlook for the future.

The survey data depicts fundamentally different site landscapes in North America and western Europe. Although the western European landscape varies from country to country, overall nearly 70 per cent of respondent sites from western Europe are affiliated with either an academic institution or government-funded hospital or clinic, while only 15 per cent are part of a private physician practice. Two large-scale site management organisations – UK-based Synexus and Denmark-based Center for Clinical and Basic Research – also operate research sites in western Europe. In North America, nearly half of the respondent sites are part of a private physician practice, most of them part-time investigators juggling clinical practice and clinical research, followed by sites affiliated with an academic institution (18 per cent) and independent research centres (17 per cent).

The average western European site has 11 employees, similar to the size of North American sites, yet western European sites employ a higher number of part-time employees (4.8) than North American sites (2.8). Sites in western Europe typically spent a greater portion of their revenue on investigator salaries (28 per cent) than those in North America (20 per cent) last year and paid a third less (14 per cent) than the amount North American sites spend on study coordinators (21 per cent). Western European sites also spend a greater percentage of site revenue on regulatory staff (14 per cent) than North American sites (4 per cent). Due to spending a disproportionately higher amount on investigator and regulatory staff salaries, the typical western European site earned a lower profit margin (7.8 per cent) than the average North American site (12 per cent) in 2011.

At the same time, the typical western European site allocates only about 11 hours a week to marketing and business development activities, which underscores how western European investigators have a less opportunistic mindset about pursing clinical studies than sites in North America. A majority of clinical trials in western Europe are conducted in government-funded hospitals and academic centres, which vary greatly in their interest in and capability to conduct industry-sponsored trials. In addition, the average part-time physician investigator usually waits to be contacted about research opportunities rather than seeking them directly. “American investigative sites have developed clinical trials into a core part of their business. In Europe, it still remains a supplementary activity for the most part,” said Premier Research’s Sean Russell.

The typical western European site also runs a smaller research operation than its North American counterpart. In 2011, western European sites conducted an average of 11 industry-sponsored trials, 13 per cent lower than the average volume for North American sites, and enrolled an average of 188 patients compared to an average of 246 at North American sites. Since they are enrolling fewer patients, the typical western European site earned smaller grants last year for individual industrysponsored trials ($37,000) compared to North American sites ($48,600).

Rebound in Trial Activity

After several difficult years brought about by the downturn in the global economy and the fallout from merger and acquisition activity in the biopharmaceutical sector, western European sites reported a rebound in clinical trial activity last year. The findings reiterate the overall results of the 2012 Site Operations Survey, which found that sites globally reported improvement in activity and financial conditions last year Survey respondents from western Europe reported growth in the size of individual clinical grants for an industry-sponsored study (one per cent), site size (two per cent) and the number of patients enrolled (14.6 per cent).

Survey respondents from western Europe also expect the number of industry-sponsored trials to increase 12.6 per cent this year. During the first four months of 2012, Synexus has seen twice as many inquiries and request for proposal (RFP) bids compared to the same time last year. At least 10 of these upcoming studies will need more than 15,000 patients each. “Unless there is another catastrophic incident in the global economy, I can’t see any reason why the trend doesn’t carry on upwards. We did have a quiet time for a year or 18 months, but we all know that there are clinical trials out there that need to be done. I am reasonably confident that the trend is going to continue. Obviously it will peak at some stage. But I wouldn’t have thought that we were at the peak yet. I’d be looking at a continuing increase in inquiries and activity through to the end of this year,” said Smith.

Since each European country has experienced economic hardship to a different degree in recent years, the level of optimism varies from country to country. However, overall western European sites expressed caution about the stability of the recovery, since the growth in clinical trial activity is modest and not sustained long enough to be a long-term trend. Only 12 per cent of survey respondents believe economic conditions for sites will improve this year. The financial crisis has led to cuts in research budgets at academic centres, where almost half of all research is conducted, and survey respondents expect the average clinical trial revenue from industry-sponsored grants will decrease 1.5 per cent this year. Sites report their profitability has suffered and more than half of sites (58 per cent) have no plans to hire this year. “There are financial difficulties in recruitment and payment of employees,” said University Hospital of Bordeaux’s Joannes-Boyau. “The needs of employees are too high.”

Looking Ahead

Although the financial crisis in western Europe has contributed to difficult operating conditions for clinical trial investigators, it has also prompted academic researchers and health officials in some countries to discuss the need for making clinical research more of a priority and for finding ways to fund research without public funds. At the same time, as cultural attitudes about clinical research in western Europe begin to evolve, the difficulties in trying to size the western European site market points to the need for better metrics about the site landscape. The EMA has moved towards a culture of greater transparency in recent years, but more robust information about the clinical research enterprise in western Europe is needed to support growth of the industry.

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Karyn Korieth has been covering the clinical trials industry for CenterWatch since 2003. Her 30-year journalism career includes work in local news, the healthcare industry and national magazines. Karyn holds an MSc from the Columbia University Graduate School of Journalism.

Annick Anderson has been conducting market research since 1998 in both the healthcare and consumer packaged goods industries. Annick holds an MBA from the Boston University Graduate School of Management.
Karyn Korieth
Annick Anderson
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