Global Clinical Trials Activity in the Details

In 2006, four out of ten (41%) active FDA regulated principal investigators were based outside the United States, according to an analysis conducted by the Tufts Center for the Study of Drug Development. Since 2002, the number of U.S.-based clinical investigators filing new Forms FDA 1572 has declined by 5.5% annually. During the same period, the number of active FDA regulated investigators based outside the United States has grown by 15% annually.

Kenneth A. Getz

But recent talk about the rapid growth of clinical trial activity overseas belies the realities of conducting studies there. It is hard to ignore Asia's 29% annual growth since 2001 in FDA regulated investigators, Latin America's 13% annual growth or Central and Eastern Europe's 16% annual growth when the number of U.S.-based FDA regulated investigators has declined during that same period. High overall regional growth fails to capture the subtleties and dynamics of individual countries within each region. Sponsors and CROs need to constantly monitor these details in order to anticipate and manage more effectively their increasingly global clinical trial activities.

Under the microscope

Take Central and Eastern Europe (CEE), for example. During the past decade, this has been the fastest growing region worldwide for FDA regulated principal investigators. CEE investigators last year accounted for 1793, or nearly 8%, of total active FDA regulated investigators. The region has experienced 41% annualized growth since 1996, when it was home to a mere 56 investigators.

CEE offers a high volume of patients and well-trained clinical research professionals as well as cost advantages. A closer look at sponsor experiences in the region, however, reveals a number of unique conditions and challenges that must be managed.

"CEE countries have made enormous progress," said Andras Madai, MD, Merck's regional medical director for CEE. "Many institutions in the region are absolutely comparable to Western institutions when it comes to infrastructure for clinical research."

"The region is home to millions of patients, many of them receiving less than optimal health care services and drug therapies," said Madai, who was raised in Hungary. "Sponsors can find the patients they need by going to fewer institutions than in the West. Grant sizes are also smaller as a consequence of the overall cost structure in CEE countries. That adds up to an important difference in cost," said Madai.

In CEE, Merck operates primarily in Hungary, the Czech Republic, Poland, the Baltic region, and Russia. The company is seeing a growing proportion of its total study volunteers coming from CEE.

"A significant downside of doing clinical studies in the region used to be the lengthy wait for approvals by local regulatory and import agencies, hospitals, and ethics boards. Those time frames have grown substantially shorter over the past several years and are now close to the EU average. Most CEE countries complete approvals within 60 to 70 days. The speed of patient recruitment into studies more than compensates for any disadvantage in terms of regulatory approval time," explained Madai.

"But the CEE is definitely not a single, homogenous region," cautioned Madai. "Individual countries have separate heritages, levels of development, and vocational backgrounds." As a result, growth in trial activity has been highly variable in the region. Since 2003, for example, Poland has experienced flat growth in the number of FDA regulated principal investigators. The number of them in Russia, on the other hand, has grown more than 25% during that same period.

"Personnel at smaller country hospitals throughout the region also may have limited knowledge of GCPs," said Madai. Sponsor companies, including Merck, have yet to attempt much training on GCP in the Balkan countries.

"As of March, regulatory authorities in Lithuania have mandated that all principal investigators take and pass a GCP course prior to conducting a clinical trial with any pharmaceutical company," says Michelle Metry, head of Merck's global training group. "It is one of the first countries in the region to identify a training need, and the requirements are quite specific. The local regulatory agency expects investigators to obtain a GCP certificate that includes names, place, and date of training, and signature of the sponsor or legal representative," added Metry. "A minimum of eight hours of basic training (four hours for refresher) is required, and the training organization must archive training materials for five years. But the regulation doesn't specifically say that the training needs to be provided by a pharmaceutical company."

Metry explained that Merck has recently put together a global training organization that will, among other things, begin proactively offering nonprotocol-specific functional training to investigative site personnel. "The same curriculum will be offered in the CEE and Asia Pacific regions. Training topics will be determined by feedback from staff based in countries within these regions," she said.

An east wind blows

"In Europe, Wyeth's patient enrollment has been steadily shifting eastward," said Mark Ridge, the company's director of global enrollment planning and performance. "A few years back, CEE accounted for a mere 15% to 20% of European enrollment. But this past year, CEE has accounted for 50% of the Phase II and III patients from Europe."

"Wyeth has a mature clinical research and development organization, particularly in Hungary," said Sheila Ronkin, MD, assistant vice president of clinical development. "Wyeth has created a global network of 15 sites (as of July '07), including two institutions in Hungary, which have agreed to accept a portfolio of Wyeth studies—global Phase II as well as Phase III, IV, and regional trials—under one master contract," she said. "Each of these clinical partners is capable of producing 300 to 500 patients per year, sufficient volume to justify having continuous on-site monitoring. Clinical trial approval times in Hungary are also favorable, allowing trials to start within three to four months."

"At this time Wyeth primarily places studies in Hungary, as well as Poland and the Czech Republic," said Robert Maguire, MD, vice president of clinical development. "Wyeth is also doing more in the Ukraine, Bulgaria, and Russia."

"GCP compliance in the CEE was problematic before 2004. We've seen considerable improvement since then, when the European Trial Directive was published and Wyeth implemented rigorous investigative site assessments and postinitiation compliance visits," said Maguire.

"I think there's a lot of untapped potential, particularly in Russia at this time," added Maguire. "But the country presents several major challenges, including a sluggish regulatory approval process and potential GCP compliance issues. Hospitals also tend to be indication-specific, making them tough to build into a new global network. But I'm optimistic that Russia will end up being a nice place to do clinical trials. Wyeth just established a commercial office in Moscow and has plans to add R&D personnel in the region."

Compliance concerns

For the past five years, Olympia, WA-based Western Institutional Review Board (WIRB) has been partnering with the World Health Organization to build the infrastructure for ethical review in developing countries. WIRB has been providing a six-month fellowship program for mid-career physicians. Two of the 50 fellows to date have been from Eastern Europe, "but we don't do anything on the ground with them," says WIRB President Angela Bowen, MD, citing concerns about political instability and a general lack of authoritative regulatory oversight.

"Without enforcement, it's been hard to persuade investigators to do what they need to do," explained Bowen. "I have seen companies venture into places like these and, almost invariably, the quality of the data is not what they hoped to see. But recruitment is good, and that's what seduces them. It seems to our board that the recruiting in Eastern Europe is rather aggressive. The FDA simply does not have the resources to monitor and audit all these sites," she said. "Neither," she adds, "does the Office for Human Research Protection."

An analysis of FDA investigative site inspection results supports WIRB's experience. Historically, the incidence of noncompliance and fraud is higher among principal investigators based outside the United States.

Informed consent, drug accountability, and adverse event reporting are among the areas where noncompliance is substantially higher for principal investigators not based in the United States. In addition, there is high variability in the incidence of investigator noncompliance and fraud between countries within a given ex-U.S. region.

The Rate of Increase for FDA Regulated Investigators Around the Globe

Globally active sponsors and CROs must understand and be attentive to the details of each country in order to deliver development performance and economic advantages. "Every region has individual countries with unique characteristics," said Merck's Madai. "There are those places where the political situation may endanger clinical research work; the quality of data provided by a country's investigators varies between country; and regulatory and import authorities are not the same in each country."

Kenneth A. Getz MS, MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: kenneth.getz@tufts.edu