A Swift Predominance of Ex-U.S. Sites

Over the past five years, there has been a largely unnoticed, yet dramatic, shift in the use of ex-U.S.–based investigative sites. Major pharmaceutical and biotechnology companies have been placing an increasing proportion of their clinical trials at offshore locations throughout eastern Europe, Latin America, and parts of Asia. Indeed, some sponsors report that they now routinely place a majority of their clinical trials among ex-U.S.–based investigative sites. This shift has major implications not only for U.S.-based investigative sites but also for sponsors and CROs looking to optimize their relationships with an increasingly global network of investigators.

Kenneth A. Getz

Shifting tides

It is widely accepted that conducting trials overseas is far less expensive, and there is a healthy supply of well-trained physicians there eager to serve as investigators and study coordinators. Drug shipment issues have largely been overcome, and the adoption of eClinical technology solutions has helped to address operating support issues that used to bottleneck overseas projects.

Most importantly, the abundance of treatment-naïve patients abroad has translated into speedier clinical trial recruitment and improved retention rates. In the developing world, vast numbers of patients suffer from diseases ranging from the familiar to the exotic. These patients are often eager to enroll in clinical trials at the request of their physicians and eager to gain access to free medical care, tests, and complimentary therapies that they otherwise could not afford.

Overseas influx

In an analysis of 1572 filings with the Food and Drug Administration (FDA), the Tufts Center for the Study of Drug Development has found that the majority of investigative sites still hail from the United States, but the geographic mix is in rapid flux. A decade ago, for FDA-regulated studies, less than one in ten investigative sites was ex-U.S.; in 2004, one out of three sites was ex-U.S. The Tufts Center also found that, whereas the overall number of principal investigators within the United States has been growing by 8% annually since the late 1990s, the number of ex-U.S. principal investigators has been growing by more than 20% annually during that same time period. Since 2001, the number of new domestic investigators has been declining by 11% each year.

Major pharmaceutical companies have already tipped the balance in favor of ex-U.S. investigative sites, or they are planning to do so within the next couple of years. Wyeth, for example, reports that it now does more than half of its clinical trials among ex-U.S.–based investigative sites. This year, nearly 60% of all investigative sites recruited by Novartis were ex-U.S. sites. Midsized P&G Pharmaceuticals, now conducting more than one-third of its trials among ex-U.S. sites, says that it is routinely looking to place trials overseas, often as replacements for traditionally U.S.-based investigators.

GlaxoSmithKline said that it conducted 29% of its clinical trials abroad last year and hopes to increase that figure to 50% by the end of 2006. "We have a robust Phase II pipeline," said Rick Koenig of GlaxoSmithKline. "The challenge is to move those compounds to Phase III and on to market in an expeditious way. We find that conducting trials in developing nations is less expensive and faster than in either the United States or western Europe. In some instances, the difference is as much as tenfold. We need sites that do strong quality work, and we can find them in places outside of traditional markets," said Koenig.

Merck is conducting significantly more studies internationally than in the past. More than 40% of its investigative sites are based outside the United States, according to Jorge Guerra, MD, executive director of clinical research operations. Merck's ex-U.S. clinical research is now being conducted predominantly in central and eastern Europe, Latin America, Australia, New Zealand, and, increasingly, the Asia-Pacific region. Korea, which until recently allowed only postmarketing studies, is the latest addition. "In the aggregate, studies conducted in 60 countries outside the United States are only slightly less expensive to do than inside the United States," said Guerra. "Personnel costs in Latin America are definitely lower," he added, "but the savings are offset by higher shipping and courier expenses."

"In general, ex-U.S. sites tend to enroll their first patient later compared to U.S. sites because of regulatory agencies and the slower ethics review committee approval process," said Guerra. "However, in our experience, ex-U.S. sites tend to recruit faster so that total enrollment targets are met either simultaneously or ahead of U.S. sites. It also seems that rescue operations—including adding more sites and intensifying patient recruitment—are needed more often for U.S. than for ex-U.S. studies."

Growing competition

As clinical trial volume and scope continue to rise, an increasingly global community of investigative sites appears ready to meet drug development capacity needs. For U.S.-based investigative sites, this trend signals that competition for clinical trials will intensify domestically. Research sponsors have already been turning to more sophisticated criteria (e.g., historical performance metrics and details on access to specific patient populations) in order to justify the higher relative costs of U.S.-based clinical investigators.

Competition among ex-U.S. investigators is also intensifying. As these sites take on more operating infrastructure, they will need to sustain a larger stream of clinical trial activity. Clinical research managers representing different global regions within biopharmaceutical companies must compete with their own colleagues to gain and sustain a larger share of their organization's finite clinical trial work. At this time, eastern Europe and Latin America tend to be the favored regions.

Growing use of ex-U.S.–based investigative sites is also expected to increase outsourcing to contract service providers that are well positioned within markets abroad and offering significantly lower operating expenses. Given the added complexity of simultaneously conducting clinical trials internationally, several sponsors report a heavier reliance on CROs to meet more aggressive development timelines.

Wyeth, for example, reports that it is using a global monitoring committee to keep up-to-date with international regulatory and customs requirements. "If necessary, supplies are shipped early, stored in a virtual warehouse, and then transferred to trial sites," said Ira Spector, vice president of clinical trial operations. "A handful of large CROs are selected for their field monitoring expertise in specific countries and must be willing to accept Wyeth's SOPs, systems, and technology so data are easily comparable," he added. Wyeth's goal is to initiate 80% of global sites within eight weeks of study start-up.

Merck, long known as an organization that has opted for minimal use of CROs to manage its portfolio of development projects, is now seeking to outsource its global studies to capable CROs. "Rather than rely on our own in-house resources, we want to pick up the pace through using CROs," explained Guerra.

Future trends

The shift toward increasing use of ex-U.S. sites will likely attract public scrutiny and eventually—with mounting political pressure—restrictions from the FDA. Media and policy-makers have already identified this trend as a potentially explosive issue, one that will fuel the fire of an already damaged and eroded relationship with the public. Despite data suggesting that regardless of where clinical trials are conducted the U.S. market typically gains early access to new medical innovations, the media tends to depict the growing prevalence of ex-U.S.–based investigative sites as profit-motivated and exploitive of vulnerable global markets. It is critical for research sponsors to proactively educate the public and policy-makers about the full rationale behind broad-based global development programs.

New drug approval in the United States requires that sponsors submit an application containing substantial evidence of effectiveness based on the results of adequate and well-controlled studies. There are a few cases where a new drug has been approved for the U.S. market based on data from well-controlled studies conducted solely by investigative sites abroad.

With regard to the exact mix of U.S.-based and ex-U.S.–based investigative sites, the FDA remains elusive. There is no minimum number of U.S. patients required in a New Drug Application. Sponsors may design and conduct their studies in any manner provided that they demonstrate, via prospectively planned analyses, that the ex-U.S. patients are similar to U.S. patients both in terms of pretreatment disease characteristics and treatment outcomes. Now and in the near future, sponsors and the FDA will continue to evaluate their studies for their applicability to patient populations and medical care settings in the United States.

U.S. participation

Select disease-specific affinity groups may vie to keep some clinical trials within the United States, given the wide variations in diet, life style, and health care consumption. Diseases most sensitive to these variations include age-related illnesses such as Alzheimer's, Parkinson's, and ALS and gastro-intestinal, CNS, and endocrine disorders.

At this time, sponsors are confident that the FDA will not reign-in on the shift toward the high use of ex-U.S. investigative sites. Even the most avid off-shoring enthusiasts foresee some limits to the trend in the future. Characteristic of several sponsors, Merck's Guerra said he can't imagine that Americans will ever constitute less than 40% of the total number of trial participants given the size of the U.S. market. For the time being, the only restrictions placed on the rapid, largely unnoticed shift toward placing clinical trials outside the United States will likely be those that the industry self-imposes.

Kenneth A. Getz MS, MBA is a Senior Research Fellow at the Tufts CSDD and Chairmanof CISCRP, both located in Boston, MA, email: kengetz@ciscrp.org.