January 5, 2006

Penn Researchers Call for New Paradigm in Clinical Trials:
Individual Factors Must Be Considered When Designing and Interpreting Clinical Trials

(Philadelphia, PA) - Two studies published this week from the University of Pennsylvania School of Medicine point to the need for a more individual approach to medicine and drug testing. The two papers, from the lab of Garret FitzGerald, MD, Director of Penn’s Institute for Translational Medicine and Therapeutics, together with Penn colleagues Tilo Grosser MD, Research Assistant Professor of Pharmacology, and Susanne Fries MD, Research Associate in Pharmacology, highlight clinical studies involving COX-2 inhibitors as an example.

The first study, published in the Journal of Clinical Investigation, summarizes comprehensively the basic and clinical evidence that explains how drugs like rofecoxib (VIOXX), celecoxib (CELEBREX), and valdecoxib (BEXTRA) confer a small, but absolute, risk of heart attack and stroke. The size of this risk is likely to be conditioned by the underlying risk in a given patient of thrombosis and heart disease; the dose and duration of action of a drug; and the duration of dosing and concurrent therapies, such as low-dose aspirin.

The authors indicate how the clinical information from placebo-controlled trials of the COX-2 inhibitors is congruent, both in outcome and in how the information became manifest, with what would be expected from how the drugs work pharmacologically to block the COX-2 enzyme. The authors synthesize information from an understanding of drug mechanisms and epidemiology to predict how traditional NSAIDs-drugs like diclofenac, ibuprofen, and naproxen-may differ with respect to cardiovascular risk. Finally, they synthesize this information to provide a rational basis for treating patients with varied risk profiles as physicians await further information from ongoing trials.

Lessons are drawn from the experience of the COX-2 inhibitors-particularly the need to develop a more interdisciplinary approach to drug development and monitoring of drug safety and how an emphasis on individualizing benefit and risk can be used to refine the design of clinical trials.

The second paper, published in Gastroenterology, builds on the theme of individualized therapy, demonstrating marked variation in individual response to COX-2 inhibitors, as measured by plasma drug levels and the degree of COX-2 inhibition within an individual. The researchers found that a marked degree of variability in individuals dosed with either rofecoxib or celecoxib, even when they studied apparently healthy, relatively young individuals in a carefully controlled environment. This rigorous study suggests that up to a third of the variability may reflect an individual's genetics. Examples are given of variants in genes that affect either drug metabolism or the COX enzymes themselves.

The study was conducted on 50 healthy volunteers between the ages of 21 and 43 years old who received a single dose of placebo, celecoxib and rofecoxib in random order. This was done to allow researchers to compare directly the responses to the drugs within the same subjects. Five of the patients went thru the entire protocol 5 times to assess variability within individuals. “A surprise of the study was that factors in our environment result in varied response of the same individual to the same dose of a drug, even when we try to standardize as many variables as we can think of,” says Grosser.

Approximately 30 percent of the variability found in patients was attributable to differences between individuals, suggesting the contribution of genetics to a variety of biomarkers of drug response.

Fries, the first author of the Gastroenterology study, explains that this work provides the impetus to develop a science-based approach to risk management. “Exploitation of variability in response can lead to tests which identify patients most likely to benefit or suffer from drugs,” she says. “Our study provides a starting point for the development of diagnostics that will let us conserve benefit while managing the risk of COX-2 inhibitors.”

Such work heralds the rapidly emerging field of individualized medicine, says FitzGerald. “This can guide both the design of future clinical trials and the use of these drugs in practice.”

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PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn’s School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report’s most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

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This release is available online at http://www.uphs.upenn.edu/news/News_Releases/jan06/trials.htm