Pharmacogenomics: Will the regulators approve?

Abstract

The data gap Why should drug regulatory agencies care about pharmacogenomics? Over the past 20 years, genetic heterogeneity has been increasingly recognized as a significant source of variation in drug response. In general, though, very few genetic markers have been validated to date as indicators of drug response. “In assessing the clinical impact of genetic markers, we’re still scratching the surface in terms of data,” says Carol Braun Trapnell, a clinical pharmacologist in the Division of Clinical Trial Design and Analysis in the Center for Biologics Evaluation and Research (CBER) at the US Food and Drug Administration (FDA; Rockville, MD). Finding these markers is largely a hit and miss process. There is a great deal of discussion as to the huge potential of genetic information in development, but very few hard data. “The ratio of vision to data is very high,” says Jerry Collins, director of the Laboratory of Clinical Pharmacology at the FDA. “We love vision, but data is our mainstay.” By far the greatest amount of information is available on the cytochrome P450 (CYP) family of enzymes, which metabolize the majority of current drugs. Four of these enzymes—CYP1A1, CYP2C9, CYP2C19, and CYP2D6—exhibit genetic polymorphism and alter responses to drugs. According to Simon Ball, senior research scientist at Wyeth-Ayerst (Princeton, NJ), many of the major pharmaceutical companies now screen their lead compounds to determine whether they are metabolized by these polymorphic CYP enzymes. If they are, that information will usually contribute to the decision to select a compound for clinical development: “Pharmacogenetic data [are] vital if you have a compound with a narrow therapeutic index or which is metabolized from a prodrug,” says

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