January 4, 2012
FDA Black Box Warning for Genetic Testing in Plavix Use is Challenged
Did the FDA jump the gun when it recommended genetic testing to accompany the use of Plavix (clopidogrel), a widely prescribed blood thinner drug? In March, 2010, the FDA issued a post-marketing black box warning for Plavix, suggesting that prescribers consider CYP2C19 genotyping (a genetic test for mutations in the gene) to identify “slow metabolizer” patients who remained at risk for heart attack, stroke, and other cardiovascular events. The theory was that a subset of patients with a particular genetic profile in the CYP2C19 gene for whom the drug was prescribed because of cardiovascular risk could not properly metabolize the drug; thus they were not protected by the drug against possible heart attacks. This warning followed reports and lawsuits over the use of Plavix (adverse side effects and ineffectiveness). A black box warning is the strictest warning that can be added to a drug label, short of recalling the drug. Such a warning may decrease use of the drug, sometimes without need. Therefore, its use (e.g., adverse reactions to drugs, contraindications for use) is optimally reserved for instances where the level of risk, as supported by data, warrants the elevated monitoring. The FDA recommendation for the genetic test was not supported by leading medical associations, specifically the American Medical Association and the American College of Cardiology, which stated that the evidence was insufficient to support a sweeping recommendation, but did issue guidelines for practitioners who prescribed Plavix. Now, research reports in the British Medical Journal and the Journal of the American Medical Association (JAMA) show that the data does not support the conclusion that the CYP2C19 genetic test results correlate with a population with increased cardiovascular events, as the underlying theory would predict. A JAMA editorial criticized the “irrational exuberance” of the FDA in its recommendation of the genetic testing and noted that “the pharmacogenomics approach to drug therapy must undergo the same rigorous testing for efficacy and cost-effectiveness that is required for other therapies. Overzealous adoption based on limited biochemical data does not serve the public interest.” Any recommendation for genetic testing immediately presents issues of cost and insurance coverage, so that patients may face a more complicated access scenario (and delay). So far, the FDA has not responded to the new research with any revisions in its recommendations. However, the episode is certainly a cautionary tale for the agency, which must balance its growing accommodation of the phamacogenetic dimension of drug prescribing with thorough attention to scientific rigor.