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FDA Reaffirms Plavix Black Box Label Decision

The US Food and Drug Administration (FDA) is standing by its original decision to update the Plavix label with pharmacogenetic information. A meta-analysis published last year in the Journal of the American Medical Association led by Michael Holmes of the University College of London, raised questions about whether the label changes were premature.

The FDA black box warnings are the strongest type of printed warnings put on prescription drugs. Many pharmaceutical companies and physicians believe black box warnings stigmatize a drug and lead to a decline in prescription rates. However, to date, there is no evidence of a meaningful relationship between the warning labels and any changes in demand.

The CYP2C19 enzyme converts Plavix into its active form. Pharmacogenetic testing identifies the amount of the enzyme a person creates and assigns a value ranging from poor to rapidmetabolizers. The FDA updated the label to inform doctors that poormetabolizers experienced a diminished response to the drug. In 2010, the FDA added the black box warning to highlight that poor metabolizers exhibited a higher cardiovascular risk following acute coronary syndrome or percutaneous coronary intervention (PCI) than normal metabolizers. Both warnings emphasized that pharmacogenetic tests could help guide therapeutic strategies, with the black box advising doctors to "consider alternative treatment strategies" in poor metabolizers.

Holmes et al noted “evidence of small-study bias” in the data collected by the original meta-analysis, and restricted their analysis to only four studies with 200 or more events. These four studies, plus six randomized trials, failed to identify any significant associations between CYP2C19 genotypes and Plavix efficacy in terms of cardiovascular events and bleeding.

According to Lawrence Lesko, former director of the Office of Clinical Pharmacology at FDA's Center for Drug Evaluation and Research, emerging data has shown that the FDA was right in updating the Plavix label. He noted that two other meta-analyses, published before the Holmes et al study, found that poor metabolizers were at heightened risk for cardiac events. Jessica Mega, a cardiologist at Brigham and Women’s Hospital authored a meta-analysis two years ago reporting Plavix-treated patients who were poor to intermediate metabolizers had a “significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.”

Scripps Health Chief Academic Officer, Eric Topol, has repeatedly argued that CYP2C19 pharmacogenetic testing is most useful in patients who have undergone PCI and are at risk of stent thrombosis. Many agree that these studies have been positive and that the resulting dialogue continues to be extremely valuable to doctors and patients. Ultimately, conversations like the Plavix/FDA debate continue to underpin the value of pharmacogenetic testing in treatment strategies.