For those unfamiliar, this black box warning, added to the drug's package insert by the FDA in March of this year, tells doctors who use this drug:
- Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
- Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function.
- Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy (and to)
- Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.
- That black box was warning based on a single non-published crossover trial on 40 subjects:
A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups. When poor metabolizers received the 600 mg/150 mg regimen, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.
- Presence of a gene does not mean it is expressed clinically.
- There are no data to demonstrate that outcomes have been effected by the use of genetic testing in a large cohort of patients, only a retrospective analysis of outcomes reported in the New England Journal of Medicine.
We know that there is a political push by President Obama and his NIH director, Francis Collins, MD, PhD (a geneticist) to use "personalized medicine" (read: genetic tests) as a way to come up with recommendations for medical care:
"As we learn more about individual's risk – from family history to DNA testing to understanding of environmental exposures – we ought to be able to come up with recommendations that are more personalized. I think people are ready for that. I think they're hungry for that. I think they are more likely to be responsive to that, but we have a long ways to go in terms of preparing people for that kind of individualized approach to medicine."Ironically, Dr. Collins admitted:
Today, "you can get fancy DNA tests for hundreds of dollars," Collins told The Endocrine Society meeting - but your better bet for now may be a simple family tree of health, checking what ailments Mom, Dad and Grandpa had to predict your own future. "That's a free genetic test of great power."So we should ask ourselves why a 40-patient crossover trial and retrospective analysis of outcomes qualifies as top-notch research on which to base a black box drug warning that also supplies no dosing recommendations to doctors if such a test is positive.
It wouldn't be the money generated by genetic testing for companies (see here and here) and hospitals who stand to make a pretty penny on them, would it?
Addendum 18 Jun 2010: They just won't quit, and admit:
"The challenge is to deliver the benefits of this work to patients. As the leaders of the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), we have a shared vision of personalized medicine and the scientific and regulatory structure needed to support its growth. Together, we have been focusing on the best ways to develop new therapies and optimize prescribing by steering patients to the right drug at the right dose at the right time."Look for more black boxes applied to more drugs with no understanding of the legal ramifications of their use. Is this the caliber of scientific rigor we are to expect from our government's reform agendas?
Addendum 29 Jun 2010 @ 14:38PM: TheHeart.org reports on the ACC and AHA's recommendations regarding the black box warning.