The Politics of Black Boxes

It's been several months since the black box warning on clopidogrel (Plavix) appeared and most cardiologists I know have not changed their practice as a result. I asked them to write about this on this blog, but because of the potential future legal ramifications of admitting as much, they politely declined.

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.

When you ask interventionalists what they think about this genetic testing to assess who might be a "poor metabolizer" you get a blank stare and many reasons why no one does it, like:

• 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.

Forty prospective patients. Non-peer-reviewed data. Retrospective studies. And a black box warning, the FDA's most severe.

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?

-Wes

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.

Shipping Innovation Overseas

... might help some university hospitals get a jump on the competition, courtesy of an NIH grant:

Aided by a $4.5 million grant from the National Institutes of Health, the two universities are expected to immediately launch joint clinical programs to treat heart disease, based at both Yale-New Haven Hospital and (University College-London) UCL-affiliated hospitals.

While Yale has thousands of international partnerships, the scale of the new collaboration and the linking of two extensive hospital complexes is unique, Yale President Richard C. Levin said Thursday.

* * *

The joint effort is expected to create a “test bed for analysis of various clinical procedures,” Levin said, noting the partnership could eventually extend beyond cardiology, and would give Yale access to extensive British data systems.

Medical devices often receive approval in the United Kingdom before they are approved in the U.S. The partnership will enable Yale to study innovative drugs before they are available in the U.S., Levin noted.

“We can be immediate adapters on the frontier of medical innovation,” he said.

Look for increased pressure on universities to forge such collaborations in Europe as the regulatory environment in the U.S. becomes increasingly hostile to researchers.

-Wes

Engorgement

Another cocktail encounter tonight. This time, with an accomplished researcher from one of the major medical centers here in Chicago. She carried more than one NIH RL-1 grant. Interestingly, before the stimulus package was announced, she had to cut her research budgets 30% due to concerns over funding availability.

Then came the Obama Stimulus package.

"So, do you think you'll be able to reinstate those budget cuts for your current research?" I asked.

"Nothing's coming for several months," she said. "So we were told to think of a totally new project and not focus on our real needs for current projects. Instead, we were told we had to create an entirely new project with ridiculous requests for equipment and staffing, above and beyond what exists today. It's crazy."

"And the former work?"

"Who knows? We'll stick to our current budget," she said.

"What a waste."

"Yep. But that seems to be the way the game will be played."

-Wes