The Voice in the Ear -- Burt's Stent Blog
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November 30, 2006 -- 3:44pm EDT

The Catch-22 of Plavix and the FDA: Not My Job
Everyone's worrying about drug-eluting stents and their increased risk of thrombosis, or blood clots. Most cardiologists know that the aspirin-Plavix combo they prescribe after stenting is critical to keeping that risk low.

But here's something I bet you didn't know...(drum roll, please)...

" not approved for PCI or stent placement outside of the setting of ACS [Acute Coronary Syndrome]. This use is off-label."

Yes, it's true! The use of clopidogrel (Plavix) in patients who receive stents in non-emergency situations is an off-label and unapproved use, according to what the Center for Drug Evaluation and Research (CDER), the FDA division that regulates the pharmaceutical industry, told me.

And get this:

"Companies, or people acting on the company's behalf, are not permitted to promote a drug for an unapproved use."

This added tidbit is from another FDA sub-agency, the Division of Drug Marketing, Advertising, and Communications (DDMAC).

So the companies that make and market clopidogrel (Bristol-Myers, Sanofi-Aventis, even the generic-maker Apotex) will get in trouble with the FDA if they start communicating with patients about taking the drug after stenting -- well, non-emergency stenting anyway, which is the vast majority of the device's use.

"This can't be correct!" said the cardiologist who disputed my information, as we stood in the corridors of the TCT meeting. He whipped out his BlackBerry, clicked onto his drug info site, then looked up. "You're right!"

Well I knew I was right, because for two years, we at Angioplasty.Org have been trying to get a small amount of funding to underwrite a patient and professional education campaign on Plavix compliance. We naively thought that because we are the top find on the Net for searches like "Plavix and aspirin" or "Plavix and stents", we offered a worthy and ethical public service opportunity. But we ran into a stone wall. More on this later.

• FDA: Mum's The Word
Every interventional cardiologist knows that drug-eluting stents and antiplatelet therapy are a package deal. Putting a stent in someone creates a risk of potentially fatal blood clots, so not prescribing anti-clotting meds would be irresponsible. It's even in the FDA-mandated "Directions For Use" (DFU) that the stent manufacturers must put in every box o' stents.

So what gives with the "off-label" label?

My query to the Center for Devices and Radiological Health (CDRH), the FDA division that regulates stents, got the answer, clear and simple:

"Clopidogrel is used in patients with drug-eluting stents because of their continued need for antiplatelet therapy. Since Clopidogrel is an antiplatelet drug, this is not considered an example of the kind of off-label use of the drug that would require re-labeling of the drug itself. Instead, the labeling for drug-eluting stents describes the treatments that patients received in the clinical trial but doesn't comment on whether they are on- or off-label. In this sense, the labeling for DES is consistent with the labeling of other approved drugs and devices in which all other therapies received by the study patients are described."

Whaaa-huh? Got that? Was the above clipped from a page of Joe Heller's novel or what? Here's my short version:

Q: When is an off-label use not an off-label use?
A: When we won't tell you one way or the other.

Okay. Cute. Enough wordplay over semantics. The fun is over. This is actually serious business and has real implications for patients, and especially for next week's FDA two-day public meeting about recent concerns voiced over late stent thrombosis in drug-eluting stents.

Well, here are my concerns.

• The Need for Patient and Professional Education
There have been numerous studies from Milan to Missouri showing that one of the major causes of potentially fatal blood clots in stents is premature cessation of antiplatelet therapy. As Dr. John Spertus of the Mid-America Heart Institute of Kansas City, Missouri told me:

"There have been no studies to date that really examined how many patients getting these new devices are stopping their medicines early. I think doctors didn't have much appreciation for how often this happened. I think we need to continue to educate patients."

Great thought, but who will pay to educate patients? Not to mention informing the few cardiologists who don't yet know the very latest recommendations for Plavix, and, oh yes, the surgeons, dentists, internists, nurses, physicians' assistants, network TV health reporters, and all the other professionals who come into contact with patients, and who may unknowingly put a stent patient's life at risk by telling them to stop their meds, even for a while?

• Drug Companies Off The Hook: A Free Ride
I have talked to people at the drug companies who would like to fund a patient education campaign, but can't because of regulatory implications. Under the FDA rules discussed above, the drug companies that make and market clopidogrel are barred from supporting such an effort."It's a happy coincidence, isn't it -- they're not allowed to spend money", Dr. William O'Neill told me.

O'Neill, a high-profile interventional cardiologist and Professor and Executive Dean for Clinical Affairs at the University of Miami's Miller School of Medicine expressed other strong thoughts on Plavix and the drug companies who make and market it:

"They haven't put a dime into clinical trials on the use of their drug in stents. They've piggy-backed onto the device makers and they haven't really needed to do the science. Like there's a real concern about Plavix resistance or hypo-responsiveness -- they haven't done squat on that.... They haven't had to act responsibly toward the use of their drug, the length of the time, and the potential premature termination. They could get it past a labeled indication if they did the proper trial, but they don't want to do it because they figure that they'll just make all the money with doctors using the drug off-label.

"You know all these trials done with clopidogrel were done as physician-sponsored or device-sponsored trials. So...they're fat and happy because they're making a fortune off of the use of Plavix for non-approved indications. Now what about that as a scandal?"

Bad drug companies; good device companies. Or is it?

• Device Companies: Laying Low
Over a year ago, on my mission to raise patient education funds, I was speaking to "the man" in charge of drug-eluting stents at one of the two approved device manufacturers (you flip the coin -- it'll take a large donation for me to tell which one). Since Angioplasty.Org gets almost 80,000 visits monthly, we hear from a lot of patients, so I challenged him with this question:

"A lot of patients seem to not be really aware, and physicians, like their doctors and dentists, don't understand the implications of stopping Plavix even for a short time. Don't you think that the device companies have a responsibility to educate patients and their physicians and corollary physicians more than seems to be the case. I mean just so many patients write in and are not aware of this."

His answer put my worries to rest:

"Well that's new news to me, Burt. And I've just made a note, and [to his assistant], I want you to also. That's something that we can definitely dial up to our patient education channels.

"It is obviously a part of all of our in-servicing with the interventional cardiology physicians. But I think the physicians you're talking about are the referring physicians, in particular, that refer into the interventionalists. So we will definitely put some more emphasis on that, if that's a common question that you are getting from your audience."

Ah yes. Dial up the Patient Education channel. I don't think I get that on my cable. Let's see, Episode One might be titled -- "That stent you're thinking of getting means you will have to take a $4 pill every day for a year or more that might cause bleeding and means you can't ever have surgery without stopping it." That will certainly sell a lot of stents, especially to the channel's main demographic: the over-60 crowd.

• Patient Education: Stonewalled
So you've got the drug companies who aren't allowed to fund patient education, and don't seem anxious to change that situation. And then you've got the device manufacturers who, until very recently, were not so interested in publicizing the fact that the Ferrari in your heart performs great but needs a lot of maintenance.

In summary (ahem!) there's a crack at the FDA and patients are falling through it. There's a problem (compliance) and a solution (education). But who will assume responsibility? Whose job is it anyway?

*          *          *          *         *

Well...doctors always like to end their PowerPoint lectures with a funny cartoon or photo, so since "I'm not a doctor, but I play one on the Web", here's my finish: the results of a Google image search for "Not My Job".

(Note: Patients who are trying to figure out what this means for them should read Angioplasty.Org's Patient Advisory.)

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