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)...
"Clopidogrel...is 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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