Saturday, May 26, 2007

Avandia: Enough Blame to Go Around

Whenever a widely promoted and blockbuster Rx drug is found to adversely affect some patients, many people focus all or most of the blame on pharmaceutical marketers, sales force and other greedy pharmaceutical executives.

Avandia is no exception to this "rule" of "blame sales & marketing first, ask questions later."

For example, take this recent posting by Roy M. Poses MD on the Healthcare Renewal blog:
"Once again, it appears that a drug company was pushing one its products beyond what the clinical research evidence supported."
I find this claim disturbing. The way I interpret this remark is that GSK made efficacy (benefit) claims beyond what the evidence supports. This is different than saying it tried to gloss over the adverse side effects, which is what the FDA warning letters (mentioned in a recent NYT article) say. The FDA never, to my knowledge, claimed that GSK was making unsubstantiated benefit claims.

This is an important distinction, because any decision by the FDA to request that Avandia be taken off the market will be based on how the risks stack up against the benefits. Other commentators -- including Bob Ehrlich -- also point out that the benefits of Avandia may outweigh the risks:
"In my view, here is another useful drug accused of being dangerous in the unrealistic desire for risk free medications...Properly warned, patients and their physicians need to weigh the risk and benefits of any drug. In some of those carefully considered cases, patients will still die because of a reaction to a drug intended to make them better. That has and always will be the case. Those deaths pale in comparison to lives saved. That part of the story gets lost because 'greedy uncaring drug company' makes better copy." [DTC Perspectives Issue 262]
What GSK marketers may be guilty of -- and what the FDA has warned them of repeatedly -- is underplaying the risks, not over hyping the benefits.

One could make the argument that Avandia, Vioxx, and other drugs should only be marketed to a subset of consumers who can tolerate the known risks. This was the gist of a comment made to a Pharma Blogosphere post on this subject by "Insider" -- the anonymous blogger at Pharma Gossip:
Avandia (and Vioxx, possibly) may be good medicine for a small sub-group of patients - but should not have been "pushed" by mass marketing for all patients with diabetes (or OA in Vioxx's case).

R&D's success has been turned into failure by "over-Sales&Marketing" due to Senior Management greed/need for a blockbuster.
I acknowledge this point, but suggest that this puts the FDA squarely in the middle of the debate. FDA could have limited Avandia's approved-for-marketing indication to a subset of patients or excluded a subset, such as patients with with Congestive Heart Failure (CHF). In fact, the Avandia label includes data showing that Avandia can people with CHF can suffer adverse cardio events including heart attacks.

The point is, GSK had approval to market the drug to as wide an audience as possible -- virtually anyone with Type II diabetes. If there were known problems with a subset of patients, then it is up to the FDA to restrict the marketing to exclude that subset as it has done with a number of other drugs.
[Note: Usually, drugs are first approved for a limited indication and eventually that approval is widened to include more indications based on new data submitted. Unfortunately, the data that is used as the basis of new indications has more to do with efficacy than with safety. Again, the FDA must accept some responsibility for this wrong-headed way of expanding a drug's indication.]
Perhaps physicians also are partly to blame for not monitoring their patients closely enough. Look carefully at the following table that is included in the Avandia package insert, which all physicians should read (click on it to see an enlarged version for easier reading):

While this data involves a small number of people, I can easily see that the CHF group suffered 5 MIs vs 2 MIs for the control group. Duh! Even a non-physician might find this worrisome.

Yes, pharma marketing & sales may use T&A to influence physicians to over prescribe or prescribe a medication to the wrong patients (see, for example, "Dumb Blonde Reps vs. Slovenly Genius Reps") , but, hey! when is it time for physicians to take some responsibility for their actions?
[NOTE: Speaking of physician accountability, I can only guess that electronic medical records and ePrescribing hasn't gained much traction with physicians because of their fear of "outcomes" monitoring and being held accountable for outcomes. Of course, pharma is complicit in this attitude and would rather not have its drugs' outcomes monitored electronically and instantly! But that's another topic.]
Maybe even patients are partly to blame. When was the last time YOU read a package insert. Yes, it's often incomprehensible (see XXX), but patients often don't even read the patient section of a drug's label, which is easy to read as opposed to the technical part of the label designed for physicians. The Avandia label includes such a patient version, which states clearly:
Before taking AVANDIA, tell your doctor about all your medical conditions, including if you:
• have heart problems or heart failure. AVANDIA can cause your body to keep extra fluid (fluid retention), which leads to swelling and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure.
Only so much blame can be placed on the drug company and marketers for unduly influencing physicians and patients. This is not to say NO blame should be placed on GSK, only that there is enough blame to go around and it's time that regulators, physicians, and, yes, patients, step up and accept some responsibility!

In our jaded society it's too easy to blame the bogey man, big bad pharma, greedy corporate executives, marketers, or anyone else rather than oneself. Let's grow up already!

7 comments:

  1. Anonymous1:03 PM

    GlaxoSmithKline Plc was warned by U.S. regulators in 2001 against playing down the risk of cardiac disease associated with Avandia, the diabetes drug linked this week to an increased risk of heart attacks.

    A year earlier, in March 2000, a diabetes expert from the University of North Carolina, Chapel Hill, wrote a letter to the Food and Drug Administration complaining about the company's ``rampant abuse of clinical trial data'' related to the drug's cardiovascular safety.

    The two letters, found on the agency's Web site, along with the concerns voiced by its own advisers before the drug reached pharmacy shelves, are providing evidence of early angst about Avandia's impact on the heart.

    So I blame:
    1 The Big Pharma Marketing Bogey Man (and the spineless researchers that went along.
    2 The FDA regulators that, in the end, buckled and didn't stand up to GSK.
    3 Seduced prescribers

    I dont blame patients - they're sick and just looking for help.

    Oh and John, I am grown up.

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  2. As noted above, in this post on Health Care Renewal:
    http://hcrenewal.blogspot.com/2007/05/expanded-avandia-story-now-echoes.html
    I was referring to the New York Times report (here: http://www.nytimes.com/2007/05/24/business/24drug.html)
    which suggested that GSK reps were glossing over Avandia risks to the heart and liver known in 2001. The FDA, in response to this, ordered the company to send a letter warning doctors of these risks, which unfortunately was sent out just before September 11, 2001 and hence was more likely to have been ignored than other such letters.

    I didn't write anything about GSK over-selling Avandia's benefits.

    By the way, you use a quote above, from Bob Ehrlich, that refers to lives saved by drugs. Drugs certainly save many lives, but I am not aware of any evidence yet reported that Avandia saves lives, especially not in comparison to other glucose-lowering drugs.

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  3. Dr. Poses:

    Thank you for your comments.

    I still stand by my interpretation of your remark: "Once again, it appears that a drug company was pushing one its products beyond what the clinical research evidence supported." as affirmation of "over-selling", although that is not how I described it.

    My main point, however, is not to engage in a "he said/she said" argument but to emphasize that there is a risk-benefit analysis that respective stakeholders must take into account when when approving, marketing, prescribing, and taking drugs.

    In Avandia's case, GSK was not warned by the FDA about inflating the drug's benefits, but underplaying its risks, which, in the long run, may have sold more porduct than is warranted by proof of benefit.

    As to your last statement, I also do not know if Avandia saves lives -- indeed no drug I know of has been approved on the basis of saving lives. Therefore, Erhlich's use of that endpoint is inappropriate. I quoted him not because I think Avandia has "saved lives" but because he and other industry supporters raise the risk-benefit argument in defense of the industry. Of course, he is inflating the benefit (saves lives) to make the risk (MIs) seem less significant in comparison.

    It seems that everyone -- depedning on which side of the spectrum you are on -- overemphasizes one side or the other of the risk-benefit equation.

    Unfortunately, none of this helps patients understand how to evaluate the risks and benefits of drugs.

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  4. Anonymous9:17 PM

    Maybe even patients are partly to blame. When was the last time YOU read a package insert. Yes, it's often incomprehensible (see XXX), but patients often don't even read the patient section of a drug's label,

    John--I thought I read recently that the illiteracy rate in the U.S. exceeded 40%. Labels are hard enough for "educated" patients to read; who speaker for--or reads to--the illiterate?

    ReplyDelete
  5. Anonymous8:55 AM

    Interesting commentary in the WSJ today regarding NEJM's role in this.

    Now, I'm not saying that GSK is the victim here, but I do think that NEJM botched this in attempt to get the scoop. I've said it before in a previous post, they (and other top journals) give too great leeway to people like Steve Nissen. They never would've published something like this with relatively little scrutiny had it come from Joe Schmoe at the Podunk Clinic.

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  6. Over the years, I have seen suggestions that glitazones have effects on the heart that were BENEFICIAL, not harmful, including possibly regression of LV dysfunction. Also, sulfonylureas always carried a risk of inhibiting the effect of NO on distal coronary flow, which is why they were often avoided by cardiologists. And metformin has its own set of possibly deadly side effects, as well as C/I in heart failure, liver failure, renal failure, etc etc.

    So the point is, I still use metformin first, but Avandia is an excellent drug. Glitazones are good drugs. ADOPT wasnt a great study, but it still seems that you get a decent bang for your buck with Avandia.

    And I'm sure an A1c reduction gets us some lives, right? Didnt Ukspds or some British study say that?

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  7. Anonymous3:28 PM

    You and your bloggers make clear doctors play a very very important role in seeeing that a potentially good drug does not become a harmful one.

    ReplyDelete