Sunday, February 1, 2009


Good-bye to the Good-bye Presents

As most here will know, as part of their final act, the political appointees and (most likely) some of the FDA career staff declared a change in guidelines for off-label promotion of drugs. The core of the new guidelines is that FDA would not require prior review of the off-label promotional materials when they were used for marketing to docs. The text about "peer-reviewed journals" remained.

As is conventional, those proffering the guidelines said that this was only formalizing what was already policy. Those not inclined to agree described the change as one more last-ditch attempt to save the world for off-label promotion. Given that the past few weeks have seen the largest busts for off-label promotion in history - both Lilly/Zyprexa and Pfizer/Bextra - adds a little irony to the development.

The Fort Worth Star Telegram reports that both the administration and key members of Congress - particular Senator Grassley and Representative Waxman - will act to reverse the guidelines.

Dare I ask: Opinions out there?


  1. Justice, thanks for posting this. The Star-Telegram is one of our local newspapers, and I missed this. The Department of Veterans Affairs deserves accolades for its stance on this issue. Here is a clip from the article (

    “The Bush FDA issued the new guidance over the objections of Bush's Department of Veterans Affairs, which pays for drugs taken by its health system patients.

    ‘We urge the FDA to withdraw’ the proposal, the VA wrote the FDA last year. ‘It will not improve drug safety and could very well result in a decline in drug safety.’ Among other things, the VA said, ‘second-rate “studies” published in journals with questionable peer-review processes will be used to convince physicians to use drugs for an ever-increasing number of unapproved uses.’

    Two researchers writing in the Journal of the American Medical Association echoed those comments, saying that medical literature is often the victim of manipulation.”

  2. Last spring when the policy was first proposed. Medscape and The Society of Obstetrics and Gynecology published a white papers on the use of psychotropic drugs in pregnancy. In essence it claimed that there was no problems with atypical antipsychotics nor with Glaxo's lamictal for bipolar disorder.

    In contrast the scientific evidence indicates that atypical antipsychotics and Lilly's Zyprexa in particular cause a phen-fen like cardiac toxicity and that Lamictal causes mental retardation. Even though there have been publications in NEJM and elsewhere that address these concerns. Close examination shows that the study designs were biased. For example Lamictal studies were done before labeling was implemented to use increased doses in pregnancy due to induction of the pathway likely responsible for the terratogenic metabolite. also studies for atypical antipsychotics looked at effects when administered in the first trimester, yet the terratogenic effect or PAH is expected to be due to exposure duering the third trimester.

    It's quite interesting that these FDA policies and these misleading articles came out around the same time as announcements for drugs to treat these orphan indications as well as around the time when a new atypical antipsychotic was expected to be approved, and around when approvals of certain atypicals in combinaton with SSRI's have been approved. (Notice the recent ads for abilify in depression without adequate response to an SSRI.


  3. Wow. I am impressed by the Telegraph's reporting. As you all well know, these issues are rarely covered at all unless a company gets busted for a few bil (going rate), and even then...

    Thanks, Salmon, as well. As has been raised on another thread - and perhaps you have insight - one wonders about the extent to which a new administration _can_ roo out all the stuff that has been done at FDA over the past several years, particularly to the degree that the careerists, assuming they will still be there, have been "co-conspirators."

  4. The focus should not be whether a drug is “on” or “off” label, but is it safe and effective. Benefits, as well as risks, need to be made known.

    To be used off-label, not only should a drug be safe, but known risks must be made clear to the doctor and patient. That is done through testing and the history of its prescribed use.

    The FDA should not be so anxious to help the drug industry in their promotion of drugs. They need to return to their responsibility of safeguarding the health of the American people.

  5. Dianne - I agree with you in principle, but the point of "off-label" is that there has _not_ been significant testing of whatever the risks/benefits of that particular use.

  6. Right, therefore, we should not be so fast to give pharma a wink and a smile when using these guidelines to push their drugs for unlabeled purposes--especially when we know the risks of many labeled drugs have not always been fully disclosed.

    We are not guinea pigs.

  7. Anonymous,

    You are wrong.

    Zyprexa was tested in the elderly prior to it being approved. Paul Leiber turned it down and clearly thought it was unsafe. Just go and read the Summary Basis of Approval. It's right on the FDA's website.

    Merck did the same thing with Singulair. They studied it for exercise induced asthma and when it didn't work they ran ads showing people mountain hiking and swimming.

    Cephalon just got busted for off-label promotion of Nuvigil (armodafinil- R-enantiomer of mofadinil). Whereas Provigil (racemic modafinil) was turned down for ADHD because it had too high a rate of Stevens-Johnson Syndrome and related hypersensitivity reactions in children (~ 20 in 1000 children) probably due to a metabolite (modafinil sulfone) that was 16 fold higher in children than in adults. This was presented at the FDA Advisory Committee in March 2006. Yet FDA didn't do anything about off label promotion until August 17, 2007 when they changed the labeling for modafinil to state in bold letters under WARNINGS

    Modafinil is not approved for use in pediatric patients for any indication.

    Yet 2 months earlier Ar-modafinl (Nuvigil) was approved without this with almost the exact same warnings that it hadn't been studied in children but without this statement, (What happened in between, and why are the warnings statements different?) Wouldn't you expect the same reactions with armodafinil and wouldn't you expect people to potentially use or promote armodafinil off-label for ADHD too?

    Lots of times companies specifically don't study an indication or specific population because they know it won't work or will be unsafe FDA just winks and puts in a statement that it hasn't been studied. So instead the companies will go ahead and promote off-label. Sometimes via key opinion leaders (KOLs).


  8. Great addition, Salmon. Thanks! You bring a critical dimension to our discussions here. It is appreciated!

  9. Rolling Stone magazine has an expose on how Zyprexa ended up being sold to everyone under the sun as a wonder drug. Good follow-up if you're interested.

    You've been talking about drugs here, what is the consensus on devices? If you produce a device that a doctor decides to use for an off-label procedure and screws up - can the company give them advice? If your rep is asked about using biliary stents in peripheral arteries - should they be able to answer the questions? What if the rep knows it is a terrible idea or has had amazing success?

    The reason I ask is because some issues that seem quite straight-forward when discussing drugs are different when discussing devices, yet both industries have to follow the same guidelines. And guidelines are mostly written for pharma with a note that says 'oh, you too, devices.' But with no consideration for how differently the industries work. What do you all think?

  10. Thanks Anonymous. While I am opposed to off-label promotion. I am not opposed to all off-label use.

    For example DDAVP has been used off label in hemophiliacs under going tooth extractions as well as in other potential bleeding situations.

    For many anticancer drugs there are cooperative groups such as the South West Oncology Group (SWOG), Pediatric Oncology Group (POG) and others that conduct studies comparing different combinations of cancer drugs and come up with state of the art recommendations. Even in rare psychiatric and neurologic conditions there are cases where there is nothing else to try.

    However, when you have 1% of all children on antipsychotics (which we know maim permanently and is dose and time related) at $400 - $500 per month as found by reviewing medicaid and private insurance records there's too much risk and insufficient information to allow off-label promotion. If something is this common and makes a ton of money for the companies then they should be adequately studied and reviewed before promotion is allowed.

    One of the problems is that off-label use was primarily the realm of specialists in tertiary care centers when there was nothing else left. Unfortunatley the money from Pharma has resulted in corruption and these Key Opinion Leaders use their positions to create an off-label use when it isn't justified.


  11. Harpy,

    I do not know devices. However I've seen too many drug studies and articles to know that sometimes the actual data is the opposite (negative) of the published conclusions (positive). Data can be spun and manipulated. In addition we know that many times the negative results aren't published or even given to the FDA yet are only found out on discovery. I don't have all the answers but I do know enough to know that off-label promotion will be abused. In fact if you go over to Shearlings got Plowed I will have some comments later tonight about one possible scenario for off-label use.


  12. Good question, Harpy. I vaguely recall a thread on Pharmalot in which material that "facilitates" spinal fusion (which I assume is a "device) was being promoted off-label for cervical (as opposed to lumber) spinal surgeries, but I may not remember that rightly.

    Given the nature of things, it seems that class III devices would be less likely than drugs to be used off-label. What would you use a pacemaker for if not pacemaking? An Ipod? But no doubt there are examples.

  13. Justice, I think membranes would be an example. A product - Seprafilm that is used to reduce adhesions has been used in different forms and is being promoted by Genzyme for use after child birth. They have listed a pending trial for post pregnancy use excluding people allergic to its main ingredient Haleronic Acid. Occasionally you will see that they promote its use for post pregnancy even without the trials having starting.

  14. You remember correctly, Justice. Medtronic is facing lawsuits for off-label use of its Infuse spinal fusion device. It is approved for use in the lumbar vertebrae, but not cervical, and some patients have died from the off-label usage. There have also been complications with the product in the lumbar region using an unapproved insertion technique.

    I asked because my focus is devices and very often they are lumped in with pharma with little consideration of how the industries function.

  15. I investigated off-label use of a few devices a couple years back.

    I admit that I don't remember much about the investigations right off the top of my head but here are some links to a few of the articles:

    March 2007

    Off-Label Stenting For Profit

    Medical Devices - April 2007 Litigation Update (Part I)

    Part II

    May 2007

    Device Makers Profit by Promoting Biliary Stents for Dangerous Unapproved Uses


    Evelyn Pringle

  16. When they give out the Device Outlaw Award, Medtronic seems to be the presumptive nominee....

  17. I used to keep up on Medtronic but haven't since the Supreme Court ruling on devices.




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