Off-Label, Ethics, and Economics

I stumbled across this news article on a law suit about Neurontin the other day and thought it was interesting:

Top drug company marketing executives suppressed a large European study suggesting their blockbuster medication Neurontin was ineffective for chronic nerve pain, and they privately strategized about how to silence a British researcher who wanted to go public with the data, according to newly filed documents and e-mails that are part of a Boston court case.

During the same period of several years, Pfizer Inc. launched an advertising blitz promoting the purportedly positive findings of a smaller Neurontin study it had published in a major medical journal – including showing a video to airline passengers before their in-flight movie.

The widespread promotion of Neurontin turned what had been a relatively minor epilepsy drug into one of the fastest-growing blockbuster drugs in the world, one that generated more than $2 billion a year in US sales for Pfizer before a generic competitor entered the market in 2004.

Taken together, the e-mails and other internal Pfizer documents produced as part of a potential class action lawsuit against the company represent one of the most detailed looks yet at how a drugmaker controls what physicians and consumers know about a drug.

Here’s what struck me about the article: 90% of gabapentin’s (Neurontin’s) sales are for what are called “off-label” use, i.e. for uses other than those for which efficacy has been demonstrated to the FDA. How do physicians know about these off-label uses?

One possibility is by observation. A physician may have observed that some of their patients being treated with a drug for the condition for which the drug has been approved show improvements in other areas. Another possibility is word of mouth, either on the part of other physicians or patients. However, it seems to me the most likely explanation is advertising in the form of studies produced by the pharmaceutical company that produces the drug. It’s possible the studies are distorted, misleading, or selective. As the article cited above suggests, how would they know?

The motivations of the pharmaceutical companies in this regard are obvious: $2 billion is a lot of jack. And a cadre of physicians or patients who believe they’re being helped by something can provide a powerful advocacy arm.

I’m even beginning to wonder about the claims of efficacy that have been accepted by the FDA. Take the example of the only two drugs (to my knowledge) that have beeen approved for use in the treatment of fibromyalgia: pregabalin (Elavil) and duloxetine (Cymbalta). Have any longitudinal studies been done that demonstrated the effectiveness of these drugs over time? I’ve written before about the commonplace experience of patients becoming inured to a drug. A typical reaction by physicians to that is to up the dosage despite the frequent fact that higher dosages of some drugs have never been demonstrated to be effective. Scientific medicine, indeed.

But back to off-label. Can somebody explain to me why off-label use, use in which a drug may not have demonstrated efficacy, is ethical, why it’s not malpractice? I recognize that in oncology, for example, the overwhelming preponderance of drugs are being used off-label. Is that an excuse? Is something always better than nothing? I don’t believe so. Prescribing ineffective drugs moves resources from other, possibly more productive uses.

IMO we need a major revision in the entire system by which drugs come to market. The incentives today are so high, the methods so antiquated, the conflicts of interests so manifest, the resources of the government agencies so limited, and the consequences possibly so severe that change is really overdue.

7 comments… add one
  • PD Shaw Link

    I’ve seen stats that as much as 50% of all drug prescriptions are off-label, but I think that includes using drugs approved for adults on children or modifying dosage.

    Doctors can find out about off-label uses from medical journals and conferences. Some of it is just implicit from knowing how the drug works and the potential assumption that the dangers of the drug are the same, whether for one use or another.

    I don’t think it’s illegal or unethical, as much as there are no laws or ethical standards against it. From a malpractice standpoint, it’s likely going to come down to whether the doctor acted reasonably based upon available knowledge and whether the patient gave informed consent. But the person that is increasingly on the line for off-label uses is the drug manufacturer. The manufacturer cannot directly promote off-label uses, but might sponsor conferences or drug trials, or hand out articles from independent doctors. At some point, the manufacturer knows enough about off-label uses to be expected to issue warnings if it has special knowledge about why something wasn’t approved for another use.

    I believe the economics are that the cost of getting FDA approval of a use are substantial and once gained, there is not much incentive to seek approval of additional uses, particularly if it might gain the financial benefits from doctors anyway or if the alternative use is such a small piece of the market that it would not be worth it.

  • I think the economics of off-label use are somewhat different than that, PD. Once a pharmaceutical company has developed a new drug and had it approved they’ve got a substantial incentive to maximize its use through the entire patent period. When a more effective alternative or one with fewer side effects is developed during the patent period the company is motivated to find other uses for it but not equally motivated to seek FDA approval for those uses. Hence off-label use.

  • PD Shaw Link

    While I think there are extreme examples (90% off-label sales probably counts), I think each situation is going to be different. Imagine a drug manufacturer that knows the drug would not only be effectuive for USE A, but also USE B, but USE B would merely eat into the manufacturer’s profits from another drug. I believe HMOs are major sources of pushing off-label uses for that reason. That would be an example of off-label uses cutting into drug company profits.

  • PD Shaw Link

    BTW/ Dave, here is a short, interesting article on off-label use from some economists who believe that a less-regulated approach comporable to off-label prescritptions would outweigh the costs. I’m not entirely persuaded, but it offers an interesting perspective.

  • Neurontin works. I used it on my patients before it was “approved” because it relieved my patient’s pain.

    It’s not placebo effect: Often we used it on those who were taking huge doses of narcotics and anti depressive medicines, but couldn’t control the pain…so we added neurontin, and they got relief.

    Wait for the FDA? You’re joking. Have you ever hurt? Besides, pain studies are notorious: Except for morphine, nothing “works” better than placebo…so does that mean we shouldn’t use aspirin or tylenol or even Percocette?

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