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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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December 5, 2012

Off-Label Promotion Is Legal, You Say?

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Posted by Derek

You'll have seen the headlines about off-label promotion of drugs by pharma companies. No, not the ones that decry it as a shady marketing technique, punishable by huge fines. I mean the ones about how a federal court has ruled that it's completely legal.

This came as a surprise, at least to me. The U. S. Court of Appeals, in United States v. Caronia ruled explicitly that "government cannot prosecute pharmaceutical manufacturers and their representatives under the (Food, Drug and Cosmetic Act) for speech promoting the lawful, off-label use of an FDA-approved drug." That does go up against the previous belief that if it's off-label, it isn't lawful. So how did the court get here, and what happens next?

The case concerns Alfred Caronia, a sales rep for Orphan Medical, who was prosecuted for off-label promotion of Xyrem (the sodium salt of gamma-hydroxybutyrate, GHB) in 2005. (The company has since been acquired by Jazz Pharmaceuticals of Dublin). He appealed his conviction on First Amendment grounds, and this argument seems to have rung the bell with the appeals court. Here's a writeup at the FDA Law Blog:

The Court explained that FDA’s construction of the FDCA legalizes the outcome of off-label use by doctors, but “prohibits the free flow of information that would inform that outcome.” The Second Circuit concluded that “the government’s prohibition of off-label promotion by pharmaceutical manufacturers ‘provides only ineffective or remote support for the government’s purpose.’”

There's some case law that backs up this decision, namely Sorrell v. IMS Health Inc.. The Supreme Court decision, for those of you who are truly hard-core about this stuff, is here. In that one, the court found that a Vermont law that restricted physicians from selling information on their prescription history violated the First Amendment as well. From this earlier post at the FDA Law Blog, it appears that a lot of the maneuvering during this latest case was about whether Sorrell applied here or not. That post also makes it clear that the FDA's own statements on the legality of off-label promotion are, to put it gently, unclear.

Well, this ruling certainly clears it up. For now. Here's the 82-page decision itself, with a vigorous dissent from the third judge on the appellate panel. But I can tell you that I'm not reading it yet. That's because I expect the FDA to try to take this to the Supreme Court, and it looks (to my non-lawyer eyes) like just the sort of thing they'd grant certiorari to. So I don't think this story is done - but for now, off-label promotion cannot be prosecuted.

And that's a big change indeed. This whole issue has been a black eye for the industry over the years, because (for one thing) the FDA made it clear, over and over, that it believed the practice was illegal, and that companies (and individuals) could be prosecuted for it. In that atmosphere, a company that went ahead was doing so in knowing violation of the rules as they were understood. No drug company, as far as I know, ever tried to make a First Amendment court case out of an FDA fine for off-label promotion (if anyone knows of any examples, send 'em along). Instead, they argued about whether it had happened or not, how much of it there really was, then paid the whacking fines, and then (likely as not) went out and did it some more. And they did it not because they were free-speech activists, but because that's where a lot of big money was to be found. Not the sort of thing that covers you with glory, for sure.

So it's not like this latest ruling is going to rehabilitate many reputations in the marketing departments. It's more like "Great! Turns out to be legal after all! Who knew?"

Comments (28) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | Why Everyone Loves Us


1. petros on December 5, 2012 9:06 AM writes...

Given the massive fines incurred recently by major pharma for such promotion this will surely be appealed by the FDA

It also seems to make the role of the FDA questionable

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2. will on December 5, 2012 9:26 AM writes...

An interesting side note from the patent the law stands now, if a brand company has a patent on an off-label use, a generic company cannot (indirectly) infringe that patent by selling an equivalent, because the generic is statutorily prohibited from telling physicians to use the drug in a manner that infringes the off-label patent. if off label marketing is back on the table, then presumably generics could be on hook for those patents as well. the upshot being that the brand would have an easier time prolonging their monopoly, since it's a lot easier to get a patent on an off label use than it is to actually get fda-approval for the new use

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3. luysii on December 5, 2012 9:34 AM writes...

Well, labeling isn't always accurate. Three examples from the remote past.

#1: At one time valium (diazepam) was contraindicated in status epilepticus (continuous seizures without regaining consciousness) due to a respiratory arrest occuring with its use. It said so right on the package insert. Later valium became one of the first line drugs for the condition.

#2 The use of beta-adrenergic blockers for the prevention (prophylaxis) of migraine only became apparent because patients receiving it for other indications told their docs that their migraines had become less frequent.

#3. At the same time back then beta-adrenergic blockers were contraindicated in congestive heart failure (again the package insert said so). Subsequently, they became part of the therapy of CHF.

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4. Anonymous on December 5, 2012 9:42 AM writes...

(And we all know that corporations are people, too, and they have a right to free speech or unlimited political spending.)

So why shouldn't we be able say whatever we want and call it free speech? Let's fudge these numbers reported in a clinical trial and call it free speech.

Where does it end? It's a very slippery slope, indeed!

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5. Chemist turned Hedgie on December 5, 2012 10:02 AM writes...

#2 will,

I think you are half right- you can't sue for infringement of off-label use patents, but that has nothing to do with prohibition of off-label promotion. See Warner-Lambert Company v. Apotex Corp., 316 F. 3d 1348 (Fed. Cir. 2003). The CAFC held that it is not an act of infringement under 35 U.S.C. §271(e)(2)(A) to submit an ANDA for approval to market a drug for a use when neither the drug nor that use is covered by an existing patent, and the patent at issue is for a use not approved under the NDA.

I agree with Derek- this has to end up with the Supremes, or an enormous can of worms has just been opened. Please sir, can I have my massive fine back?

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6. NoDrugsNoJobs on December 5, 2012 10:03 AM writes...

#4 I think there is a long precedent of SCT decisions regarding the extent of free speech that corporations are allowed and it is intermediate in scope - not as much as an individual but still a recognized constitutional right. Just because the line is difficult to draw shouldn't mean we don't try to strike a balance. Most behavior is on a slippery slope and there are still multiples ways of checking deceptive practices. For example, your idea that recognizing free speech would allow for fudging data is well-recognized as fraud and is established to be outside the free speech protections already.

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7. will on December 5, 2012 10:12 AM writes...

hedgie - you have cited the correct case, but the logic behind it was that because generics (and brands for that matter) are prohibited from promoting off-label uses, generic cannot be liable for indirect infringement via inducement of an off label patent, since they are statutorily prohibited from instructing physicians (via their label or other means) to use their product in an off-label manner. if that prohibition goes away, then the question of whether a generic has induced infringement becomes a question of fact, and not of law.

in the limited context of ANDA litigation, the off label patent may not be listable in the orange book, but that won't stop a brand from suing a generic after launch

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8. Tim on December 5, 2012 11:04 AM writes...

When I first saw news of this yesterday, my immediate response was "This won't last long". The ruling contradicts long standing business practice and regulatory environment. It's hard to see how this will be upheld in a higher court.

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9. Chemjobber on December 5, 2012 11:09 AM writes...

Chemist Turned Hedgie: it sounds like you have an interesting job. Willing to talk about it? E-mail me at chemjobber -at- gmaildotcom.

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10. John on December 5, 2012 11:48 AM writes...

Watch some of these companies try to have their cake and eat it too: In the UK recently (I can't remember the exact details) a pharma company has been trying to prevent doctors from off-label prescribing a much cheaper alternative (which they also own) to one of their very expensive macular degeneration drugs. They have deliberately chosen not to apply for a licence for their cheaper drug to treat AMD as they know it would cut off their cash cow.

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11. FormerEpileptic on December 5, 2012 1:08 PM writes...

@luysil: As an individual who has had an ADR to diazepam (or some sort of benzo) in status epilepticus, this is news to me. Follow-up was dismal at the time, and I still have no idea whether I tolerate the stuff in general or not. Benzos being first-line in several critical conditions where I may not be able to give consent, I would appreciate it much if you could give me some references on this (are there any particularly vulnerable groups? why was the warning withdrawn?). Thanks!

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12. Sigivald on December 5, 2012 2:02 PM writes...

Is it just me, or was the status quo before this, summarized as "it's perfectly legal but you can't tell anyone [but doctors] about it" completely stupid, even by Government standards?

(Also, Anonymous said: So why shouldn't we be able say whatever we want and call it free speech? Let's fudge these numbers reported in a clinical trial and call it free speech.

Because fraud has never been protected by "free speech"?

Also, what does that entire line of argument have to do with the ability to promote a use that is medically recognized?

I'm not seeing the slippery slope you were worried about, between "true but not approved by the FDA under one interpretation of the statute" and "simply making up falsehoods".)

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13. Jim on December 5, 2012 2:23 PM writes...

@12: I agree that fraud is nowhere near the slippery slope that may lie ahead, but one thing to think about is whether it leads to off-label DTC advertising.

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14. gippgig on December 5, 2012 2:29 PM writes...

Isn't there a line in the FDCA that flatly states that nothing in the law restricts informing either the general public or the medical community about a drug?
I recall reading once (maybe around a decade ago???) about a court decision ruling on free speech grounds that the FDA could not prohibit drug companies from distributing copies of scientific journal articles about off-label uses to doctors.

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15. sympa on December 5, 2012 3:24 PM writes...

Lok at the price of that Xyrem... basically GHB. Wikipedia's $2,333.20 per 180 mL bottle, which would be 90 grams of GHB.

In the Netherlands this is a still whopping 410 euro.

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16. Addi on December 5, 2012 3:45 PM writes...

From reading the abstracts and opinions, Caronia was a sales rep promoting GHB, the "date rape drug", in all sorts of indications where it's not been approved by FDA or even tested in large, randomized clinical trials. Caronia's income was based on his ability to increase prescribing of GHB. There's a transcript of him saying directly that GHB could be used in fibromyalgia, in restless legs, and sleep disorders. He calls it a "very safe drug" and suggests using it in children. He's a slimeball snake-oil salesman who would say or do anything to increase prescriptions of GHB.

Before we start talking about lofty ideas like "truth," the First Amendment and "Free Speech" let's go back to the facts of the case and examine the practices that are being defended. Is it a good idea to let drug salesmen say anything to get a physician to prescribe a drug? Do we, as patients, want prescriptions for drugs when there is little to no evidence that the drug works and won't cause unnecessary harm? Do we want our doctors to learn about drugs from dubious salesmen who can say or do anything to increase prescriptions (and their pocketbooks)?

Of course, the drug companies want their salespeople to be able to say and do anything to increase prescriptions. However, I think its disgusting that we are letting the drug companies hide their shady marketing practices behind the pillar of "Free speech." In this appeal, the drug companies (via Caronia) are asking the court to give them permission to lie to doctors and patients. I disagree with that.

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17. Jim on December 5, 2012 4:17 PM writes...

I don't think anyone's interest is really served by letting an employee (rep) "lie" to a physician. But if we take some of the emotion out of the discussion, we can see the original intent of the FDAC. It is intended to protect the public interests by preventing dubious claims. Now, in order to prevent such claims, you have to define what "facts" are. In this regard, a fact is something that has been established through rigorous clinical trials as determined by an FDA panel. I personally don't think that that is an unreasonable bar. If fraud is making misstatements, then this is designed to prevent fraud by clarifying what statements are definitely NOT fraudulent.

Pharmaceutical companies have many ways in which employees (namely medical science liaisons) can have discussions with physicians regarding scientific findings that represent off-label uses.

So when is making a statement that "drug A cures cancer...just let me show you a case study" analogous to shouting "fire" in a crowded movie theater?

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18. Owen Hughes on December 5, 2012 6:21 PM writes...

I'm surprised by the comments that assume drug reps lie to doctors. That's a great way to lose an account, get fired and, probably, prosecuted. But never mind that: whatever happened to the idea that the doctor is --wait for it-- a highly trained medical professional, skeptical of claims made by a rep (whose interest is, obviously, to encourage use of his or her company's products), sworn to put patients first, with a wealth of clinical experience against which to test what he or she is told. The FDA seems to think that doctors are hothouse flowers who cannot survive exposure to any information not in the label. I wonder.

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19. monochromatic on December 6, 2012 12:54 AM writes...

> but for now, off-label promotion cannot be prosecuted

Well, at least in the three states within the Second Circuit's jurisdiction...

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20. FDA reviewer on December 6, 2012 7:51 AM writes...

A thought. This actually could be perversely bad for pharma:

We FDA reviewers operate on risk-benefit analysis of a drug for an indication and intended population. If labeling is now unenforceable, I see myself wanting to ask for everything before the NDA stage, thereby guaranteeing that all potential populations will be evaluated BEFORE marketing to ensure safety and efficacy for all future indications.

This decision essentially undermines the negotiated goals of PDUFA 1-5 and may severely impact lifecycle management.

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21. tocket on December 6, 2012 10:42 AM writes...

Maybe I'm missing something here, but isn't it the clinical trial that makes the difference between knowing that a drug works and thinking (or worse - pretending) that a drug works against a certain condition? It may sound like a small difference but, at least to me, a person promoting this drug is either an honest man or a quack depending on that clinical trial. Is this the kind of stuff that the marketing division in pharmaceutical companies does? In that case I suggest that the money is better spent actually getting the drug approved for that use.

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22. Addi on December 6, 2012 11:01 AM writes...

Jim - You definitely are getting to the heart of the matter. There's a difference between the types of "truthful" statements made in commercial speech that are protected by the First Amendment, and statements that have been vetted by FDA to accurately reflect the efficacy and safety of a drug. FDA has set a higher standard for "truth" in promotional claims for prescription drugs (e.g. need for fair balance, and need for substantial evidence to substantiate) and the courts are unwilling to support that evaluation of "truth" as applied to first amendment protection for commercial speech of pharmaceutical companies.

Owen - When it comes to processing promotional information for (new branded) drugs, and persuasive communication from drug reps, docs are just as susceptible to persuasion and cognitive biases as are consumers. Additionally, doctors get inducements to prescribe (banned by some medical school and clinics) like free cheap gifts, free meals, honoraria and speakers panels. There's a great piece from PLoS Med describing the techniques used by one sales rep: While I agree with you that docs are not "hothouse flowers" they are _extraordinarily_ busy people who may not have the time (or energy) to independently evaluate the evidence for every new drug.

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23. zandperl on December 6, 2012 11:13 AM writes...

I think the off-label usage of drugs is important for exploring the properties and benefits of said drugs. For example, one of the most effective treatments for hidradenitis suppurativa (HS for short, for info) right now is off-label usage of TNF-alpha blocking drugs for psoriasis and rheumatoid arthritis such as Humira, Enbrel, and Remicade. I'm not saying TNF-alpha blockers are appropriate for all HS patients, nor am I saying those of us who do try them should be on them for life, but doctors and patients who know about this possibility have more options for treatments to try.

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24. Drugwonk on December 6, 2012 12:10 PM writes...

Actually, Allergan sued the FDA on free-speech grounds over off-label promotion of Botox -- a suit later dropped.

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25. Xplodyncow on December 6, 2012 8:22 PM writes...

prohibits the free flow of information that would inform [the outcome of off-label use]

False. Although reps could not discuss off-label uses, they could put a physician in touch with their company's medical department for more information.

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26. petros on December 7, 2012 2:48 AM writes...

And Intermune want to abuse the first amendment to justify claims about clinical trial outcomes

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27. John Thacker on December 7, 2012 9:25 PM writes...

It has always struck me as strange that companies have been gone after for making entirely truthful claims about real pharmaceuticals, but you can make up all kinds of vague crap about snake oil, so long as you don't claim that it's a real drug.

Sober, realistic evaluations of the FDA process all agree that it is killing more people than it's saving through its excessive strictness. But people favor it in exactly the same way that they favor expensive and useless airport security.

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28. Nile on December 11, 2012 3:29 AM writes...

I remember a cautionary remark from a paediatrician:

"Everything we prescribe - everything! - is off-label. Nobody does clinical trials for our patients: no-one want the headline 'experiments on children' and no-one sees a profit in it."

On the other hand, his hospital (or healthcare trust, as we now say) keeps exhaustive case records, indexed and accessible, the clinicians always compare notes; and, of necessity, they take the time to evaluate new pharmaceuticals and new uses in a way than general practitioners cannot afford the time to.

And I guess that last sentence encapsulates the point: specialists can and do make detailed study and assessments in their prescribing decisions - and generalists have too wide a field to cover, and very little time, and no administrative and analytical resources, for that to be remotely feasible.

My contact's other point was carefully-worded: "Reps are… (pause) Unhelpful".

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