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Regulatory Affairs

Off-Label Marketing and Free Speech

As is well known, drugs are approved by the FDA for specific uses. These are spelled out in detail on the label, and by label one means “package insert”, and more generally the FDA’s own regulatory language regarding what the drug has been cleared for. Companies spend a great deal of effort to get drug labels extended for new indications, and wrangle with the agency about the exact wording, because “off-label” promotion can lead to billions of dollars worth of fines. And has, several times. Keep in mind that (as in that example) whistleblowers from inside the sales and marketing organization are well-placed to alert the authorities if enough evidence piles up, and there are legal rewards in place for them if they’re successful.

But this entire system has been challenged over the last few years. In late 2012, a federal appeals court actually ruled that the FDA’s restrictions were illegal under the First Amendment, and that off-label promotion was protected commercial speech. This did not lead to a rush by drug companies into such behavior – they have well-paid legal counsel, too, and the advice (one infers) was to wait for the case law to stop bouncing around before making any big decisions. Earlier this summer, though, a company tried to force the issue.

Amarin is a small shop whose big product is a prescription fish-oil capsule, Vascepa. They have been trying for years now to get the FDA to expand their label, so that more physicians will prescribe their product and more insurance plans will pay for it, but the agency has been reluctant. Part of the problem has been that some recent clinical data have suggested that fish oil/omega-3 supplements don’t do as much for cardiovascular health as had been thought, although overall, the effect does seem to be positive. (The whole lipidology/cardiovascular disease relationship is undergoing some rethinking these days, which will be the subject of a different post). Amarin has been wanting to say that “supportive but not conclusive” research has shown that omega-3 supplementation is helpful, but the agency has been worried that this might lead some physicians (and their patients) to conclude that lifestyle changes and/or other therapies might not then be needed.

So Amarin finally sued them, on just the grounds of commercial speech mentioned above. On Friday, the judge agreed with them, granting a preliminary injunction saying that as long as the company is making truthful statements, the FDA doesn’t have the authority to stop them from doing so. His ruling was based on the 2012 decision, so if the eventual court case goes the same way, there would seem to be a pretty solid legal foundation for other companies to start pushing into this territory. That will move the entire relationship between the drug companies and the FDA towards “Are these statements truthful?” rather than the current “Did we tell you that you could say that?”

In theory, those two are already coupled, but not in practice. The scientific consensus keeps changing, and the regulatory agencies are not always known for their speed in these matters. Overall, as long as everyone knows what the rules are, I’m not necessarily upset by such a change. My biggest worry is that the definition of “truthful” might well encompass statements like “A recent study has shown. . .” when that recent study is actually poorly run, underpowered, etc. And there are plenty of those out there. And then there are the sins of omission: would it be truthful to cite a favorable study, but to gloss over the fact that there are equally valid-looking unfavorable ones? (I would say no, you have to refer to the whole landscape, but this is just the sort of thing that may well be fought out if things go in this direction).

And these, to be fair, are just the sorts of reasons that the FDA has traditionally advanced to justify its own regulatory restrictions. But it looks more and more like a new regime is coming, and they (and we) are going to have to get ready for it.

Update: here’s a review of past cases in this area, from Marginal Revolution, where Alex Tabarrok leans more towards the free-speech and less towards the regulatory-authority side.

34 comments on “Off-Label Marketing and Free Speech”

  1. Stu West says:

    I’ve never understood the rationale for granting free expression (a fundamental human right) to a corporation (fundamentally not a human). But clearly I’m just an unsophisticated Old Worlder in this matter.

  2. Am I Lloyd says:

    The point of free speech is to protect individuals from retaliation and oppression. No idea why a billion dollar corporation with armies of lawyers needs that kind of protection.

  3. Derek Lowe says:

    Stu, one response is that corporations are owned by humans, invested in by humans, staffed by humans, and run in such as way as to advance their human interests. But this has been a contentious area of law in the US. In the 1940s, the US Supreme Court first brought up the separate category of “commercial speech”, and a number of decisions since then have turned on that concept. But not everyone agrees that it is one, or (if it is) that it’s entitled to somewhat less protection than “regular” speech, which is where decisions (and regulatory agencies) have tended to take it.

    As for the topic of “corporate personhood”, this has been a big political punching bag in recent years, as I’m sure you aware. But corporations have been treated in this way under US law going back well into the 1800s, starting with their ability to enter into contracts, be sued in court, claim equal protection under the Fourteenth Amendment, and so on. This is not some radical new doctrine – although, from your perspective, it may well be a radical old one.

  4. Small Biotech says:

    I am a free speech person and yes that does apply to corporations and limiting such for corporations could set disastrous consequences. So, how do we proceed here where I think the scientific community would agree that off label advertising is deleterious since the drug is not proven to work there? If the gov cannot limit corporations from marketing such drugs, they can limit physicians’ ability to prescribe drugs off label. I never really understood why physicians had that ability in the first place since it just set up an incentive for corporations to under the table convince doctors to prescribe their drug for other indications. There are good uses to giving physician’s freedom to prescribe off label as in desperate cases or in rare disorders where there are no treatments. Perhaps a finer balance can be struck here at the prescription step which is more observable than the marketing step.

  5. Blabla says:

    So this would make it a constitutional right to sell drugs for applications where there is no safety data, let alone efficacy data? What a great move…..

  6. ClutchChemist says:

    I fear that, as was alluded to, some drug companies will end up resorting to strategies like the people who sell essential oils/detox kits, citing horrible references as truth and leaving the uneducated consumers and/or insurance companies to figure out which treatments are legit. I don’t have a good answer, but it seems like there should be more oversight to drug advertising than simply leaving it in the hands of the companies to do the right thing.

  7. NoDrugsNoJobs says:

    Even with these federal decisions, companies will take a cautious tack, I’m sure. Drug companies are already sued, and frequently, for promoting within their FDA-guidelines. The Courts have repeatedly held that simply following the FDA agreed upon labeled indication and promotion is not sufficient to avoid law suits – so there is always that to deal with.

    Of course corporations need at least some free speech, just like unions, political groups, etc – they are a representative of a group of people’s interests and accordingly earn their seat at the table. However, there are limits and the federal courts have always held laws affecting business speech to an intermediate level of scrutiny rather than the strict scrutiny observed when discussing constitutional rights applied to individuals. Free speech laws are not just about preventing blowback or retaliation but are important that as much information be available as possible – we need more information and not less. Ultimately, Doctors have the drug’s label when they prescribe the drug – they know what is off-label and what is not and they are highly paid, highly trained individuals who we should expect to do what is best for their patient. Beyond this, many of the prescribing decisions occur before the doctor even makes the diagnosis, large insurers as well as public insurers determine what drugs are on what tier and for what indication. A doctor prescribing a drug not approved for that indication presumably would be negating his patient’s ability to get the drug reimbursed.

  8. Sid says:

    This sounds similar to dietary supplement business where marketing is favored over science. This will soon become “cant hurt might help” with prescription drugs and there is a reason why these are regulated

  9. Hap says:

    Having the rights of a person without the responsibilities of one seems like a bad idea, no? With contracts, one can at least argue that the responsibilities of a company and a person are similar – if we don’t live up to them, the penalties are similar. With free speech (in this case, for example), the penalties differ significantly – if I lie and get someone killed, I may very well die (and the responsible parts of me die accordingly), or if I do not, will go to jail for a long time and be unlikely to work in most jobs for the rest of my life. If a company does so (unless the corporate veil is pierced, which can happen but is rare), the company might die (which will mostly nail people who had little to do with the guilty actions) while the responsible parties are unlikely to bear the consequences of their actions. This seems wrong, and seems like a very big temptation for companies to do lucrative wrongs.

    The freedom to sell based on claims that aren’t dishonest seems like a poor place for pharma to make its stand. Considering how well DTC marketing has gone for pharma’s reputation, pharma does not resist temptation well, and giving them a bigger one (with potential lucrative stakes) does not seem like it will end well.

  10. O.W. Holmes says:

    I guess if we can’t shout, “fire” in a movie theatre we should be allowed to shout, “fire could be starting”…no falsehoods there

  11. Bob says:

    How would this situation be any different from what currently exists for dietary supplements?

  12. David Borhani says:

    I think it is important not to miss a key point: What, or rather, who, should be the arbiter of what is “true”?

    Amarin claims that Vascepa has health benefits not listed on the FDA-approved label. Amarin says its free speech is being unconstitutionally encumbered, because it is simply advancing the “truth”, and neither the FDA nor any other governmental agency (or person) should be allowed to stop Amarin from speaking truthfully.

    But what is truth in this situation? Should society unilaterally trust Amarin’s claims? Or should society instead request the presumably unbiased (at least, by promise of commercial gain) FDA to review Amarin’s claimsi.e., dispassionately review the data behind the claimed health benefitsand rule accordingly?

    I believe the latter approach, or some variant thereof, is the better approach. Doing otherwise is, in essence, a rejection of governmental regulation for the public good.

  13. Chrispy says:

    Only being able to market for approved indications is a huge incentive for companies to run follow-on, label expanding trials. If fewer of these are run, there will be less evidence with which to compel insurance companies to pay for “unproven” treatments. Perhaps it is the insurance companies themselves who will demand clinical trial-level proof before paying. This doesn’t even seem all that unreasonable, on the face of it. Or, as Express Scripts demonstrated with Sovaldi, even clinically proven efficacy is insufficient to require the treatment to be covered. We’re rapidly getting to a point where you can sell however you want, and you can prescribe whatever you want, but there is no one to pay for it in the end.

    I think we can all agree that fewer clinical trials would be bad for our business — clinical trials are the best science we do.

  14. John Galt III says:

    I saw in recent months a very interesting point about the meme about yelling fire in a crowded theater. My recollection is that it was posted at a place like Popehat or Volokh. The thrust of the argument was that at least one court had ruled that since the advent of acetate film, asbestos curtains (before those became unpopular) and sprinklers, there no longer was a reason to panic in a crowded theater when someone yells fire. If I can find my notes, I’ll post the link. I love rabid first-amendment libertarians.

  15. Andy II says:

    I hate to say but is it another way of “Out-of-the-Box” thinking for increasing a revenue by MBA’s? As Derek pointed out, the caveat is the definition of “true statement” or a “validity” of the study data that such a statement is based. We were trained not to go into “off-label” promotion by the sponsored company by Legal and Med Affairs. Doctors may use the drug as off-label for patients who don’t have other treatment options and doctors believe it would give them benefits. Sales people may highlight these after the results have been published in a peer reviewed journal. I think it is outrageous to use “Free speech rights to promote an off-label use.

  16. Eric says:

    I have always found it to be somewhat absurd that physicians can prescribe off-label based on ‘experience’. Anecdotal findings from a handful of subjects in an open label study is enough for a physician to prescribe a drug. There is ample evidence that this is a horrible approach. If pharma companies used this as evidence they would be under fire immediately (and rightfully so!). The new ruling makes it seem like this is more of a real possibility moving forward.

    It seems a little ironic, as others have pointed out, that insurance companies may now be the best gate keeper. They have little incentive to pay for a treatment that hasn’t been proven to work, especially if there is a cheaper alternative.

    Most everyone is in agreement that more clinical data from well designed trials is essential. I’m not sure if this ruling helps get us there.

  17. Christophe Verlinde says:

    Do we want to go back to the era of snake-oil salesmen who claimed just about anything? I don’t think so. We need an arbiter who validates each claim and throws out false and marginal ones so that public health is protected. And that is precisely why the FDA was created.

  18. AQR says:

    This is a really terrible idea. I think it is very likely that a study designed to demonstrate efficacy would be underpowered to identify safety issues in that patient population. This negates the possibility of understanding the benefit/risk ratio.

  19. Andy II says:

    How can we demonstrate what you say is “true” in this case? It is the registration trials that the sponsor intended to claim the use of their drug for. FDA will review the data and approve their claim. Right?

  20. John Thacker says:

    Do we want to go back to the era of snake-oil salesmen who claimed just about anything?

    No, but there’s fairly large differences between FDA authority between 1906 and 1938, between 1938 and 1962, and after the Kefauver-Harris Amendments of 1962. The body of the scientific literature clearly suggests that the changes in 1962 have killed far more people than they’ve saved. To put it another way, do we so clearly distrust the work of European regulatory agencies, that we think that they are killing their own citizens (by, among other things, approving sunscreen)?

    Everything said regarding motivations of corporations applies to the FDA and its employees as well. The FDA (and particularly individual FDA employees) face little to no penalty themselves for delaying a drug that would have saved lives; however, it faces intense criticism and penalty for letting through a drug that causes harm. Therefore, Hap’s argument implies a very big temptation for the FDA to reject more drugs than it should and stretch out the drug approval time. It is difficult to believe that the FDA is purely dispassionate or rational in its decisions. Even allowing a defense for truth here would hardly immunize companies from lawsuits, just as currently FDA approval for safety and efficacy does not immunize companies from lawsuits.

    There certainly are many off-label prescriptions that lack scientific support or have only weak support. But there are also off-label prescriptions where the scientific support is strong, to the point where it is downright malpractice if a physician does not consider it. (The use of antibiotics for stomach ulcers was this way for a number of years.) There are harms on both sides of the equation.

  21. crni says:

    Off label marketing and off-label use are two different things. Physicians do and should have the option of prescribing off-label drugs. A typical example I have encountered recently is Misoprostol (Cytotec) used for initiating birth. No company bothered to do the clinical study for this use, probably because getting enough pregnant women to participate is a nightmare. So it’s either that, or some vaginal creme which does have the necessary paperwork. But if you use the creme, you can’t walk around for fear of the stuff leaking out and not being active. Since the original drug is safe, many women pick the pill over the creme. At least in Germany, the insurance foots the bill if you sign the consent form.

  22. Roy says:

    Both what is considered ‘truth’ and ‘off label promotion’ are vague. If a company runs a trial which shows efficacy of a drug in an indication other than label, (e.g. trazadone for insomnia) and gets that published in a peer review journal, why shouldn’t a sales rep be able to drop off reprints to doctors? At my old company, that would have been considered off-label promotion and my guess is that this is what the FDA told the company.

  23. I shake my head that the US says:

    I continue to be absolutely baffled by the free-speech absolutists in the US. In so many areas of life, be it medical, social, teaching, etc., we (educated, intelligent people) look around, study, evaluate and gather best practices. When it comes to free speech the US is an abject failure. Yes, limiting free speech is a slippery slope. But step outside the bubble of your own nation (I’m Canadian and I’ve lived in Europe for several years) and every other Western nation has limits on free speech that curtail the shenanigans of snake-oil salesmen far better than the US does. Moreover, they have not degenerated into a police state or one where citizens feel unable to speak. In fact, when it comes to advanced economies and health societies, the US is clearly the country with the most social struggles (crime, violence, debt, poverty…) so it truly is time to take not only a good look in the mirror but also a look around to see how it can be done better.
    The truth is that the US consumes more medication per capita than any other nation on Earth (source: WHO). Per capita the US spends more money on health care than any other nation on Earth. In fact, it spends 50% more than second place. (Source: OECD and WHO). The US has the lowest life expectancy of any of the G7 countries and is tied for 34th globally (WHO). Is it really a good idea to allow for more liberal consumption of pharmaceuticals?
    To those who stated that this is what’s already done with nutraceuticals and dietary supplements, I ask what makes you think that the status quo in that area is a good thing? I don’t. Yes, regulation costs money. But you are currently shelling out absurd amounts for health care. More regulation will, if done properly, lead to decreased health care costs. And if you are a fiscal conservative that truly is the bottom line. If you doubt me about the cost/benefit analysis, look around the globe at best practices. Everyone else has more regulation, more limited freedom of “speech” (which is really “freedom to advertise”) and yet they spend less and live longer.
    I have clearly digressed from the original topic but my point is that this issue is symptomatic of a much broader problem in the US.

  24. flem says:

    Freedom is never absolute. One person’s freedom end when it encroaches over someone else’s freedom. Oneone watching TV commercials can observe that companies are largely free to lie to propective consumers. However you must draw limits to that freedom to decieve when it comes to precription drugs. Unlike other consumer products, inappropriate use of these have serious consequences. Prescribing, dispensing, and paying for these products is limited to professional 3rd party decisionmakers. The “truthiness” of claims for these products should also be limited to professionals such as the FDA otherwise how do we draw the line between precfiption drugs and snakeoil

  25. gippgig says:

    What if a drug was marketed by an individual rather than a corporation?
    Oversight is a good idea, but who is qualified to exercise it? I don’t think governments are. Consumer groups (Consumer Reports)? Public interest organizations? Insurance companies? Same thing for deciding whether a statement is true.

  26. Shion Arita says:

    @I shake my head that the US:

    I understand your point, but with respect to the US’s relatively lower life expectancy compared to its world prominence and high healthcare expenditures, correlation doesn’t imply causation.

    However it is evident that something is amiss when more medication and higher expenditures don’t translate into longer lifespans. I do think however, that the US’s bad performance in life expectancy is mostly caused by obesity and poor diet.

    I’ve never found good numbers for this, but I’d very much like to see values of life expectancy corrected for obesity and smoking.

  27. Kelvin says:

    Perhaps the FDA should also have free speech and be entitled to write “NOT APPROVED for XYZ”, right next to where the company claims that there is “some supportive evidence for XYZ”?

  28. gippgig says:

    “Unlike other consumer products, inappropriate use of these have serious consequences.” Unlike other consumer products?

  29. Hap says:

    Obesity might explain life expectancy, but I don’t think it helps explain our infant mortality rate.

  30. regdoug says:

    I’d like to add another tidbit about off-label use:

    My parents are veterinarians, and will sometimes prescribe medications off-label because they haven’t been indicated for the species in question. Many times this is simply because the drug hasn’t been studied for that particular species. As @crni says, medical professionals have training that should allow them to determine when off-label use is appropriate and when it is not.

  31. Anonymous BMS Researcher says:

    I like the bumper sticker “I’ll believe corporations are people when Texas executes one.”

  32. Sam Adams the Dog says:

    Here’s a late-breaking analysis of how the freedom-of-speech issue might affect expected FDA regulation of e-Cigarettes:

    (Full disclosure: the author is the little cousin of my human counterpart.)

  33. One who knows more than he should says:

    Maybe I’m late to the game here, but physicians are paid (quite a lot, actually) to sort out the wheat from the chaff of pharmaceutical claims. The patient wants to get better, and the ethical physician puts that first. No stone should be left unturned in the quest to alleviate suffering from illness, correct? To answer someone’s comment above, this is why the FDA or anyone else at the federal level can regulate physician prescribing–physicians are licensed by the state, not the federal government, among other things.

    Both the FDA and pharma are being very paternalistic here. The FDA thinks that they think these poor ignorant MDs don’t have a brain cell among them, and pharma can just steamroll them into prescribing anything they want with some free meals and pens, and they need their betters (obviously the FDA, or better yet, guys like Jerry Avorn of Harvard in this week’s NEJM) to tell them what is truth. Pharma also thinks that MDs are just a bunch of neanderthal yo-yos as well, and will respond to slick advertising and good looking pharma reps with more prescriptions.

    Both are wrong, and that is the nugget of the solution here. Physicians should be constantly reminded to be true to their ethics–which is to treat their patients to the best of their ability at all times. This is in the Hippocratic Oath, after all. “The best of their ability” includes the determination of what they think is the best course of treatment, judging their individual interpretation of the state of the clinical science.

    The FDA is committing a First Amendment crime by denying the dissemination of truthful medical information to physicians to help make their decisions, and this judge rightly called them out on it. Suppressing speech of any kind requires an absolutely compelling governmental interest, and suppression of speech that is considered to be truthful requires the strictest scrutiny of all by the courts. There is no compelling interest strong enough in the mandate of the FDA as defined by the Food and Drug Cosmetic Act of 1962 and its amendments that requires them to suppress truthful speech by anyone.

    There is a new wind blowing. It’s about time.

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