Thursday, February 28, 2008

Developments In Off-Label Promotion And The First Amendment

A little over a week ago (in other words, an eternity in the blogosphere), the FDA announced new draft guidelines that slightly relaxed some aspects of the Agency's prohibitions concerning promotion of off-label uses by manufacturers of FDA-regulated products. See 73 Fed. Reg. 9342 (FDA Feb. 20, 2008). The draft guidance itself is available here.

We were busy at the time – Riegel, after all, was decided later the same day. Then there was the oral argument in Warner Lambert v. Kent. Oh yeah, and we had real work too.

Anyway, as a result we’re ended up rather behind the curve on this particular issue. It’s been covered in the New York Times, the Wall Street Journal (twice), FDA news, Pharmalot, PharmTech, PharmExec, MedicalDeviceLink, DrugTopics, Shalhoub, MedicalNewsToday, NCPA, HospitalBuyer, PharmaceuticalOnline, HealthNewsDigest, ClinicalTrials, the Mass Torts LawProfessors, and lots of others.

Predictably - almost reflexively - Public Citizen and the ususal suspects in Congress jumped all over the FDA for this allegedly significant loosening the rules about off-label promotion. Bloomberg provided a comprehensive report on the criticism. Pharmalot also covered these dissenters. Public Citizen took the oh-so nuanced position that “People will die if they are getting drugs that don’t have clear evidence that the benefits outweigh the risks.” The reaction of Rep. Henry Waxman (D-CA) is reported in several places as commenting that the FDA’s proposed rule “caters to the industry’s desire to market their products without adequate testing or review,” as commenting that the FDA is creating a “large loophole,” and as hinting darkly at industry collusion with the FDA. Other critiques couched in greater or lesser hyperbole can be found here, here, here, and here.

So what can we belated latecomers add?

Before we answer that, we want to be quite frank about our positions on off-label use and manufacturer promotion of it. As far as off-label use itself, we’re unabashedly for it, and we’ve said so before. While there are, of course, risks to using drugs and medical devices in ways that have not been subjected to the rigors of the FDA’s approval processes (just as there are risks to using drugs for their approved uses), there are also huge benefits. Medical science moves much faster than FDA regulatory evaluation, so cutting edge medical advances are almost by definition off-label – in other words, off-label use is frequently the recognized medical standard of care. Also there are many relatively rare medical conditions that have no on-label treatments at all because economics unfortunately doesn’t justify the expense of clinical trials (one of us has a close family member with just such a condition). Nor with the rise of the generic industry is there any incentive for manufacturers to spend the money to get FDA approval for new uses of drugs that are, or soon will be, off-patent.

As far as off-label promotion is concerned, we recognize that it’s illegal. That being said, we’ve always believed (and have been on record since 1998) that the FDA’s extensive prohibitions against manufacturers being able to publicize beneficial off-label uses of their products is detrimental to the public health. Doctors engage in off-label use because, in their medical judgment, the benefits of a particular off-label use outweigh the risks for individual patients. We think doctors are more competent than both regulators and lawyers to make those decisions.

Thus we believe that doctors should have more, rather than less, truthful information so they can best make what can be very difficult judgment calls. We don’t think it’s beneficial to put obstacles in the way of doctors being able to get accurate information about off-label uses. Further, we think that manufacturers are a logical source for this kind of information, since the whole point of the FDA’s post-marketing reporting regime is to ensure that manufacturers know more about their drugs and devices than anybody else.

As the Supreme Court has held, “The First Amendment directs us to be especially skeptical of regulations that seek to keep people in the dark for what the government perceives to be their own good.” 44 Liquormart, Inc. v. Rhode Island, 517 U.S. 484, 503 (1996). Thus, it’s our position – and we disagree with the FDA on this – that off-label promotion is constitutionally protected speech, as long as: (1) the information being disseminated is truthful (we cannot emphasize “truthful” enough), and (2) is identified as involving an off-label (and thus to some extent less-than-fully vetted) use. Again, we’ve gone on record before taking this position, so none of this will come as any surprise to longtime readers of this blog.

Our take: the FDA's proposed guidance is a baby step; and the “controversy” about it is much ado about very little. The FDA is not giving up anything that the courts wouldn’t eventually take from the Agency anyway. To avoid an adverse ruling on the First Amendment in 2000, see Washington Legal Foundation v. Henney, 202 F.3d 331 (D.C. Cir. 2000), the FDA was forced to agree to a “safe harbor” for reprints, which it formalized at 65 Fed. Reg. 14286 (FDA Mar. 16, 2000). Now, the Agency recognizes that truthful off-label information is of distinct benefit to doctors, patients, and society:

FDA does, however, recognize the important public policy reasons for allowing manufacturers to disseminate truthful and non-misleading [medical and scientific information] on unapproved uses of approved drugs and. . .medical devices to healthcare professionals and healthcare entities. Once a drug or medical device has been approved or cleared by FDA, generally healthcare professionals may lawfully use or prescribe that product for uses or treatment regimens that are not included in the product’s approved labeling. . . . These off-label uses or treatment regimens may be important and may even constitute a medically recognized standard of care. Accordingly, the public health may be advanced by healthcare professionals’ receipt of [medical and scientific information] on unapproved or new uses of approved or cleared medical products that are truthful and not misleading.
FDA Draft Guidance at 3-4 (emphasis added).

Lost in all the brouhaha is how limited the FDA’s relaxation of off-label promotion restrictions really is. The Agency has not given a green light to all off-label promotion – or even to all truthful off-label promotion, with stringent truthfulness criteria (our preferred position). The relaxation is limited to one thing and one thing only, reprints of “medical journal articles and scientific or medical reference publications” (that is, articles that appear in independent medical journals and in medical textbooks) or what the FDA calls “medical and scientific information” in its draft guidance. That’s it. There’s no FDA go-ahead for anything that a manufacturer itself might put together, however accurate it might be.

And even with respect to this limited category already consisting of inherently the most reputable sources, the FDA has added still more layers of restrictions:
  • The editorial board of the publishing organization must select articles on “objective” criteria.

  • The editorial board of the publishing organization must use “independent” peer review, and that peer review process must in fact have been followed with respect to the article in question.

  • The publishing organization must require “full disclosure of any conflict of interest or biases.”

  • The article in question must be from the ordinary publication, and not from any “special supplement.”

  • The publication of the article must not be specially funded by the manufacturer.

  • If it’s a textbook, it must be generally sold in stores and other places that medical textbooks are normally distributed.

  • The article can’t be “written, edited, excerpted, or published specifically for, or at the request of, a. . .manufacturer.”

  • Not only the author, but any editors as well, must not have “financial relationship[s] with the manufacturer.”

  • The article in question must solely “address adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training and experience.”

  • The article in question cannot be “false or misleading” (that’s an FDA term of art).

  • The article in question cannot be “inconsistent with the weight of credible evidence derived from adequate and well-controlled clinical investigations.”

  • The article in question cannot be “withdrawn by the journal or disclaimed by the author.”

  • The article in question cannot “discuss[] a clinical investigation where FDA has previously informed the company that the clinical investigation is not adequate and well-controlled.”

  • The article in question cannot “pose a significant risk to the public health.”

  • The article in question cannot be a letter to the editor, a publication abstract, involve a Phase I (very preliminary) clinical trial, or “contain little or no substantive discussion of the relevant investigation or data” – all because such sources are not likely to be reliable.

  • The article in question must be distributed in “unabridged” (that is, nothing can be left out) form.

  • The article in question must “not be marked, highlighted, summarized, or characterized by the manufacturer.”

  • The article in question must “be accompanied by the approved labeling for the drug or medical device.”

  • The article in question must “be accompanied by a comprehensive bibliography “of other published material about the product.

  • If the conclusions of the article in question have been “called into question” by other published sources, copies of those conflicting sources must also be included.

  • The article in question cannot be accompanied by other “information that is promotional in nature” – meaning that it can’t be distributed as part of a sales pitch by a sales representative.

  • The article in question must be “accompanied” by a bunch of disclaimers that disclose: (1) that it discusses an off-label use, (2) that it’s being distributed by somebody with a financial “interest” in the product being, (3) any financial ties to the authors of the article (this is in addition to the financial disclosure rules of the journal itself, discussed above), (4) anybody who did provide funding for the article, even if not related to the manufacturer, and (5) any safety risks of the off-label use that aren’t mentioned in the article.
FDA Draft Guidance at 4-6.

This kind of thing isn’t new. Congress itself authorized companies to distribute this type of material in part of some 1997 legislation (FDAMA §401) that sunseted in September, 2006. But the statutory exception never worked very well, because Congress included an onerous precondition that, in order to distribute such reprints, the manufacturer had to agree to undertake expensive (costing millions of dollars) clinical trials within three years. Almost all the time, that just wasn’t worth it, so the exception wasn’t ever used very much.

All of this leads us to ask, have the critics of the FDA’s proposal even read it?

At the outset we’re talking about the most facially reliable information that there is – independently published scientific articles and medical textbooks. The FDA has surrounded even that information with a forest of restrictions designed to prevent even the possibility of either scientific shenanigans or overreaching by the manufacturer. On top of all that, the articles must be accompanied both by contrary information (if there is any) and by extensive disclaimers.

So what’s the great harm here? We just don’t see it.

Also, is distribution of this type of truthful information under these restrictive conditions something that anybody really thinks the FDA could legally prohibit under the First Amendment?

We rather suspect that the FDA’s critics here are driven by political rather than scientific agendas. They’ve demonized the industry so much in their own minds that they’ve lost all objectivity. Can somebody tell us, please, how dissemination of published peer-reviewed scientific articles or textbooks under these restrictive conditions is likely to mislead anybody?

Put it another way. Would the FDA’s critics be willing to accept the same restrictions that the FDA is imposing here with respect to medical claims made in attorney advertising?

We didn’t think so.

That’s point one.

Point two is the First Amendment.

Does either the FDA or its critics really believe that public dissemination of truthful medical information, with all these safeguards imposed by the FDA (and given the FDA’s statement of policy), can be prohibited consistently with the First Amendment?

This accuracy of this information is far more assured than the liquor and casino ads that the Supreme Court has found constitutionally protected from governmental bans in 44 Liquormart and Greater New Orleans Broadcasting Ass’n v. United States, 527 U.S. 173 (1999). Indeed, the accuracy of this information is far better protected than the pharmacy compounding advertisements that the FDA was told it could not constitutionally prohibit in Thompson v. Western States Medical Center, 535 U.S. 357 (2002).

We’re tempted to say to the FDA’s critics “Go ahead, make my day.” That is, if you defeat the FDA’s proposal, fine. The legal prohibitions the critics wish to retain would provide just about the best test case possible for a full-blown First Amendment challenge to FDA restrictions on truthful promotion of off-label use generally. Maybe such a First Amendment challenge could even be raised through an administrative appeal of the fate of this proposal (we leave that to the administrative law types out there – which we aren’t – to parse through).

And a very recent legal event that one of us was involved with only cements our view.

Yesterday the Seventh Circuit addressed a First Amendment challenge to a government prosecution for off-label promotion on really bad facts – light years away from the FDA’s proposal – in Caputo v. United States, copy available here. As we mentioned before, Bexis filed an amicus brief on First Amendment issues for the Washington Legal Foundation in Caputo, due to the trial court’s adverse ruling on the First Amendment. Bexis was attempting, quite frankly, to limit the damage to the industry’s First Amendment arguments that an off-label promotion test case chosen by the FDA might have. In that he was successful.

How bad were the facts in Caputo for a First Amendment challenge? Well, here’s how the court described them:

[Defendant company] submitted the small [device] for approval. . . . It also submitted only those tests that favored the device’s effectiveness; others, less helpful. . .were concealed. . . . [Defendant company] understood that [it] would never be able to sell a single unit of the small [device] for the limited use approved by the FDA, [and]. . . did not try. Instead [all defendants] immediately began promoting the large [device] as a replacement for [other] devices, and thus as suitable for general-purpose sterilization. . . . [L]ong before receiving the FDA’s approval to sell the small [device], [defendants] knew that the small device would never be marketed and that the large [device] would be promoted for use with many kinds of instruments – though [defendnts] did not tell the FDA these things. . . .

[T]he FDA found out what [defendant company] was telling customers and reminded it about the limitations on the scope of approval. . . . [Defendants] then sought the FDA’s approval to sell the large [device] to sterilize a wider class of instruments; when the FDA rejected [defendants’] request. . .[defendants] went on promoting the large [device] as before. . . . The agency never authorized [defendants] to sell the large [device] for any use.
Slip op. at 2-4. If we were representing the government, that’s just the kind of case we’d look for to make arguments that the First Amendment doesn’t protect off-label promotion. And that’s what the government did.

There are even more bad facts, read them in the opinion if you want, but what we’ve quoted is quite enough for our purposes. These defendants did a lot of things that richly deserved prosecution. But, as the court commented, when the government eventually “threw the book at” the defendants, id. at 5, it not only charged them with all kinds of false and fraudulent things, but also sought to hold them criminally liable for a few truthful statements that (so the government charged at trial) also promoted off-label use. Id. at 5.

Even on this horrific set of facts – shot through with misconduct that nobody would claim the First Amendment protects – the First Amendment argument gave the Seventh Circuit much pause:

[I]n Virginia Board of Pharmacy v. Virginia Citizens Consumer Council, Inc., 425 U.S. 748 (1976), [the court] h[e]ld[] that the government cannot regulate by ensuring ignorance among consumers. If it is lawful to sell a product then, the Court held, it must be lawful to inform consumers that the product is available to buy. Consumers themselves must decide what to do; the Constitution forecloses an enforced ignorance based on a paternalistic view that informed consumers will make mistakes. See also, e.g., Greater New Orleans Broadcasting Ass’n, Inc. v. United States, 527 U.S. 173 (1999); Rubin v. Coors Brewing Co., 514 U.S. 476 (1995); Bolger v. Youngs Drug Products Corp., 463 U.S. 60 (1983); R.H. Coase, Advertising and Free Speech, 6 J. Legal Studies 1 (1977).

For a time judges thought the Supreme Court’s new understanding inapplicable to drugs (and, by implication, medical devices): Federal law allows vendors to tell customers about all lawfully available drugs and devices, after all, and thus avoids the precise problem presented by Virginia Citizens Consumer Council. But federal law does prohibit manufacturers from alerting consumers to lawful off-label uses, and Thompson v. Western States Medical Center, 535 U.S. 357 (2002), held that this limit is unconstitutional in at least some applications. A federal law allowed pharmacists to compound some drugs that had been approved for stand-alone sales, creating substances that had not been subjected to the normal testing. The legislation granting pharmacists this compounding privilege attached conditions to the way they could promote the compounded drugs. The Court held these limits unconstitutional: if the compounded drug could be sold, the Court held, then it could be freely promoted for every lawful use. Western States Medical Center establishes that drugs are not a special case for first-amendment analysis. . . . The Court suggested in Western States Medical that Congress either adopt a substantive rule prohibiting compounding (or, here, prohibiting off-label uses) or allow the FDA to supply warnings via its own speech. Compelling private persons to toe the government’s line, or shut up, is unconstitutional, the Court held. This is the doctrine that [defendants] propose to invoke in their defense.

Caputo, slip op. at 5-7 (emphasis added). That’s the First Amendment argument in a nutshell – FDA regulation is not a “special case” under the First Amendment, and truthful off-label promotion is protected commercial speech that cannot be prohibited consistently with Western States Medical.

The court in Caupto – even with really bad facts before it – only affirmed the convictions by holding, (1) that there really wasn’t off-label promotion at all, and (2) that the instructions given the jury did not in fact permit conviction for truthful promotion, but only for the fraud that the government claimed (and the jury found) had been committed. The court recognized the vulnerability of the FDA’s ban on truthful off-label promotion under the doctrine of “unconstitutional conditions”:


Whether Virginia Citizens Consumer Council and Western States Medical Center apply to promotion by a product’s manufacturer, which struck a bargain with the FDA in the approval process by promising to limit its promotion – a bargain that the private litigants in the earlier cases had not struck – is a difficult question. The doctrine of unconstitutional conditions places limits on the promises that an agency may extract from those who seek approval. And if a given use is lawful, and thus can be written about freely in newspapers or blogs, and discussed among hospitals that already have purchased [the defendants’ product], doesn’t it make a good deal of sense to allow speech by the device’s manufacturer, which after all will have the best information? Why privilege speech by the uninformed? The manufacturer has an incentive to slant the speech in its favor and may withhold bad news, but many listeners (especially professionals such as physicians) understand this and can discount appropriately. That, at any rate, is the anti-paternalist view of Virginia Citizens Consumer Council and the cases that followed in its wake.
Caputo, slip op. at 7 (emphasis added).

The Caputo court recognized that there were other, more restrictive alternatives not involving speech that the FDA could employ if its speech-related restrictions against off-label promotion were declared unconstitutional:


Yet if a manufacturer’s promise to the FDA to avoid speech about off-label uses is unenforceable, the FDA may respond by withholding any approval of drugs or devices that have questionable additional uses. . . . Other firms, with no desire to promote off-label uses (or, at least, no desire to pay for the expensive tests needed to persuade the FDA to sanction wider use), would be made worse off by their inability to strike deals allowing the FDA to approve a subset of all possible uses. Consumers who could benefit from drugs or devices that would be excluded from the market by the FDA’s response to a broad privilege to tout off-label uses also would be made worse off. Doubtless the first amendment differs from Bentham’s felicific calculus [it’s Easterbrook, after all], but a court should hesitate before extending an a historical reading of the Constitution in a way that injures the very audience that is supposed to benefit from free speech.
Caputo, slip op. at 7-8 (emphasis added). These are tough questions, as we recognize. If the FDA cannot ban truthful speech, it could do something non-speech related that is actually more restrictive of off-label use – the Agency could, for example (as Bexis mentioned in his brief):


require separate reporting and labeling of adverse events associated with off-label use to alert physicians specifically about off-label risks, where they exist. The Agency could also increase incentives for manufacturers to seek approval for off-label uses through any number of indirect economic means. The government could provide tax incentives for clinical research related to bringing off-label uses onto the label. It could provide manufacturers with a preemption defense in product liability cases involving off-label uses brought onto the label. Products with few off-label uses could receive faster and easier export authorization. Another approach would be to extend or reduce patent exclusivity depending upon the prevalence of off-label use.
WLF brief, Caputo, at 30.

Not wanting, either, to reject First Amendment protection that Supreme Court decisions had conferred upon truthful commercial speech, or alternatively, to let these defendants off the hook, the Caputo court ultimately avoided deciding the issue (“Fortunately, we need not decide today whether a seller of drugs or medical devices has a constitutional right to promote off-label uses. Caputo, slip op. at 8) – by finding (1) no off-label use and (2) no conviction for truthful promotion.

As to the first, the court concluded that the FDA never approved the device the defendants actually sold for anything. “Unless the machine itself could be sold lawfully, there were no lawful off-label uses to promote. And the jury found, by its verdicts on both the fraud-on-the-United-States count and the misbranded-device counts, that the large [device] could not lawfully be sold.” Caputo, slip op. at 8. No approved label – ergo no legal off-label uses (or promotion of same) were possible. See also Id. at 9 (additional discussion of unapproved device issues).

As to the second, the court held that the jury instructions in fact required a finding of fraud as a predicate for conviction, and thus the defendants could not have been convicted for truthful off-label promotion. “Defendants insisted at oral argument that the jury could have convicted, under the instructions given, without finding either lies to the FDA or sale of a never approved device. We have reviewed the instructions and conclude that, to convict on all counts as it did, the jury had to find both.” Caputo, slip op. at 8-9.

In Caputo the Seventh Circuit thus took care to recognize the strength of the First Amendment argument for protection of truthful off-label promotion even in the context of facts that the government charged, and a jury found, proved a fraud committed against both the government and the public. In light of Caputo - and the line of Supreme Court First Amendment cases that (to date) culminate with the Western States finding that FDA prohibitions (like the rest of the government’s) cannot transgress the bounds of constitutionality - is it any surprise that the FDA has given ground on off-label promotion involving indisputably truthful, peer-reviewed articles and textbooks?

We don’t think so.

We think that the FDA issued its latest guidance on off-label promotion not for any nefarious reasons, but because it sees the handwriting on the wall the same as we do. The FDA is proposing to confirm the legality of truthful off-label promotion that it has no constitutional power to prohibit in the first place. It’s a long overdue baby step by the Agency in the direction of constitutionality. The FDA isn’t stupid. It knows that there are just some legal battles that are hopeless, and thus not worth fighting.

If the FDA’s critics stopped to think about it, maybe they’d agree too. But if the other side wants to fight the constitutional battle over off-label promotion on turf that the FDA’s willing to concede in its proposed guideline, we’re happy to fly the First Amendment flag on that battlefield.

2 comments:

Anonymous said...

Great blog guys!

In your opinion, does this guidance affect manufacturers who provide articles/reprints on off label uses in response to unsolicited requests from physicians/surgeons? Do the articles/reprints that are sent in response to an unsolicited request have to meet the laundry list of criteria laid out by FDA?

mike said...

love to see this discussion! It’s great to see you all working through the issues and also, it’s great to see recommendations for testing. In the end, it’s what your actual users do and prefer that should be your biggest driver in making these decisions.

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