Enough things – well, three, anyway – about off-label use have piled up in our inbox to warrant yet another point of the subject. In case anybody has forgotten, our basic views about off-label use are: (1) on the whole, it’s far more medically beneficial than not and often represents the medical standard of care; and (2) while it’s illegal for FDA-regulated manufacturers to promote off label use, the First Amendment should protect truthful dissemination of scientific and medical information concerning such uses.

The first thing we’ve had kicking around deals with the first of these two positions; the other two involve the second.

One current hotbed of off-label use-related legal activity is the “qui tam” lawsuit. That’s where “private attorneys general” – nowadays basically lawyers without actually injured clients trying to stir up litigation – claim that private persons defrauded the government. For more on what modern qui tam litigation is all about (and for our opinions on some really dubious legislative proposals to increase it), go here.

Given our jaded view of what goes on in qui tam litigation generally, we were quite interested to read the recent decision in Hopper v. Solvay Pharmaceuticals, Inc., 2008 WL 4177927 (M.D. Fla. Sept. 8, 2008), where the court thoroughly trashed a suit claiming that that “illegal promotion” of off-label uses led to false claims against the government, merely because the government paid for a drug that tens of thousands of doctors had chosen to prescribe for their patients – and even though there was no allegation that the off-label uses were anything other than standard of care treatment.

And before we go further, it’s proper netiquette to give credit where credit is due. We learned of this case from the folks at the FDA law blog, who put up a post on it even before the original magistrate’s order had been affirmed by the court (which it now has).

Hopper involves the drug Marinol – which is itself interesting, because that drug is a synthetic form of THC, the active ingredient in marijuana. On the basis of what’s probably the largest uncontrolled human trial of any drug anywhere, it’s been established (if not necessarily scientifically) that smoking pot gives people the munchies. THC is an appetite stimulant. Anyway, that’s what Marinol does. It’s FDA approved to increase appetite in cancer and AIDS victims, to give them medically prescribed munchies, if you will.

Off-label use is all about doctors being able to use FDA approved drugs however they want, subject to state medical oversight, the criminal law (which could possibly be an issue given pothibition), and medical malpractice liability. Thus doctors, not being ignorant of the real world, use Marinol in off-label situations where appetite enhancement is medically appropriate. It’s off-label use, plain and simple.

But Solvay, the manufacturer, can’t legally promote such off-label uses. The plaintiffs in Hopper were a couple of disgruntled ex-Solvay sales representatives attracted to the bounties offered under the False Claims Act for exposing supposed fraud against the government. See 2008 WL 4177927, at *1, *4 (qui tam plaintiffs stand to pocket between 25% and 30% of anything the government gets back). The defendant, they alleged, promoted off-label uses (such as by overwhelming doctors’ independent medical judgment with free “lunches, ice cream, and Starbucks coffee”). That encouraged doctors to prescribe presumably medically appropriate (albeit off-label) treatments that, again presumably, helped their patients. We say “presumably” because plaintiffs did not allege that the treatments were harmful, and the sheer number of prescriptions suggests that standard of care medicine was involved.

Anyway, the Hopper plaintiffs alleged that the off-label promotion defrauded the government because the doctors sought reimbursement of these medically appropriate, yet off-label, treatments. Their allegation was that “federal programs do not pay for drugs that were prescribed as a result of unlawful inducements or unlawful marketing activities by the manufacturer.” 2008 WL 4177927, at *2. Again, not a word that the treatment was medically inappropriate.

How terrible. One wonders how much the government would have had to pay had these patients gotten worse without the treatment and had to be hospitalized.

The case got thrown out because the qui tam plaintiffs couldn’t even plead, let alone prove, causation. Causation in the False Claims context means that the allegedly illegal off-label marketing must actually cause somebody else to submit false claims to the government. 2008 WL 4177927, at *6. The plaintiffs argued that just because there were hundreds of thousands of “false” off-label Marinol claims submitted, causation should be presumed. Id.

No way, José.

Incredibly, the plaintiffs had nothing whatever to back up their allegations that the defendant’s alleged promotion of medically appropriate off-label uses caused anything false to be submitted to the government. Plaintiffs “concede that they have no evidence of a false claim.” 2008 WL 4177927, at *6. This case thus fully justifies our jaded view of this area of the law as encouraging litigation with no social benefit – in the off-label use context, at least, it seeks to penalize standard-of-care medical treatment for technical reasons.

As far as we’re concerned, that admission means that those plaintiffs should have been hit with sanctions for filing a pleading that itself was more thoroughly false than anything it alleged that the defendant had been done.

No such luck. They just got booted out of court – because, fortunately, the actual submission of a false claim must be pleaded and eventually proved with particularity. Id. at *7. “[L]iability under the False Claims Act arises from the submission of a fraudulent claim to the government, not the disregard of government regulations.” Id. (quoting Corsello v. Lincare, Inc., 428 F.3d 1008, 1012 (11th Cir. 2005)). What this means is that bare allegations of “illegal” off-label promotion won’t cut it. There have to be actual false claims, and those have to be pleaded.

Where doctors are prescribing off-label for medically appropriate treatments, causation of a false claim isn’t easy to plead.

In this case, the [plaintiffs] have provided detailed allegations of various schemes to promote Marinol’s off-label use, but their allegations that the defendants’ alleged illegal marketing campaign caused the submission of false claims for government reimbursement totaling millions of dollars are not supported by any facts concerning false claims actually submitted to the government for reimbursement. The [plaintiffs] concede that they cannot identify a specific false claim. Further, they have no information about the contents, or processing, of a false claim, such as who created a false claim or when false claims were created, the substance of the false representations, or alleged improper billing practices. In short, the [plaintiffs] lack knowledge of any false claim that was submitted to the government.

2008 WL 4177927, at *8 (emphasis added). Mere allegations that the prevalence of off-label use increased in tandem with allegedly illegal promotion isn’t enough. Id. at *8-9 (“while the defendants’ allegations may state a regulatory violation, they have not stated with particularity an [False Claims Act] violation”).

Plaintiffs had no argument that they satisfied these statutory requirements. Instead they pointed to the proposed really dubious False Claims Act amendments that we oppose, which would do away with this requirement to actually prove the false claims. Id. at *9. In short, those amendments would let loose a horde of false claims suits where nobody got hurt and doctors were following the standard of care. What good is that?

Thus, Hopper provides a concrete example – if any were needed – why that proposed legislation is a really bad idea. In our view, submission of a medically appropriate off-label use cannot be a false claim, because it is standard of care medical treatment, whether or not there was off-label promotion. That the doctor was doing what s/he thought was best for that particular patient should be dispositive, since s/he probably would have written the same prescription anyway. The law should encourage up-to-date, state-of-the-art medical practice. Otherwise we’re into the Through-The-Looking-Glass world of liability for standard of care medicine, the only practical effect of which would be to drive up the cost of proper medical care through unnecessary litigation.

In short, the Hopper court held, and we agree, that False Claims Act litigation should be limited to situations where the medical treatment being billed was non-existent or bogus. 2008 WL 4177927, at *9-10 (discussing cases of this nature).

We’re not so happy with the other two things that landed in our inbox. They both have to do with First Amendment protection of truthful promotion of off-label use. One of these items is United States v. Caronia, ___ F. Supp.2d ___, 2008 WL 4210777 (E.D.N.Y. Sept. 11, 2008), and the other is one of the worst law review articles that we’ve read lately, Rogers, “Freedom Of Speech & The FDA’s Regulation Of Off-Label Drug Uses, 76 Geo. Wash. L. Rev. 1429 (Aug. 2008). Both of these suffer from the same defect, which is that they end their First Amendment analysis under the relevant (so-called “Central Hudson”) test prematurely.

Caronia deals with the off-label promotion of a drug (Xyrem) that the FDA approved to treat a couple of conditions associated with narcolepsy. It’s a heavy duty drug (a Schedule III Controlled Substance) that had not been tested in children and not much in the elderly. It’s hard to say, but it looks like there was some sort of sting involved, because a sales rep was busted for promoting the drug off-label to a another unnamed physician (described as a “confidential informant”), who promptly turned the rep in. 2008 WL 4210777, at *2, *4.

The defendant claimed the FDA’s misbranding provisions were overbroad and violated the First Amendment in the context of truthful promotion of off-label use. The FDCA, as interpreted by the Court, made the accuracy of the off-label promotion irrelevant:

Stated differently, if, as the manufacturer’s representative, [defendant] promoted [the drug] for off-label uses, whatever information (accurate or inaccurate) [defendant] may have provided in the course of the promotion of those off-label uses is irrelevant to a misbranding charge.

2008 WL 4210777, at *3 (emphasis added). That holding set up the First Amendment argument:

Reduced to its essence, [defendant’s] argument is that the government cannot restrict truthful, non-misleading promotion by a pharmaceutical manufacturer (or its employees) to a physician of the off-label uses of an FDA-approved drug.

Id. at *4.

We’ve discussed the basic framework of the First Amendment treatment of off-label promotion before here and here; and Bexis discussed that background ad nauseum in his amicus brief filed in United States v. Caputo, 517 F.3d 935 (7th Cir. 2008). We’re not going to get into that again.

The bottom line in Caronia on the preliminary First Amendment issues: (1) off-label promotion concerns speech, not conduct, and thus the First Amendment applies, 2008 WL 4210777, at *5-6; (2) off-label promotion, at least when being done by a manufacturer’s sales representative, is commercial speech, id. at *6-7; (3) because off-label use is legal, speech promoting it concerns lawful activity, id. at *8 (Central Hudson prong 1a); (4) “[p]romotion of off-label uses is not inherently misleading simply because the use is off-label,” id. (Central Hudson prong 1b); (5) the FDA has a “substantial interest” in curtailing off-label promotion – the interest of “compelling manufacturers to get off-label treatments on-label,” id. (Central Hudson prong 2); and (6) the speech restrictions “directly advance” the FDA’s interest “in subjecting off-label uses. . .to the FDA’s evaluation process.” Id. at *9 (Central Hudson prong 3).

Thus Caronia got to what it correctly viewed as the “essential question” – the fourth Central Hudson prong: are “there. . .less-burdensome alternatives available”? Id. Caronia found that there weren’t any less restrictive alternatives to the FDA’s ban on all promotional speech, truthful or otherwise, about off-label use. It first followed the Caputo district court in that regard:

[T]he Caputo district court found that the defendants’ First Amendment challenge “strikes at the very heart of the FDA’’s ability to proscribe manufacturer promotion of off-label uses.” [288 F.Supp. 2d] at 922 . . . . [T]he court held that “permitting Defendants to engage in all forms of truthful, non-misleading promotion of off-label use would severely frustrate the FDA’s ability to evaluate the effectiveness of off-label uses.” Id. More importantly, the Caputo court was unable to identify a less burdensome alternative that would advance the government’s substantial interest. Id. Consequently, it held that the restrictions were not more extensive than necessary under prong four of Central Hudson.

2008 WL 4210777, at *10.

While noting that the Seventh Circuit’s dictum in Caputo, 517 F.3d at 939-40, cast some doubt on the prior analysis, the opinion continued following the Caputo district court in its professed inability to identify any equally efficient but less speech-restrictive alternatives to the FDA’s ban. 2008 WL 4210777, at *10. Apparently the defendant did not offer any alternatives and the Caronia court was not inclined to look very hard:

[C]onstraining the marketing options of manufacturers is one of the few mechanisms available to the FDA to ensure that manufacturers will not seek approval only for certain limited uses of drugs, then promote that same drug for off-label uses, effectively circumventing the FDA’s new drug requirements. . . . [H]ere, the FDA’s maintaining through the FDCA’s misbranding provisions some control over the off-label promotion of manufacturers does appear essential to maintaining the integrity of the FDAs new drug approval process. Furthermore. . ., this Court is unable to identify non-speech restrictions that would likely constrain in any effective way manufacturers from circumventing that approval process.

Id. at *11.

We’ll stop here for a moment and turn to the law review article. We frankly had high hopes for it when we started. It had a lengthy discussion of the background and of the various pros and cons of off-label use. 76 Geo. Wash. L. Rev. at 1431-35. Then it started falling down in its discussion of current law. Id. at 1435-40. The article didn’t discuss Caputo at all – either the district court of court of appeals decision – and it basically limited itself to the ulitigation and the Supreme Court’s decision in Thompson v. Western States Medical Center, 535 U.S. 357 (2002), which invalidated similar speech restrictions under the First Amendment involving pharmacy compounding.

Well, we could live with that. After all, being familiar with the First Amendment arguments in Caputo, we didn’t need that much elucidation.

No, what we were hoping for was an interesting read about the controversial fourth prong of Central Hudson. Boy were we disappointed. The article never came to grips with any alternative at all. All it did was declare that the FDA’s speech ban “is constitutional and sound policy,” 76 Geo. Wash. L. Rev. at 1440, and then criticize drug companies as “tempted to market dangerous off-label uses,” doctors for “accepting gratuities from manufacturers,” and scientists for being “susceptible to being influenced by financial ties to drug companies” and for their “desire to highlight the importance of their research.” Id. at 1442. Doing this all in less than a page, the article concludes that “full disclosure” is not the answer:

[These problems] cannot be dismissed by simply requiring that drug companies disclose. Full disclosure does not alter the institutional realities. Drug companies, immunized by disclosure, will have an incentive to market more recklessly; scientists and physicians will be even more exposed to the industry’s influence. Despite the allure of full disclosure’s simplicity, it is not a satisfactory solution. The FDA’s current policy is, on the other hand, satisfactory.

Id. It would have been useful if the article had even considered Pearson v. Shalala, 164 F.3d 650, 657 (D.C. Cir. 1999), which in an FDA case specifically held disclosure preferable to outright speech bans. But we’ll let that go for now.

Both the Caronia opinion and, more severely, the George Washington Law Review article suffer from the same basic flaw. They don’t do what the court in Central Hudson required: that is to take a hard look at realistic alternatives to the FDA’s ban on truthful speech. Caronia doesn’t look very hard, and the law review article doesn’t even acknowledge the need to look.

Neither pays sufficient attention to the alternatives that gave the Seventh Circuit such pause in Caputo. There are several ways, even putting aside disclosure, to run an effective non-speech-related regime that reins in manufacturer off-label promotion excesses. This is a critical omission. “[I]f the government could achieve its interests in a manner that does not restrict speech, or that restricts less speech, the government must do so. Thompson, 535 U.S. at 371. Bexis’ amicus brief put those squarely before the Seventh Circuit:

  • Require separate reporting systems for off-label use adverse events, to alert physicians specifically to off-label risks.
  • Increase incentives to bring off-label uses on label, such as by tax incentives, longer exclusivity periods, or a preemption defense in product liability actions.
  • Easier export authorization for products with few off-label uses.
  • Require companies to keep statistics about off-label uses, and if a particular use exceeds some dollar amount or percentage threshold, require the manufacturer to submit a supplemental new drug application.

None of these alternatives burdens speech in the slightest. All of them would provide powerful incentives – and the last one an outright directive – to bring off-label uses on label. Further, as for the problems the George Washington Law Review article identifies with manufacturers giving “gratuities” to doctors or having “financial ties” with scientists, these practices could be restricted directly, either by the FDA or by the relevant trade or professional bodies, which in fact is happening.

These less speech-restrictive alternatives to FDA’s ban on truthful promotion of off-label use are no secret. They gave the appellate court in Caputo a lot to think about. The government knows about them, since it was party to Caputo. Unless and until either a court (unlike both Caputo and Caronia) or a legal scholar (unlike the George Washington article) confronts these alternatives and thoroughly slices, dices and mutilates them, we’re not going be convinced that truthful promotion of off-label use can be constitutionally prohibited.

Like we could be anyway.