In 1993, the FDA approved a drug called Neurontin for use – in doses of up to 1800 mg per day – as an add-on (or “adjunctive”) therapy for partial complex seizures.  Doesn’t sound like a blockbuster drug, does it?

Well, you’d be surprised.  Parke-Davis earned more than $3 billion in Neurontin sales in 2004 alone.  How did they do it?  Let’s listen in on a motivational speech a Parke-Davis executive gave to the company’s marketing managers:

I want you out there every day selling Neurontin. . . . We all know Neurontin’s not growing for adjunctive therapy, besides that’s not where the money is. Pain management, now that’s money. Monotherapy [for epilepsy], that’s money. . . . We can’t wait for [physicians] to ask, we need [to] get out there and tell them up front. Dinner programs, CME programs, consultantships all work great but don’t forget the one-on-one. That’s where we need to be, holding their hand and whispering in their ear, Neurontin for pain, Neurontin for monotherapy, Neurontin for bipolar, Neurontin for everything. I don’t want to see a single patient coming off Neurontin before they’ve been up to at least 4800 mg/day. I don’t want to hear that safety crap either, have you tried Neurontin, every one of you should take one just to see there is nothing, it’s a great drug.

Warner-Lambert (Parke-Davis’ former corporate parent) ended up pleading guilty to criminal charges and paying $430 million in fines stemming from its off-label promotion of Neurontin.  But a federal appellate court ruling last Monday suggests the real victims in the Neurontin case were not the patients prescribed the drug for unapproved uses, but the drug company that was punished for profiting from them.  In United States v. Caronia – a case involving a different company (Jazz Pharmaceuticals) and a different drug, Xyrem – the U.S. Court of Appeals for the Second Circuit held that the longstanding ban on off-label promotions violates drug companies’ First Amendment rights.

The active ingredient in Xyrem is gamma-hydroxybutryate, or “GHB.”  It is better known as “the date rape drug” for its role in many sexual assault cases – the drug is virtually undetectable when mixed with a drink and causes relaxation and reduced inhibitions when consumed.  As noted by the court:

“Xyrem can cause serious side effects, including difficulty breathing while asleep, confusion, abnormal thinking, depression, nausea, vomiting, dizziness, headache, bedwetting, and sleepwalking. If abused, Xyrem can cause additional medical problems, including seizures, dependence, severe withdrawal, coma, and death.

“To protect against its serious safety concerns, in 2002, the FDA required a ‘black box’ warning to accompany Xyrem.  The black box warning is the most serious warning placed on prescription medication labels.  Xyrem’s black box labeling stated, among other things, that the drug’s safety and efficacy were not established in patients under 16 years of age, and the drug had ‘very limited’ experience among elderly patients.”

The FDA approved Xyrem to treat narcolepsy.  But, of course, “that’s not where the money is.”  When the federal government launched an investigation into Jazz’s promotion of the drug, it caught one of the company’s sales reps, Caronia, promoting Xyrem for a variety of other uses.  Here’s an excerpt from one of Caronia’s conversations with Dr. Stephen Charno, who posed as a potential customer:

[Caronia]: And right now the indication is for narcolepsy with cataplexy . . . excessive daytime . . . and fragmented sleep, but because of the properties that . . . it has it’s going to insomnia, Fibromyalgia[,] periodic leg movement, restless leg, ahh also looking at ahh Parkinson’s and . . . other sleep disorders are underway such as MS.

[Charno]: Okay, so then so then it could be used for muscle disorders and chronic pain and . . .

[Caronia]: Right.

[Charno]: . . . and daytime fatigue and excessive sleepiness and stuff like that?

[Caronia]: Absolutely. Absolutely. Ahh with the Fibromyalgia.

In other conversations, Caronia and a doctor he’d hired to help promote Xyrem were caught promoting the drug for use in children under age 16 – in one case children as young as 8.

Caronia was charged with criminal counts under the “misbranding” provisions of the Food, Drug, and Cosmetic Act (FDCA), and was convicted at trial.  His punishment for promoting this dangerous drug for unsupported uses, including in young children? A year of probation, 100 hours of community service, and (I’m not making this up) a $25 special assessment.  For those keeping score at home, that’s less than 2 hours of community service per week for a year, and a dinner for two . . . at Applebee’s.

Caronia appealed that conviction on the grounds that criminalizing off-label promotion violates the First Amendment’s free speech protections, and the Second Circuit agreed.  Drawing on the Supreme Court’s determination last year in Sorrell v. IMS Health that “[s]peech in the aid of pharmaceutical marketing . . . is a form of expression protected by the Free Speech Clause of the First Amendment,” two members of the three-judge panel concluded that drug companies and their representatives cannot be prosecuted “for speech promoting the lawful, off-label use of an FDA-approved drug.”  In reaching that conclusion, the court found it damning that drug companies could be prosecuted for promoting off-label uses when those uses are themselves lawful, and other parties (like doctors) are free to discuss them.  And it attacked the ban on off-label marketing as an offensively “paternalistic” policy that prevented drug companies from helping to “ensure that decisions about the use of prescription drugs, including off-label usage, are intelligent and well-informed.”  (“Neurontin for everything”?)

The majority’s reasoning is deeply flawed.  To understand why, it helps to have a little background about FDA requirements for drug approvals and marketing.  The Food, Drug, and Cosmetic Act requires anyone who wants to sell a drug to seek FDA approval.  Whether a chemical is a “drug” for purposes of the FDCA depends on its intended use.  If a company wants to sell a compound that is “intended to affect the structure or any function of the body,” the product is a “drug” and the company must obtain FDA approval before marketing it.  If, however, a company wants to market the same compound as an industrial solvent, it is not subject to the FDCA.

To obtain FDA approval for a drug, the petitioning company must show that it is safe and effective for its intended use and then must provide labeling that contains “adequate directions for use of the drug” – i.e., a label that provides “directions under which the layman can use a drug safely and for the purposes for which it is intended.”  If the company intends the product to be used in a way that is inconsistent with the drug’s label, the product is “misbranded,” which is a criminal offense.

Traditionally the way prosecutors have shown that a company intended a product to be used in a manner inconsistent with its label is by pointing to statements made by the company’s representatives.  If the company obtains FDA approval to label and market the drug for one purpose but its sales representatives promote the drug for other purposes, the reps’ statements are evidence that the company intends the drug to be used in a manner inconsistent with its label.

So there is nothing puzzling about the fact that drug companies can be held liable for promoting drugs for unapproved uses, even if those uses are themselves legal.  As the dissenting opinion notes, that restriction is supported by the same principle according to which “hardware stores are generally free to sell bottles of turpentine, but may not label those bottles, ‘Hamlin’s Wizard Oil: There is no Sore it will Not Heal, No Pain it will not Subdue.’”  “Simply put,” writes the dissent, “that Caronia was otherwise free to introduce Xyrem into interstate commerce does not give him a First Amendment right to introduce it into interstate commerce for any intended purpose he wished.”

In any event, unless and until the majority’s decision is overturned (either by a full panel of Second Circuit judges or by the Supreme Court), its opinion is the one that matters.  Just how big an effect it will have on the FDA’s regulation of drug marketing remains to be seen.  On a narrow reading the decision could be construed as merely requiring prosecutors to be more careful in how they present their cases, and district court judges to be more careful in crafting jury instructions.  The majority opinion emphasizes aspects of Caronia’s trial in which prosecutors’ statements and certain jury instructions appeared to suggest that Caronia’s off-label statements were themselves the punishable offense, rather than merely serving as evidence of misbranding.  The opinion seems to leave open the possibility that Caronia’s conviction would not have violated the First Amendment if it had been more clear during the trial that his speech was simply evidence that Jazz intended the drug to be used in a manner inconsistent with its label.

But there is also reason to think, as the dissenting judge claimed, that the court’s decision “calls into question the very foundations of our century-old system of drug regulation.”  While the majority insists “we do not hold, of course, that the FDA cannot regulate the marketing of prescription drugs,” it is not clear what form that regulation might take in light of the court’s conclusion that drug companies and their representatives cannot be prosecuted “for speech promoting the lawful, off-label use of an FDA-approved drug.”  While the majority emphasizes that the government may still prosecute drug companies for marketing that is false or misleading, it fails to consider what such prosecutions would entail.

Take, for example, Caronia’s claim that Xyrem’s properties make it a good candidate for treating Fibromyalgia.  Under the existing system of regulation, if Jazz Pharmaceuticals wanted to market Xyrem as a treatment for Fibromyalgia, it would have to conduct clinical trials that demonstrated to the FDA’s satisfaction that the drug was safe and effective in treating that condition.  But if the Caronia decision means Jazz can promote its drug however it wishes as long as it is not false or misleading, the government would bear the burden of showing that Xyrem is not a safe and effective treatment for Fibromyalgia.  How would it do that?  Would the agency have to conduct multi-billion dollar clinical trials of its own, with the aim of proving the drug is not an effective treatment for that condition?  And additional clinical trials to disprove the drug’s efficacy for periodic leg movement, restless leg, Parkinson’s, MS, and all the other conditions for which Caronia marketed the drug?  Needless to say, this isn’t something the FDA could possibly undertake.  Nor would requiring the agency to go around disproving the efficacy of drugs for various purposes be a sensible use of resources.

It’s also not clear what the Caronia decision means for FDA rules requiring drug company promotions to include a “fair balance” of drugs’ risks and benefits.  This is the requirement responsible for the laundry list of side effects described in the drug ads we see on TV.  If drug companies have a constitutional right to make any statements they want about a drug as long as they’re not demonstrably false, it seems they could not be prosecuted for failing to describe a drug’s risks unless failing to do so amounted to fraud.  In other words, the heightened restrictions traditionally applied to drug marketing would be replaced with the standard applicable to other consumer products – i.e., “buyer beware.”

Finally, there seems no reason to think drug companies would be limited to marketing their drugs as treatments for diseases.  Why pitch Adderall as merely a treatment for ADHD when there’s a huge market of healthy people who could use it to perform better at school and work?  Why list Cialis’ notorious 4-hour erection as an unfortunate side-effect of treating erectile dysfunction when you have a First Amendment right to pitch it as a fun way to spend an evening?   If you love the existing direct-to-consumer drug ads, Caronia could usher in a golden age.

The moral of the story?  If you want to sell the date rape drug to 8 year-olds, make sure you’re on a drug company’s payroll when you do.  It’s what the Founding Fathers would have wanted.

Matt Lamkin
Twitter: @lawbioethics