What's at Stake in the Off-Label Promotion Debate: It's NOT Free Speech!

In case you haven't heard, in a 2-to-1 split decision, the 2nd U.S. Circuit Court of Appeals in New York on Monday threw out the conviction of a sales representative for promoting off-label use of a prescription drug (see story here).

The majority decision written by Circuit Judge Denny Chin -- the same judge that rejected Google’s deal to digitize books (see here) -- was based on last year's Supreme Court ruling that "Speech in aid of pharmaceutical marketing . . . is a form of expression protected by the Free Speech Clause of the First Amendment." According to Judge Chin, the "pharmaceutical representative's promotion of an FDA-approved drug's off-label use is speech" and he was prosecuted "precisely" because of his "speech in aid of pharmaceutical marketing." Ergo, "we VACATE the judgment of conviction and REMAND the case to the district court."

There's enough legal issues in this case to keep a ship-load of constitutional and pharma lawyers busy for years. But I'd like to look at this from a different perspective -- i.e., what pharma has to gain from this and what patients have to lose.

This particular case involves several off-label discussions between a sales rep and a physician who recorded the conversations. The drug being promoted by the sales rep was Xyrem, a powerful central nervous system depressant, approved for "narcolepsy patients who experience cataplexy" and "narcolepsy patients with excessive daytime sleepiness." Xyrem's active ingredient is gamma-hydroxybutryate ("GHB"). GHB has been federally classified as the "date rape drug" for its use in the commission of sexual assaults. Xyrem can cause serious side effects and, if abused, it can cause additional medical problems, including seizures, dependence, severe withdrawal, coma, and death. It's FDA labeling includes a "black-box" warning.

To promote this drug off-label, say for use in children under the age of 16, or for "restless leg syndrome" (which can be diagnosed without any evidence other than what the patient testifies to), might be considered by any sane person a danger to public health, akin to yelling FIRE! in a crowded theater when there is no fire.

But that is exactly what the sales rep did. On October 26, 2005, Caronia (the sales rep defendant in the case) "plainly promoted the use of Xyrem in unapproved indications with Charno (a physician who recorded the conversation as an agent for the FDA):

[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."

On separate occasions, Caronia and Gleason (the physician paid by the drug company) each explained to prospective physician-customers that Xyrem could be used with patients under age sixteen, an unapproved Xyrem subpopulation:

[Caronia]: Um, the youngest patients we have are sixteen in the studies as old as sixty-five. Ahh there have been reports of patients as young as fourteen using it and obviously greater than sixty-five. It's a very safe drug.

[Gleason]: Well, it's actually approved for sixteen and above um, I've had people under thirteen and I've certainly talked to neurologists that have narcoleptics . . . between eight and ten . . . [but] I start at two-thirds the dose, but [if] they're real frail I only start with one-third the dose.

Other than quoting the above conversation,  Judge Denny Chin did not consider the safety of patients as part of his reasoning for reversing the lower court's decision. And neither did the drug industry, which filed a "friends of the court" brief (see "Drug Firms Push to End Ban on Off-Label Marketing").

Judge Chin only only conceded that "While some off-label information could certainly be misleading or unhelpful, this case does not involve false or misleading promotion [my emphasis]. Moreover, in the fields of medicine and public health, 'where information can save lives,' it only furthers the public interest to ensure that decisions about the use of prescription drugs, including off-label usage, are intelligent and well-informed."

That kind of thinking supposes that all information is helpful, whereas we know that a lot of information promulgated by many marketers, including pharmaceutical marketers, can be unsupported by evidence; i.e., some "information" can be "carefully wrought bullshit" (see here).

Even the "evidence" that pharma companies use to "prove" the efficacy and safety of drugs is being questioned (see "The Case Against EBM"). But I rather not get into that here.

In her dissenting opinion, Circuit Judge Debra Ann Livingston was more focused on the safety issue: "one way in which a drug is misbranded is if its labeling lacks adequate directions for layperson use." She points out that the FDA defines “adequate directions for use” as “directions under which the layman can use a drug safely and for the purposes for which it is intended."

"But some uses of drugs are never safe, at least for a layperson," said Judge Livingston, "because it is impossible to provide adequate directions for such uses, this provision also effectively prohibits introducing drugs into interstate commerce with the intent that the drugs be used in ways that are unsafe for laypersons... the simple fact that one is generally allowed to sell something does not imbue one with a constitutional right to sell it for any intended purpose. And the prohibition here on distributing drugs with the intent that they be used for purposes not supported by their labeling is entirely consistent with the broader purposes of the FDCA -- namely, minimizing those occasions on which patients use drugs that have not been shown to be safe and effective."

Drug companies would save a bundle of money if they did not have to prove to the FDA's satisfaction that a drug is effective for every medical condition for which they have a shred of evidence. In this case, Caronia did not even mention specific evidence, but merely inferred that his company was "looking at" uses of Xyrem in the treatment of MS, Fibromyalgia, Parkinson's, whatever! I pity the patients whose physicians take this "carefully wrought bullshit" as evidence and prescribe a drug as dangerous as Xyrem for off-label indications.