In the latest round of the expansion of commercial speech doctrine to eat away at the basic foundations of the regulatory state, the Second Circuit reversed a pharmaceutical rep’s conviction for conspiracy to introduce a misbranded drug into interstate commerce because all he did was promote the drug Xyrem for off-label use.
FDA drug approvals require clinical proof of the safety and efficacy of a new drug for each intended use or indication. But once approved, drugs can be prescribed for non-approved uses. The FDA itself has recognized that doctors do this and that it may be “appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.” However, the FDCA prohibits misbranding. Misbranding occurs if a label fails to bear “adequate directions for use,” defined as “directions under which the lay[person] can use a drug safely and for the purposes for which it is intended.” The regulations define intended use by reference to “the objective intent of the persons legally responsible for the labeling of drugs,” which may be demonstrated by, among other evidence, “oral or written statements by such persons or their representatives” and “the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised.” Misbranding bears criminal penalties.
The FDCA and its regs don’t explicitly ban promotion or marketing of drugs for off-label use, but recognize that promotional statements by pharma reps can serve as proof of a drug’s intended use. Thus, off-label promotional statements could constitute evidence of an intended unapproved use. The FDA has concluded that “[a]n approved drug that is marketed for an unapproved use (whether in labeling or not) is misbranded because the labeling of such drug does not include ‘adequate directions for use.’” “Thus, the government has treated promotional speech as more than merely evidence of a drug's intended use—it has construed the FDCA to prohibit promotional speech as misbranding itself.”
Caronia was a rep for Orphan (now known as Jazz), which made Xyrem, a powerful central nervous system depressant with serious side effects and risks from abuse. Its active ingredient is GHB, known as the “date rape drug.” The FDA approved Xyrem to treat narcolepsy patients who experience cataplexy and those who experience excessive daytime sleepiness, but required a “black box” warning, the most serious warning available. It was not approved for teens. To identify side effects, the FDA also regulated Xyrem distribution, allowing only one pharmacy to distribute Xyrem nationally.
Caronia’s salary was based on his sales. He started “speaker programs” for Xyrem, which pay doctors to speak to other doctors about FDA-approved drug use. Orphan’s procedures required Caronia to decline to answer questions about off-label uses of Xyrem, and instead fill out “medical information request forms” sent to Orphan. Orphan would then send information to the inquiring physician. But doctors employed as promotional speakers by Orphan were permitted to answer off-label use questions.
Caronia and a speaker program doctor, Gleason, promoted Xyrem for unapproved uses, including unapproved indications and unapproved subpopulations—e.g., “the youngest patients we have are sixteen in the studies as old as sixty-five. … [T]here have been reports of patients as young as fourteen using it and obviously greater than sixty-five. It's a very safe drug.” The criminal information filed against Caronia said that he “was marketing Xyrem for medical indications that were not approved by [the] FDA when, as the defendant then and there well knew and believed, Xyrem's labeling lacked adequate directions for such uses and adequate warnings against such uses where uses could be dangerous to the user's health.” That is, it didn’t contain adequate directions for use “because such an ‘off-label’ indication or use and related information were not included in the FDA-approved labeling for the drug.”
Gleason and Orphan pled guilty to related charges. The majority found it to be clear that “the government prosecuted Caronia for his off-label promotion …. Thus, the government's theory of prosecution identified Caronia's speech alone as the proscribed conduct.” (Like many a conspiracy.) The jury found Caronia guilty of conspiracy to introduce a misbranded drug into interstate commerce.
On appeal, Caronia argued that the First Amendment didn’t allow the government to criminalize a pharmaceutical company’s truthful and non-misleading promotion of an FDA-approved drug to physicians for off-label use “where such use is not itself illegal and others are permitted to engage in such speech.” The court found in his favor, on what it said were narrower grounds.
The statute and its regs don’t expressly prohibit or criminalize off-label promotion. They use “promotion” only as evidence of a drug’s intended use. “Thus, under the principle of constitutional avoidance, we construe the FDCA as not criminalizing the simple promotion of a drug's off-label use because such a construction would raise First Amendment concerns. Because we conclude from the record in this case that the government prosecuted Caronia for mere off-label promotion and the district court instructed the jury that it could convict on that theory, we vacate the judgment of conviction.”
The government argued that Caronia’s off-label promotion was used only as evidence of intent to misbrand the drug: evidence that the “off-label uses were intended ones[ ] for which Xyrem's labeling failed to provide any directions.” The court disagreed. Even assuming that the government can offer evidence of off-label promotion to prove intended use (which really must be the case) under the rule of Wisconsin v. Mitchell, 508 U.S. 476 (1993), that the First Amendment “does not prohibit the use of speech to establish ... intent,” that’s not what happened here. The government repeatedly argued that Caronia was a criminal because he promoted and marketed off-label use of Xyrem. Even if the government could have used Caronia’s speech as evidence of intent, the government didn’t limit its use of the speech in that way. Mitchell instructs that speech introduced as evidence of intent should be carefully scrutinized “to be certain the statements are not expressions of mere lawful and permissible difference of opinion with our own government.” The only misbranding alleged was promoting off-label use. (Since Caronia isn’t responsible for the labeling, how could he engage in “misbranding” at all under this theory? Indeed, the court points out that the government never argued that Caronia “conspired to place false or deficient labeling on a drug.”) In a footnote, the court wondered about how the speech-as-evidence-of-intent rule would work here—“would a manufacturer be guilty of misbranding if it ships Xyrem to a doctor who, in placing his order, reveals that he prescribes the drug for off-label use—on a theory that the manufacturer now knows that the drug is not properly labeled for that use—but not if the manufacturer ships to a doctor who does not reveal that he prescribes the drug off-label?”
The district court “flatly” told the jury that pharma reps are prohibited from off-label promotion. But “[s]peech in aid of pharmaceutical marketing ... is a form of expression protected by the Free Speech Clause of the First Amendment,” Sorrell v. IMS Health. To construe “simple promotion” of off-label use by manufacturers and reps as misbranding would violate the First Amendment.
Sorrell held that a Vermont statute regulating pharmaceutical information-sharing was content- and speaker-based and thus subject to heightened scrutiny and presumptively invalid. Even under Central Hudson, the law would have been invalid. The government’s view that the FDCA’s misbranding provisions criminalized the promotion of off-label drug use by pharmaceutical manufacturers was content- and speaker-based, and, therefore, subject to heightened scrutiny. Speech about government-approved use of drugs was permitted, while certain speech about off-label uses wasn’t, even though the off-label use was itself allowed and even though non-manufacturers, including doctors and academics, could speak without restriction. As in Sorrell, the “express purpose and practical effect” of the government's ban on promotion is to “diminish the effectiveness of [off-label drug] marketing by manufacturers.” The government’s interpretation “thus has the effect of preventing [pharmaceutical manufacturers]—and only [pharmaceutical manufacturers]—from communicating with physicians in an effective and informative manner.” Plus, the First Amendment claim was even stronger because this was a criminal regulatory scheme subject to more careful scrutiny.
Under Central Hudson, promoting off-label drug use concerns lawful activity, and its promotion is not itself false or misleading. The government’s asserted interests in drug safety and public health were substantial (though maybe not according to the D.C. Circuit!). The government claimed an interest in preserving the effectiveness and integrity of the FDCA's drug approval process, and an interest in reducing patient exposure to unsafe and ineffective drugs. The government didn’t argue that off-label promotion was itself false or misleading; if it were, it wouldn’t be entitled to any First Amendment protection.
In a footnote, the majority rejected the dissent’s reliance on Whitaker v. Thompson, 353 F.3d 947 (D.C.Cir. 2004), which rejected an asserted First Amendment right to label a product with a drug claim despite its lack of FDA approval. Whitaker “constituted speech about unlawful activities and therefore did not enjoy First Amendment protection because it was unlawful to sell an unapproved product pursuant to claims about disease treatment.” But, as the dissent will point out a number of times, it’s only unlawful because it’s a drug: if you sold it as “paint” the FDCA wouldn’t apply, which means that the rule violated in Whitaker is exactly as speech-based and speaker-based as the rule here.
So the court turned to Central Hudson prongs three and four: does the regulation directly advance the government’s interests and is it narrowly drawn? No. Off-label drug use isn’t unlawful, and the FDA generally expects that approved drugs will be used off-label. Thus, prohibiting the truthful promotion of off-label drug usage by a particular class of speakers wouldn’t directly further the government's goals of preserving the efficacy and integrity of the FDA's drug approval process and reducing patient exposure to unsafe and ineffective drugs. Instead, it’s a paternalistic interference with “the ability of physicians and patients to receive potentially relevant treatment information; such barriers to information about off-label use could inhibit, to the public's detriment, informed and intelligent treatment decisions.” In fact, in its safe harbors for manufacturers’ dissemination of off-label information through scientific journals, the FDA itself “recognizes that public health can be served when health care professionals receive truthful and non-misleading scientific and medical information on unapproved uses” of approved drugs. It’s the doctor’s job to consider multiple factors, including FDA approval or lack thereof, in deciding what drugs to use. “If the government's objective is to shepherd physicians to prescribe drugs only on-label, criminalizing manufacturer promotion of off-label use while permitting others to promote such use to physicians is an indirect and questionably effective means to achieve that goal.” (Note that the majority has only really addressed interest two, limiting unsafe prescriptions; it’s said nothing about the FDA approval process, and for good reason—the off-label promotion limits are the thread that unravels the “safety and efficacy” approval process.)
Nor was the regulation narrowly drawn to further the government’s interests. Less speech-restrictive alternatives were available, as were noncriminal penalties. (Ok, wait: now we can’t prosecute criminal fraud if civil fraud remedies are available? Remember that fraud is a classic content-based regulation; it’s just ok to ban.)
The government could “guide physicians and patients in differentiating between misleading and false promotion, exaggerations and embellishments, and truthful or non-misleading information.” It could “develop its warning or disclaimer systems [ed. note: unless R.J. Reynolds applies!], or develop safety tiers within the off-label market, to distinguish between drugs.” It could require manufacturers to list all “applicable or intended indications” when initially applying for FDA approval, allowing people to track the drug’s development. (Hunh? I’m all for mandatory reporting of drug data, but how would this initial requirement help?) To minimize evasion of the approval process, the FDA could create caps on off-label prescriptions. It could “remind” doctors and manufacturers of the legal liability surrounding off-label promotion and treatment, and even perhaps further regulate that liability. (Query: if the doctor says “I think you should take this drug,” is that protected speech?) And it could prohibit off-label use entirely where there are exceptional concerns.
The First Amendment means that regulating speech must be a last, not a first, resort. (One who considered the historical development of the FDA’s powers through the 20th century, including that time when all those kids died drinking antifreeze sold as medicine, might have thought that the current scheme was something of a last resort.) The government’s response to the proposed alternatives was that they weren’t administrable, feasible, or effective, but its claims were too conclusory to credit.
Thus, manufacturer promotion alone can’t be misbranding, even if speech can be used as evidence of a drug’s intended use. “We construe the misbranding provisions of the FDCA as not prohibiting and criminalizing the truthful off-label promotion of FDA-approved prescription drugs.”