US Pharm. 2013;38(1):40-42.
In U.S. v Caronia, decided on December 3, 2012, a
federal Court of Appeals panel in a 2-1 decision ruled that the
promotion of prescription drugs by manufacturer’s agents for off-label
purposes is protected “free speech” under the First Amendment to the
U.S. Constitution.1 The FDA’s prohibition against such
practices was ruled unconstitutional. This decision, if it remains
unchanged by any further appeals, will have dramatic implications for
marketing of prescription pharmaceuticals.
Facts of the Case
Alfred Caronia was a sales representative for Orphan Medical (acquired by Jazz Pharmaceutical in 2005), the manufacturer of Xyrem (sodium oxybate).1 The drug is approved by the FDA for treatment of narcolepsy (excessive daytime sleepiness) and cataplexy (weak or paralyzed muscles) related to narcolepsy.2 Xyrem is a powerful central nervous system (CNS) depressant. The drug 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 seizures, dependence, severe withdrawal, coma, and even death. The active ingredient in Xyrem is gamma-hydroxybutyrate (GHB), which is also called the “date rape drug” because of its association with sexual assaults. In order to discourage and control abuse, the FDA limited distribution of the drug to one pharmacy located in Missouri.
In July 2005, Mr. Caronia established a speakers bureau for Orphan Medical whereby he enlisted physicians to talk to other doctors about the uses of Xyrem.1 This plan was developed to avoid the FDA prohibition against manufacturers or their representatives from “detailing” a drug to prescribers for off-label uses. The physicians who were hired to do continuing education programs for other prescribers were not subject to the same restrictions. This was, in essence, the basis for the allegation that Mr. Caronia conspired to promote Xyrem for unapproved uses.
The drug generated sales of $20 million in 2005. In the United States, the cost of Xyrem is $2,333.20 per 180 mL bottle (500 mg/mL). The effective dose range is 4.5 to 9 g per night, which equates to $3,499.80 (4.5 g) to $6,999.60 (9 g) per month as of 2012.3
Mr. Caronia was accused of promoting Xyrem to physicians for insomnia, fibromyalgia, restless legs syndrome, Parkinson’s disease, chronic pain, general muscle disorders, and other off-label conditions. In 2005, he became the target of a federal investigation.1 Promotion of drugs for uses other than those approved by the FDA is a misdemeanor crime.4 Mr. Caronia was caught on audiotape twice discussing unapproved uses of Xyrem as well as its unapproved use in minors (under the age of 16 years) with a physician who was a government informant. He also discussed how to use different billing codes for insurance purposes, indicating it should be delineated as prescribed for an approved use even when the drug was prescribed for off-label uses. This physician met with other prescribers and discussed the off-label benefits of using the medication.
Lower Court Proceedings
In 2008, a jury convicted Mr. Caronia of conspiracy to introduce a misbranded drug into interstate commerce. Promotion of a drug for purposes not approved by the FDA is deemed to be an act of misbranding. Mr. Caronia argued that his conviction unlawfully restricted his freedom of speech. He pointed out that physicians are free to prescribe drugs for off-label purposes and that his activities were designed to improve prescribing practices by providing prescribers with truthful information about the drug. The FDA argued that off-label promotion is evidence that the sales representative or his employer intended to sell misbranded products. The court sentenced him to one year of probation, 100 hours of community service, and a $25 fine.1
Mr. Caronia argued that the misbranding provisions of the Food, Drug, and Cosmetic Act (FDCA) prohibit off-label promotion and, therefore, unconstitutionally restrict speech. He claimed that the First Amendment does not permit the government to prohibit and criminalize a pharmaceutical manufacturer’s truthful and nonmisleading 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 agreed that Mr. Caronia’s conviction should be reversed, but on far narrower reasons than he expressed. The Court summarized its reasoning as follows:
“While the FDCA makes it a crime to misbrand or conspire to misbrand a drug, the statute and its accompanying regulations do not expressly prohibit or criminalize off-label promotion. Rather, the FDCA and FDA regulations reference ‘promotion’ only as evidence of a drug’s intended use.5 Thus,…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.”1
“To the extent there is any ambiguity as to whether off-label promotion is tantamount to illegal misbranding, we construe the FDCA narrowly to avoid a serious constitutional question…. We decline the government’s invitation to construe the FDCA’s misbranding provisions to criminalize the simple promotion of a drug’s off-label use by pharmaceutical manufacturers and their representatives because such a construction—and a conviction obtained under the government’s application of the FDCA—would run afoul of the First Amendment.”1
In very practical terms, the Court stated: “[O]ff-label drug usage is not unlawful, and the FDA’s drug approval process generally contemplates that approved drugs will be used in off-label ways. In effect, even if pharmaceutical manufacturers are barred from off-label promotion, physicians can prescribe, and patients can use, drugs for off-label purposes. As off-label drug use itself is not prohibited, it does not follow that prohibiting the truthful promotion of off-label drug usage by a particular class of speakers would 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. Prohibiting off-label promotion by a pharmaceutical manufacturer while simultaneously allowing off-label use ‘paternalistically’ interferes 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.”1
Quoting from an earlier Supreme Court decision also involving free speech issues in the pharmaceutical industry, the court recognized the importance of the free flow of information: “[B]ans against truthful, nonmisleading commercial speech…usually rest solely on the offensive assumption that the public will respond ‘irrationally’ to the truth.…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.”6
Taking this principle into account, this court noted: “[By] granting safe harbor to manufacturers by permitting the 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 nonmisleading scientific and medical information on unapproved uses of approved drugs.”7
One judge dissented. She would have upheld Mr. Caronia’s conviction on the grounds that freedom of speech was not even an issue in the case.
One of the court’s main problems with the facts of this case was that under the FDA regulations, content-based speech is restricted to approved indications but use of the drug for unapproved indications is not restricted. Also problematic was the fact that the manufacturer and its representatives could not talk about off-label uses to physicians (or pharmacists), but the physicians themselves could talk about and prescribe the drug for unapproved uses. In addition, there was the problem of prosecuting Mr. Caronia for conspiracy when the person he was supposed to be conspiring with (the physician) could openly and freely talk about off-label uses to practically anyone. It is not much of a conspiracy when there is no other conspirator.
This case addresses a long-running and costly issue for the pharmaceutical industry, which has paid billions of dollars in penalties to the federal government in recent years after being accused of marketing blockbuster drugs for off-label uses.8 In July 2012, GlaxoSmithKline agreed to pay $3 billion in fines, in part for promoting antidepressants and other drugs for unapproved uses. In August 2012, Johnson & Johnson announced that its pharmaceutical unit had reached a $181 million consumer fraud settlement with 36 states and the District of Columbia over its marketing of Risperdal. “Most if not all of these cases have been based on a central premise: that it is unlawful for a company and one of its employees to be promoting a drug or a medical device off-label,” said John Fleder, who represented the FDA while working at the Justice Department. “And this decision hits at the heart of the government’s theory.” 8 If the Caronia decision stands, the industry will no longer be paying penalties for off-label promotion of drugs.
Depending on how one looks at it, the upside of this case is that in the federal Court of Appeals Second Circuit (Connecticut, New York, Vermont), pharmaceutical representatives are now able to communicate truthful and accurate information about off-label uses of FDA-approved drugs. Whether this holding will spread to other states may take a while, until courts in the other federal circuits or the U.S. Supreme Court takes up this issue.
1. Slip Op No. 09-5006-cr (December 2, 2012), 2nd Cir.
Accessed December 5, 2012.
2. Xyrem (sodium oxybate) oral solution. www.xyrem.com. Accessed December 5, 2012.
3. Jazz Pharmaceuticals, Inc. Q1 2010 earnings call transcript. Seeking Alpha. May 5, 2010. http://seekingalpha.com/article/203249-jazz-pharmaceuticals-inc-q1-2010-earnings-call-transcript. Accessed December 5, 2012.
4. 21 USC §331(a)(1).
5. 21 USC §201.128, which discusses how a drug’s intended use can be demonstrated.
6. Sorrell v IMS Health, 131 SCt 2563 (2011) at 2670-72.
7. Washington Legal Foundation v Henney, 202 F3d 331, 335 (DC Cir 2000), which discusses FDA “safe harbor,” where certain forums for off-label discussion, such as continuing medical education programs and scientific publications, would not be used against manufacturers in misbranding enforcement actions.
8. Thomas K. Ruling is victory for drug companies in promoting medicine for other uses. NY Times. December 3, 2012. www.nytimes.com/2012/12/04/business/ruling-backs-drug-industry-on-off-label-marketing.html?_r=0. Accessed December 14, 2012.
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