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
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
“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
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.
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.
Accessed December 14, 2012.
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