United States v. Caronia , 703 F.3d 149 ( 2012 )

09-5006-cr
United States v. Caronia
UNITED STATES COURT OF APPEALS
FOR THE SECOND CIRCUIT
August Term 2010
(Argued: December 2, 2010 Decided: December 3, 2012)
Docket No. 09-5006-cr
UNITED STATES OF AMERICA,
Appellee,
v.
ALFRED CARONIA,
Defendant-Appellant.*
Before:
RAGGI, LIVINGSTON, and CHIN, Circuit Judges.
Appeal from a judgment of the United States
District Court for the Eastern District of New York (Eric N.
Vitaliano, J.) convicting defendant-appellant Alfred Caronia
of conspiracy to introduce a misbranded drug into interstate
*
The Clerk of the Court is directed to amend the
official caption in accordance with the above.
commerce in violation of the Federal Drug and Cosmetic Act.
Caronia contends that he was convicted for his speech -- for
promoting the off-label use of an approved prescription drug
-- in violation of the First Amendment.
VACATED and REMANDED.
Judge LIVINGSTON dissents in a separate opinion.
DOUGLAS LETTER and MARTIN COFFEY (Jo Ann M.
Navickas, Assistant United States
Attorney, Scott R. McIntosh,
Attorney, Appellate Division, United
States Department of Justice, Anne
K. Walsh, Associate Chief Counsel,
Office of General Counsel, Food and
Drug Division, on the brief), for
Loretta E. Lynch, United States
Attorney for the Eastern District of
New York, Brooklyn, New York, for
Appellee.
JENNIFER L. MCCANN (Thomas F. Liotti, on the
brief), Law Offices of Thomas F.
Liotti, Garden City, New York, for
Defendant-Appellant.
ERIC E. MURPHY, Jones Day (Michael A.
Carvin, Jones Day, Daniel J. Popeo,
Richard A. Samp, Washington Legal
Foundation, on the brief), for
Amicus Curiae Washington Legal
Foundation.
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Joan McPhee, Ropes & Gray LLP (Douglas
Hallward-Driemeier, Alan Bennett,
Ropes & Gray LLP, and Paul Kalb,
Coleen Klasmeier, Sidley Austin LLP,
on the brief), for Amicus Curiae The
Medical Information Working Group.
CHIN, Circuit Judge:
Defendant-appellant Alfred Caronia appeals from a
judgment of conviction entered in the United States District
Court for the Eastern District of New York (Eric N.
Vitaliano, J.) on November 30, 2009, following a jury trial
at which Caronia was found guilty of conspiracy to introduce
a misbranded drug into interstate commerce, a misdemeanor
violation of 21 U.S.C. §§ 331(a) and 333(a)(1).
Specifically, Caronia, a pharmaceutical sales
representative, promoted the drug Xyrem for "off-label use,"
that is, for a purpose not approved by the U.S. Food and
Drug Administration (the "FDA"). Caronia argues that he was
convicted for his speech -- for promoting an FDA-approved
drug for off-label use -- in violation of his right of free
speech under the First Amendment. We agree. Accordingly,
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we vacate the judgment of conviction and remand the case to
the district court.
STATEMENT OF THE CASE
1. The Regulatory Scheme
Under the Federal Food, Drug and Cosmetic Act (the
"FDCA"), before drugs are distributed into interstate
commerce, they must be approved by the FDA for specific
uses. 21 U.S.C. § 355(a). To obtain FDA approval, drug
manufacturers are required to demonstrate, through clinical
trials, the safety and efficacy of a new drug for each
intended use or indication. 21 U.S.C. § 355(d); see
Weinberger v. Hynson, 412 U.S. 609, 612-14 (1973).1
Once FDA-approved, prescription drugs can be
prescribed by doctors for both FDA-approved and -unapproved
uses; the FDA generally does not regulate how physicians use
1
The FDCA provides: "No person shall introduce or
deliver for introduction into interstate commerce any new drug,
unless an approval of an application filed pursuant to subsection
(b) or (j) of this section is effective with respect to such
drug." 21 U.S.C. § 355(a). A "new drug" is defined as: "Any
drug . . . not generally recognized . . . as safe and effective
for use under the conditions prescribed, recommended, or
suggested in the labeling thereof." 21 U.S.C. § 321(p).
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approved drugs. See Buckman Co. v. Plaintiffs' Legal Comm.,
531 U.S. 341, 350 (2001); Weaver v. Reagen, 886 F.2d 194,
198 (8th Cir. 1989); John E. Osborn, Can I Tell You The
Truth? A Comparative Perspective on Regulating Off-Label
Scientific and Medical Information, 10 Yale J. Health Pol'y
L. & Ethics 299, 303 (2010) ("Physicians may prescribe FDA-
approved drugs . . . for any therapeutic use that is
appropriate in their medical judgment."); Randall S.
Stafford, Regulating Off-Label Drug Use: Rethinking the Role
of the FDA, 358 N. Engl. J. Med. 1427, 1427 (2008)
(discussing 2003 study of 160 common drugs where off-label
use accounted for approximately 21 percent of
prescriptions).
Indeed, courts and the FDA have recognized the
propriety and potential public value of unapproved or off-
label drug use. See Buckman, 531 U.S. at 350 (Off-label use
is an "accepted and necessary corollary of the FDA's mission
to regulate in this area without directly interfering with
the practice of medicine."); Weaver, 886 F.2d at 198-99("FDA[-]approved indications were not intended to limit or
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interfere with the practice of medicine nor to preclude
physicians from using their best judgment in the interest of
the patient." (internal quotation marks omitted)); U.S. Food
and Drug Administration, Draft Guidance, Good Reprint
Practices for the Distribution of Medical Journal Articles
and Medical or Scientific Reference Publications on
Unapproved New Uses of Approved Drugs and Approved or
Cleared Medical Devices 3 (2009) ("[O]ff-label uses or
treatment regimens may be important and may even constitute
a medically[-]recognized standard of care.").2 The FDA
itself has observed:
Once a drug has been approved for
marketing, a physician may prescribe it
for uses or in treatment regimens or
patient populations that are not included
in approved labeling. Such "unapproved"
or, more precisely, "unlabeled" uses 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.
2
See also James M. Beck & Elizabeth D. Azari, FDA, Off-
Label Use, and Informed Consent: Debunking Myths and
Misconceptions, 53 Food & Drug L.J. 71, 76-77 (1998); cf. 21
U.S.C. § 396 (protecting physician authority to prescribe or
administer any legally-marketed device to patient).
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U.S. Food and Drug Administration, FDA Drug Bulletin, 12 FDA
Drug Bull. 1, 5 (1982).
The FDCA prohibits "misbranding," or "[t]he
introduction or delivery for introduction into interstate
commerce of any . . . drug . . . that is . . . misbranded."
21 U.S.C. § 331(a). A drug is misbranded if, inter alia,
its labeling fails to bear "adequate directions for use," 21
U.S.C. § 352(f), which FDA regulations define as "directions
under which the lay[person] can use a drug safely and for
the purposes for which it is intended," 21 C.F.R. § 201.5.4FDA 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
4
A drug is also misbranded if, inter alia: its label is
false or misleading; the label fails to display required
information prominently; its container is misleading; or it is
dangerous to health when used in the dosage, manner, frequency,
or duration prescribed, recommended, or suggested on the label.
See 21 U.S.C. §§ 352(a)-(n).
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representatives, offered and used for a purpose for which it
is neither labeled nor advertised." 21 C.F.R. § 201.128.
The consequences for misbranding are criminal. 21
U.S.C. § 333(a)(2) ("[I]f any person commits such a
violation . . . such persons shall be imprisoned for not
more than three years or fined not more than $10,000, or
both."). Pharmaceutical manufacturers and their
representatives can face misdemeanor charges for misbranding
or felony charges for fraudulent misbranding. 21 U.S.C. §
333(a); see Osborn, Can I Tell You The Truth?, supra, at
328-29 (collecting cases). The government has repeatedly
prosecuted -- and obtained convictions against --
pharmaceutical companies and their representatives for
misbranding based on their off-label promotion. See, e.g.,
Judgment, United States v. GlaxoSmithKline, LLC, 12-cr-10206
(RWZ), ECF Doc. No. 13 (D. Mass. July 10, 2012)
(Information, GlaxoSmithKline, No. 12-cr-10206 (RWZ), ECF
Doc. No. 1 (D. Mass. July 2, 2012)); Judgment, United States
v. Merck Sharp & Dohme Corp., No. 11-cr-10384 (PBS), ECF
Doc. No. 30 (D. Mass. May 18, 2012) (Information, Merck, No.
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11-cr-10384 (PBS), ECF Doc. No. 1 (D. Mass. Nov. 22, 2011));
Agreed Order of Forfeiture, United States v. Abbott Labs.,
No. 12-cr-26 (SGW), ECF Doc. No. 7 (W.D. Va. May 7, 2012)
(as a result of the guilty plea to the Information
(Information, Abbott, No. 12-cr-26 (SGW), ECF Doc. No. 5-1
(W.D. Va. May 7, 2012))); Judgment, United States v.
Allergan, Inc., No. 10-cr-375 (ODE), ECF Doc. No. 20 (N.D.
Ga. Oct. 7, 2010) (Information, Allergan, No. 10-cr-375
(ODE), ECF Doc. No. 1 (N.D. Ga. Sept. 1, 2010)); see
Sentencing Transcript, Merck, No. 11-cr-10384 (PBS), ECF
Doc. No. 27 (D. Mass. April 30, 2012) ("I want to emphasize
that off-label marketing has been . . . a big problem
. . . . I hope in a way that the . . . fact that all these
cases are being pressed by the federal and state
governments, the 44 state Attorney Generals, will be a
signal that it isn't acceptable conduct."); see also
Press Release, U.S. Department of Justice, GlaxoSmithKline
to Plead Guilty and Pay $3 Billion to Resolve Fraud
Allegations and Failure to Report Safety Data, Largest
Health Care Fraud Settlement in U.S. History (July 2, 2012);
Osborn, Can I Tell You The Truth?, supra, at 328-29.
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The FDCA and its accompanying regulations do not
expressly prohibit the "promotion" or "marketing" of drugs
for off-label use. The regulations do recognize that
promotional statements by a pharmaceutical company or its
representatives can serve as proof of a drug's intended use.
See 21 C.F.R. § 201.5. Off-label promotional statements
could thus presumably constitute evidence of an intended use
of a drug that the FDA has not approved. See id. The FDA,
however, 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.'" See FDA, Draft
Guidance, supra, at 2-3 (quoting 21 U.S.C. § 352(f)); accord
United States v. Caronia, 576 F. Supp. 2d 385, 392 n.5
(E.D.N.Y. 2008); see also Gov't Br. 48 n.18 (contending no
set of directions can constitute adequate labeling for
drug's off-label 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.
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2. The Facts5
a. Orphan Medical and Xyrem
Orphan Medical, Inc. ("Orphan"), now known as Jazz
Pharmaceutical, was a Delaware-incorporated pharmaceutical
company that primarily developed drugs to treat pain, sleep
disorders, and central nervous system disorders. Orphan
manufactured the drug Xyrem, a powerful central nervous
system depressant. In 2005, after Jazz Pharmaceuticals
acquired Orphan, Jazz continued to
manufacture and sell Xyrem, grossing $20 million in combined
Xyrem sales in 2005.
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.
5
The facts are drawn primarily from the trial record.
On appeal, this Court must view the evidence in the light most
favorable to the government, drawing all reasonable inferences in
its favor. See United States v. Amico, 486 F.3d 764, 780 (2d
Cir. 2007).
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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.
b. The FDA's Regulation of Xyrem
Despite the risks associated with Xyrem and GHB,
the FDA approved Xyrem for two medical indications. In July
2002, the FDA approved Xyrem to treat narcolepsy patients
who experience cataplexy, a condition associated with weak
or paralyzed muscles. In November 2005, the FDA approved
Xyrem to treat narcolepsy patients with excessive daytime
sleepiness ("EDS"), a neurological disorder caused by the
brain's inability to regulate sleep-wake cycles.
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.
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To identify patients suffering side effects from
the drug, the FDA also regulated Xyrem distribution,
allowing only one centralized Missouri pharmacy to
distribute Xyrem nationally.
c. Caronia's Employment with Orphan
In March 2005, Orphan hired Caronia as a Specialty
Sales Consultant to promote Xyrem. Caronia primarily worked
in Queens, Nassau, and Suffolk counties. Caronia's salary
was based on his individual sales.
In July 2005, Caronia started Orphan's "speaker
programs" for Xyrem. Speaker programs enlist physicians,
for pay, to speak to other physicians about FDA-approved
drug use. Orphan's speaker programs for Xyrem presented the
benefits of the drug among patients with cataplexy and
narcolepsy. Orphan hired Dr. Peter Gleason to promote Xyrem
through its speaker programs.
Under Orphan's procedures, if Caronia, as a sales
consultant for Xyrem, was asked about the off-label use of
Xyrem, he was not permitted to answer; instead, when such
questions were posed, Orphan sales consultants would fill
out "medical information request forms" and send them to
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Orphan, and Orphan would send information to the inquiring
physician.6 In contrast, physicians employed by Orphan as
promotional speakers for Xyrem were permitted to answer off-
label use questions; their responses were often informed by
their own experiences with Xyrem.
d. Caronia's Participation in the Conspiracy
In the spring of 2005, the federal government
launched an investigation of Orphan and Gleason. The
investigation focused on the off-label promotion of Xyrem.
Caronia and Gleason were audio-recorded on two occasions as
they promoted Xyrem for unapproved uses, including
unapproved indications and unapproved subpopulations. The
first conversation was recorded on October 26, 2005 between
Caronia and Dr. Stephen Charno, a physician who, as a
government cooperator, posed as a prospective Xyrem
customer. The second conversation was recorded on November
2, 2005; it taped a meeting arranged by Caronia to introduce
Charno to Gleason.
6
In December of 2011, the FDA released recommendations
for the pharmaceutical industry with respect to how manufacturers
and their representatives can respond to "unsolicited requests
for off-label information." See generally U.S. Food and Drug
Administration, Guidance for Industry, Responding to Unsolicited
Requests for Off-Label Information About Prescription Drugs and
Medical Devices (2011).
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On October 26, 2005, Caronia plainly promoted the
use of Xyrem in unapproved indications with Charno:
[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.
(October 26, 2005 Recording Tr. (I) at 4-5). Caronia
further directed Charno to list different "diagnosis codes"
when prescribing Xyrem, for insurance purposes, including
Fibromyalgia, chronic fatigue, or chronic pain.
On separate occasions, Caronia and Gleason each
explained to prospective physician-customers that Xyrem
could be used with patients under age sixteen, an unapproved
Xyrem subpopulation:
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[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.
(October 26, 2005 Recording Tr. (I) at 7).
[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.
(November 2, 2005 Recording Tr. (II) at 51).
3. Proceedings Below
a. The Charges
On July 25, 2007, a grand jury returned its first
Indictment against Caronia. The charging document at issue
on this appeal, however, is the Superseding Information
filed by the government on August 19, 2008, which charged
Caronia with the following two misdemeanor offenses:
Count One: Conspiracy to introduce a
misbranded drug into interstate commerce
in violation of 21 U.S.C. §§ 331(a) and
333(a)(2); and
Count Two: Introducing a misbranded
drug, Xyrem, into interstate commerce, in
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violation of 21 U.S.C. §§ 331(a) and
333(a)(2).
(Inf. ¶¶ 12-17).
With respect to Count One, the Information alleged
a two-prong conspiracy. The first prong charged that
between approximately March 2005 and March 2006, Caronia,
"together with others, did knowingly and intentionally
conspire to" introduce Xyrem and cause the introduction of
Xyrem into interstate commerce when Xyrem was misbranded
within the meaning of the FDCA. (Inf. ¶ 13). The second
prong alleged that "[i]t was part of the conspiracy that
[Caronia], together with others, marketed Xyrem for medical
indications that were not approved by [the] FDA when, as
[they] . . . well knew and believed, Xyrem's labeling lacked
adequate directions for and warnings against such uses,
where such uses could be dangerous to the user's health."
(Inf. ¶ 14).
The Information alleged, in Count One, that
Caronia, "together with others, committed and caused to be
committed," the following two overt acts. (Inf. ¶ 15).
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a. On or about October 26th, 2005,
. . . Caronia promoted Xyrem to
[Charno], a physician, so as to
cause [Charno] to prescribe Xyrem
for fibromyalgia, excessive daytime
sleepiness, muscle disorders,
chronic pain and fatigue, which were
"off-label" indications.
b. On or about November 2, 2005, . . .
Caronia introduced [Charno] to
[Gleason], a physician, who was paid
by Orphan and whom Orphan used to
promote Xyrem for "off-label"
indications, including fibromyalgia,
excessive daytime sleepiness, weight
loss and chronic fatigue.
(Inf. ¶¶ 15(a), (b)).
With respect to Count Two, the Information alleged
that between approximately March 2005 and March 2006,
Caronia "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." (Inf. ¶ 17).
Additionally, the Information alleged: "A drug
that was marketed to the public for an 'off-label'
indication or use did not contain 'adequate directions for
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use' because such an 'off-label' indication or use and
related information were not included in the FDA-approved
labeling for the drug." (Inf. ¶ 8). The Information
further stated: "Xyrem's labeling lacked adequate
directions for such uses and adequate warnings against such
uses where such uses could be dangerous to the user's
health." (Inf. ¶¶ 14, 17).
Orphan and Gleason were also charged under the
misbranding provisions of the FDCA; both pled guilty.
United States v. Caronia, 576 F. Supp. at 389-90 & n.1.
b. Caronia's Pre-Trial Motion to Dismiss
On October 9, 2007, before trial, Caronia moved to
dismiss the charges against him. In part, Caronia argued
that the application of the FDCA's misbranding provisions to
his off-label promotional statements unconstitutionally
restricted his right to free speech under the First
Amendment and that the provisions were unconstitutionally
vague and broad.
On September 11, 2008, the district court denied
Caronia's motion, including his First Amendment challenge,
which it recognized as raising constitutional issues "very
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much unsettled, not only in this circuit but nationwide."
Id. at 403. Although ruling for the government, the
district court rejected the government's argument that
Caronia was being prosecuted for the unlawful conduct of
misbranding and conspiring to misbrand a drug and not for
his promotional speech, the latter of which the government
contended only constituted proof of Xyrem's intended use.
See id. at 394-95. The court observed that "the criminal
information . . . allege[d] Caronia's promotion of off-label
uses of an FDA-approved drug," and concluded that Caronia
stood charged with a crime the actus reus of which was First
Amendment speech. Id. at 395. Nevertheless, the district
court held that, to the extent the FDCA criminalizes speech,
the law passed constitutional muster under the commercial
speech doctrine because the FDCA was not more extensive than
necessary to achieve the FDA's objectives. Id. at 401-02.
c. The Trial
The case was tried before a jury from October 6 to
October 16, 2008.
The record makes clear that the government
prosecuted Caronia for his off-label promotion, in violation
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of the FDCA. The government, in its summation and rebuttal,
repeatedly asserted that Caronia was guilty because he, with
others, conspired to promote and market Xyrem for off-label
use. For example, the government argued:
• "[Caronia is] promoting, he's marketing a
dangerous drug for use not approved by
the FDA" (id. at 825);
• "He knew the rules: you can't promote and
market Xyrem for uses that have not been
approved by the FDA. He admits it" (id.
at 839);
• "[Caronia] conspired through some act of
misbranding, and that act of misbranding
. . . was the promotion on October 26th
and November 2nd[,] marketing [a] drug
for unapproved uses" (id. at 848);
• "That's misbranding. That's promoting
and marketing a drug by a pharmaceutical
company representative for muscle
disorders, chronic pain, daytime fatigue,
excessive sleepiness" (id. at 870); and
• "[Caronia was] promoting, promoting,
selling, selling, trying to get Charno to
prescribe Xyrem. He tried on the 26th.
He tried with Gleason on the 2nd" (id. at
875).7
7
The government's summation and rebuttal include
numerous additional examples of the government's assertion that
Caronia was guilty because he conspired to promote and market
Xyrem for unapproved uses. (See, e.g., Trial Tr. 834 ("On
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Thus, the government's theory of prosecution identified
Caronia's speech alone as the proscribed conduct.
The district court, in its jury charge, reinforced
the idea that Caronia's promotional speech was enough to
support a guilty verdict:
A misbranded drug may be shown by a
promotion of the drug by a distributor
for an intended use different from the
use for which the drug was approved by
the [FDA].
. . .
The manufacturer, its agents,
representatives and employees, are not
permitted to promote uses for a drug that
have not been cleared by the United
States Food and Drug Administration.
These non-cleared uses are commonly
November 2nd . . . Gleason, comes in to pitch to [Charno] and he
right away goes off-label, promotes and markets Xyrem for uses
that are not approved by the FDA, clear as a bell."); id.
("[Caronia is] misbranding. He's promoting a drug, Xyrem, that's
dangerous for unapproved uses."); id. at 836 ("[H]e crossed the
line and here's the labeling and you can only promote Xyrem for
cataplexy associated with narcolepsy and you can't do it for
anything else."); id. at 847 ("The conspiracy is promoting it and
then trying to persuade through off-label communications to get
Charno to write prescriptions off-label"); id. at 883 ("And the
facts are one prong the drug was promoted for unapproved uses in
a meeting with Charno on the 26th of October and the 2nd of
November with the expectation or with the effort or with the
attempt or with the conspiracy that by promoting it for off-label
use, Charno would write a prescription and cause the drug to be
shipped from St. Louis to some patient out of state."); see also
id. at 821-22, 827, 829, 840-43, 847-48, 872-74, 878).
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referred to as 'off-label uses' because
they are not included in the drug's
labeling.
(Trial Tr. 920-21).
Prior to jury deliberation, the district court
provided a proposed verdict sheet to the parties. With
respect to Count One, the verdict sheet read as follows:
1. How do you find defendant,
ALFRED CARONIA, on Count One of
the Information?
(a) Conspiracy to introduce or
deliver for introduction
into interstate commerce a
drug, Xyrem, that was
misbranded?
NOT GUILTY _____ GUILTY _____
(b) Conspiracy to do an act
with respect to a drug,
Xyrem, when such drug was
held for sale after
shipment in interstate
commerce when such act
would result in Xyrem being
misbranded?
NOT GUILTY _____ GUILTY _____
(Verdict Sheet, ECF Doc. No. 103, United States v. Caronia,
No. 06 Cr. 229 (E.D.N.Y. Oct. 23, 2008)). The district
court overruled Caronia's objection that the verdict sheet
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was erroneous and therefore permitted the jury to reach an
inconsistent verdict.
On October 23, 2008, the jury found Caronia guilty
as to the first prong of Count One of the Information
(Question 1(a)): conspiracy to introduce a misbranded drug
into interstate commerce under 18 U.S.C. § 371(a) and 21
U.S.C. § 331(a). As to the second marketing prong of Count
One (Question 1(b)), the jury found Caronia not guilty. The
jury also found Caronia not guilty of Count Two of the
Information.
d. Caronia's Post-Trial Motion for Acquittal
After the jury verdict and before judgment was
entered, Caronia renewed his Rule 29 motion for acquittal.
See Fed. R. Crim. P. 29. On December 13, 2008, after
briefing, the district court denied the motion.
e. Caronia's Sentence
On November 30, 2009, the district court sentenced
Caronia to one year of probation, 100 hours of community
service, and a $25 special assessment.
This appeal followed.
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DISCUSSION
On appeal, Caronia principally argues that the
misbranding provisions of the FDCA prohibit off-label
promotion, and therefore, unconstitutionally restrict
speech.8 Caronia argues that the First Amendment does not
permit the government to prohibit and criminalize a
pharmaceutical manufacturer'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.
We review Caronia's First Amendment challenge to
his conspiracy conviction de novo. See Conn. Bar Ass'n v.
United States, 620 F.3d 81, 89 (2d Cir. 2010) ("We review
constitutional challenges to a federal statute de novo.");
see also United States v. Dhafir, 461 F.3d 211, 215 (2d Cir.
2006) (same). We agree that Caronia's conviction must be
vacated, but for narrower reasons than he urges.
8
Caronia also argues that the verdict sheet was
improperly phrased and the jury's verdict was inconsistent. In
light of our disposition of the First Amendment issue, we need
not reach these issues.
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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. See supra 7-8, 10.
Rather, the FDCA and FDA regulations reference "promotion"
only as evidence of a drug's intended use. See 21 U.S.C.
§ 201.128 (discussing how drug's intended use can be
demonstrated). Thus, under the principle of constitutional
avoidance, explained infra, 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.
We begin by addressing the government's contention
that Caronia's off-label promotion was used only as evidence
of intent in this case. Finding the government's argument
unpersuasive, we turn to the principal question on appeal:
whether the government's prosecution of Caronia under the
-26-
FDCA only for promoting an FDA-approved drug for off-label
use was constitutionally permissible.
I. Speech versus Evidence of Intent
The government contends -- and the dissent agrees
-- that the First Amendment is not implicated in this case.
Specifically, the government argues that "[p]romoting an
approved drug for off-label uses is not itself a prohibited
act under the FDCA" and "the promotion of off-label uses
plays an evidentiary role in determining whether a drug is
misbranded under 21 U.S.C. § 352(f)(1)." (Gov't Br. 51
(citing 21 U.S.C. § 331)). The government contends that
Caronia was not prosecuted for his speech, but that
Caronia's promotion of Xyrem for off-label use served merely
as "evidence of intent," or evidence that the "off-label
uses were intended ones[] for which Xyrem's labeling failed
to provide any directions." (Gov't Br. 52).
Even assuming the government can offer evidence of
a defendant's off-label promotion to prove a drug's intended
-27-
use and, thus, mislabeling for that intended use,9 that is
not what happened in this case.
First, the government's contention that it did not
prosecute Caronia for promoting the off-label use of an FDA-
approved drug is belied by its conduct and arguments at
trial. The excerpts quoted above demonstrate that the
government repeatedly argued that Caronia engaged in
criminal conduct by promoting and marketing the off-label
use of Xyrem, an FDA-approved drug. See supra 21-22 & n.7.
The district court record thus confirms overwhelmingly that
Caronia was, in fact, prosecuted and convicted for promoting
Xyrem off-label. See supra 12-24. Indeed, in the
government's summation and rebuttal at trial, Caronia's off-
label promotion of Xyrem is highlighted over forty times.
(See Trial Tr. 819-49, 870-80, 883-85).
9
See Wisconsin v. Mitchell, 508 U.S. 476, 489 (1993)
(concluding First Amendment "does not prohibit the use of speech
to establish . . . intent"); Whitaker v. Thompson, 353 F.3d 947,
953 (D.C. Cir. 2004) (holding product's labeling may be used to
infer its intended use and, thus, whether it is an unapproved
drug under FDCA).
-28-
Second, the government's assertion now that it
used Caronia's efforts to promote Xyrem for off-label use
only as evidence of intent is simply not true. Even if the
government could have used Caronia's speech as evidence of
intent, the district court record clearly shows that the
government did not so limit its use of that evidence. See
Mitchell, 508 U.S. at 489-90 (instructing that, when speech
is introduced as evidence of intent, "'[s]uch testimony is
to be scrutinized with care to be certain the statements are
not expressions of mere lawful and permissible difference of
opinion with our own government'" (quoting Haupt v. United
States, 330 U.S. 631, 642 (1947))). The government never
argued in summation or rebuttal that the promotion was
evidence of intent. (See Trial Tr. 819-49, 870-80, 883-85).
The government never suggested that Caronia engaged in any
form of misbranding other than the promotion of the off-
label use of an FDA-approved drug. The government never
suggested, for example, that Caronia conspired to place
false or deficient labeling on a drug. See 21 U.S.C. §§
352(a)-(n). Rather, the record makes clear that the
-29-
government prosecuted Caronia for his promotion and
marketing efforts.
Third, the government's summation and the district
court's instruction left the jury to understand that
Caronia's speech was itself the proscribed conduct. See
supra 21-23. Indeed, the district court flatly stated to
the jury that pharmaceutical representatives are prohibited
from engaging in off-label promotion. See id. Although the
district court explained the remaining elements of
misbranding and conspiring to misbrand to the jury, this
specific instruction -- together with the government's
summation -- would have led the jury to believe that
Caronia's promotional speech was, by itself, determinative
of his guilt. See generally United States v. Dyer, 922 F.2d
105, 107-08 (2d Cir. 1990) (stating specific jury
instruction may be reviewed in isolation if "it is so far
removed from the standards set by the law that the appellate
court is convinced that the jury might have been misled"
(internal quotation marks omitted)).
-30-
Fourth, the government clearly prosecuted Caronia
for his words –- for his speech. A pharmaceutical
representative's promotion of an FDA-approved drug's off-
label use is speech. As the Supreme Court has held:
"Speech in aid of pharmaceutical marketing . . . is a form
of expression protected by the Free Speech Clause of the
First Amendment." Sorrell v. IMS Health, Inc., 131 S. Ct.
2653, 2659 (2011). Here, the proscribed conduct for which
Caronia was prosecuted was precisely his speech in aid of
pharmaceutical marketing.
Accordingly, we conclude that the government did
prosecute Caronia for his speech, and we turn to whether the
prosecution was permissible.
II. The Prosecution of Caronia's Speech
While the government and the FDA have construed
the FDCA's misbranding provisions to prohibit off-label
promotion by pharmaceutical manufacturers, see supra 10; see
FDA, Draft Guidance, supra, at 2-3, as we have observed, the
FDCA itself does not expressly prohibit or criminalize off-
label promotion. See supra 7-8, 10. The FDCA defines
-31-
misbranding in terms of whether a drug's labeling is
adequate for its intended use, and permits the government to
prove intended use by reference to promotional statements
made by drug manufacturers or their representatives. See
id. Assuming that this approach to the use of evidence of
speech is permissible,10 it affords little support to the
government on this appeal because Caronia was not prosecuted
on this basis. Rather, the government's theory of
prosecution identified Caronia's speech alone as the
proscribed conduct. The district court accepted this
theory.
To the extent there is any ambiguity as to whether
off-label promotion is tantamount to illegal misbranding, we
10
Although we assume, without deciding, that such use of
evidence of speech is permissible under Mitchell, 508 U.S. 476,
we observe that it still remains unclear how the government would
identify criminal misbranding from communications between drug
manufacturers and physicians authorized to prescribe drugs for
off-label use. For example, 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? Because this case does not present us with that
circumstance or others that might raise questions about the scope
of the misbranding proscription, we need not address them here.
-32-
construe the FDCA narrowly to avoid a serious constitutional
question. See Skilling v. United States, 130 S. Ct. 2896,
2929-30 (2010) (instructing courts to "avoid constitutional
difficulties by adopting a limiting interpretation if such a
construction is fairly possible" (internal quotation marks
and brackets omitted)); Edward J. DeBartolo Corp. v. Fla.
Gulf Coast Bldg. & Constr. Trades Council, 485 U.S. 568, 575
(1988); Allstate Ins. Co. v. Serio, 261 F.3d 143, 150 (2d
Cir. 2001) ("Thus, the courts will take pains to give a
statute a limiting construction in order to avoid a
constitutional difficulty.").
As we now explain, 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.
A. Applicable First Amendment Doctrine
The First Amendment protects against government
regulation and suppression of speech on account of its
-33-
content. Turner Broad. System, Inc. v. F.C.C., 512 U.S.
622, 641-42 (1994); see Ward v. Rock Against Racism, 491
U.S. 781, 791 (1989); R.A.V. v. City of St. Paul, 505 U.S.
377, 386 (1992). Content-based speech restrictions are
subject to "strict scrutiny" –- that is, the government must
show that the regulation at issue is narrowly tailored to
serve or promote a compelling government interest. See
Brown v. Entm't Merchs. Ass'n, 131 S. Ct. 2729, 2738 (2011)
(citing R.A.V., 505 U.S. at 395). Content-based government
regulations are "presumptively invalid." R.A.V., 505 U.S.
at 382. Meanwhile, non-content-based regulation and
regulation of commercial speech -- expression solely related
to the economic interests of the speaker and its audience --
are subject to intermediate scrutiny. See Turner Broad.,
512 U.S. at 642; Cent. Hudson Gas & Elec. Corp. v. Pub.
Serv. Comm'n of N.Y., 447 U.S. 557, 563-64 (1980). Criminal
regulatory schemes, moreover, warrant even more careful
scrutiny. See Holder v. Humanitarian Law Project, 130 S.
Ct. 2705, 2724 (2010) (applying more rigorous scrutiny); id.
at 2734 (Breyer, J., dissenting) ("It is not surprising that
the majority, in determining the constitutionality of
-34-
criminally prohibiting the plaintiffs' proposed activities,
would apply . . . a more demanding standard. Indeed, where,
as here, a statute applies criminal penalties . . . I should
think we would scrutinize the statute and justifications
strictly." (internal quotation marks and citations omitted)
(citing cases))); see also City of Houston v. Hill, 482 U.S.
451, 459 (1987) ("Criminal statutes must be scrutinized with
particular care." (internal citations omitted)).
In applying these principles, we have a benefit
not available to the district court: the Supreme Court's
decision in Sorrell v. IMS Health, Inc., 131 S. Ct. 2653(2011), a case involving speech restrictions on
pharmaceutical marketing. In Sorrell, the Vermont
Prescription Confidentiality Law (the "VPCL") prohibited
pharmaceutical companies and similar entities from using
prescriber-identifying information for marketing purposes;
it was challenged on First Amendment grounds. Id. at 2661-
62; see also Vt. Stat. Ann., Tit. 18 § 4631(e)(4).
The Sorrell Court held that "[s]peech in aid of
pharmaceutical marketing . . . is a form of expression
protected by the . . . First Amendment. . . . [The] creation
-35-
and dissemination of information are speech within the
meaning of the [Constitution]." Id. at 2659, 2667. The
Court held that the Vermont statute set forth content- and
speaker-based restrictions, and that the statute was
therefore subject to heightened scrutiny. Id. at 2662-65.
Because the VPCL disfavored speech with a particular content
(marketing) when expressed by certain disfavored speakers
(pharmaceutical manufacturers), the Court held that it
unconstitutionally restricted speech. Id. at 2662-65, 2672.
In reaching this conclusion, Sorrell engaged in a
two-step inquiry. First, the Court considered whether the
government regulation restricting speech was content- and
speaker-based. See id. at 2662-64. The Court held that it
was; the regulation was therefore subject to heightened
scrutiny and was "presumptively invalid." See id. Second,
the Court considered whether the government had shown that
the restriction on speech was consistent with the First
Amendment under the applicable level of heightened scrutiny.
Id. at 2663, 2667-68. The Court did not decide the level of
heightened scrutiny to be applied, that is, strict,
intermediate, or some other form of heightened scrutiny.
-36-
Id. Rather, after observing that "[i]n the ordinary case,
it is all but dispositive to conclude that a law is content-
based," the Court concluded that the Vermont statute was
unconstitutional even under the lesser intermediate standard
set forth in Central Hudson. Id. at 2667; see Cent. Hudson,
447 U.S. at 566. The Court further observed that the
"outcome is the same whether a special commercial speech
inquiry or a stricter form of judicial scrutiny is applied."
Sorrell, 131 S. Ct. at 2667.
In considering whether the government had shown
that the restriction on speech was consistent with the First
Amendment, the Sorrell Court turned to Central Hudson. See
id. at 2667-68. Central Hudson sets forth a four-part test
to determine whether commercial speech is protected by the
First Amendment. Cent. Hudson, 447 U.S. at 566. First, as
a threshold matter, to warrant First Amendment protection,
the speech in question must not be misleading and must
concern lawful activity. Id; see infra note 11 and
accompanying text. Second, to justify regulations
restricting speech, the asserted government interest must be
substantial. Id. Third, the regulation must directly
-37-
advance the governmental interest asserted, id., "to a
material degree," 44 Liquormart, Inc. v. Rhode Island, 517
U.S. 484, 505 (1996) (quoting Edenfield v. Fane, 507 U.S.
761, 771 (1993)). "[A] commercial speech regulation 'may
not be sustained if it provides only ineffective or remote
support for the government's purpose.'" Liquormart, 517
U.S. at 505 (quoting Cent., 447 U.S. at 564). Fourth, the
regulation must be "narrowly drawn," and may not be more
extensive than necessary to serve the interest, Cent.
Hudson, 447 U.S. at 565-56; see also Sorrell, 131 S. Ct. at2667-69 (citing Bd. of Tr. of State Univ. of N.Y. v. Fox,
492 U.S. 469, 480-81 (1989)); Thompson v. W. States Med.
Ctr., 535 U.S. 357, 374 (2002). The government cannot
"completely suppress information when narrower restrictions
on expression would serve its interests as well." Cent.
Hudson, 447 U.S. at 565. "Under the commercial speech
inquiry, it is the [government's] burden to justify its
content-based law as consistent with the First Amendment."
Sorrell, 131 S. Ct. at 2667 (citing Thompson, 535 U.S. at
373).
-38-
B. Application
In prosecuting Caronia, the government construed
the FDCA's misbranding provisions to prohibit and
criminalize the promotion of off-label drug use. We review
the government's theory of prosecution under the Sorrell
Court's two-step analysis to determine whether it runs afoul
of the First Amendment. First, we conclude that the
government's construction of the FDCA's misbranding
provisions imposes content- and speaker-based restrictions
on speech subject to heightened scrutiny. Second, we
conclude the government cannot justify a criminal
prohibition of off-label promotion even under Central
Hudson's less rigorous intermediate test.
1. Heightened Scrutiny
The government's construction of the FDCA's
misbranding provisions to prohibit and criminalize the
promotion of off-label drug use by pharmaceutical
manufacturers is content- and speaker-based, and, therefore,
subject to heightened scrutiny. See id.First, the government's interpretation of the
FDCA's misbranding provisions to prohibit off-label
-39-
promotion is content-based because it distinguishes between
"favored speech" and "disfavored speech on the basis of the
ideas or views expressed." See Turner Broad., 512 U.S. at
643; accord Sorrell, 131 S. Ct. at 2663. Under this
construction, speech about the government-approved use of
drugs is permitted, while certain speech about the off-label
use of drugs -- that is, uses not approved by the government
-- is prohibited, even though the off-label use itself is
not. See 21 U.S.C. §§ 331(a), 333(a)(2). Indeed, the
content of the regulated speech drives this construction of
the FDCA; 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." See Sorrell, 131 S. Ct. at 2663.
Second, this construction is speaker-based because
it targets one kind of speaker -- pharmaceutical
manufacturers -- while allowing others to speak without
restriction. See id. at 2663. In Sorrell, pharmaceutical
companies were barred from obtaining and using prescriber-
identifying information for marketing purposes, but a wide
range of other speakers, including private and academic
-40-
researchers, could acquire and use the information. Id.Similarly, here, because off-label prescriptions and drug
use are legal, the government's application of the FDCA
permits physicians and academics, for example, to speak
about off-label use without consequence, while the same
speech is prohibited when delivered by pharmaceutical
manufacturers. See 21 U.S.C. §§ 331(a), 333(a). This
construction "thus has the effect of preventing
[pharmaceutical manufacturers] -- and only [pharmaceutical
manufacturers] -- from communicating with physicians in an
effective and informative manner." Sorrell, 131 S. Ct. at
2663.
Additionally, a claim to First Amendment
protection here is more compelling than in Sorrell because
this case involves a criminal regulatory scheme subject to
more careful scrutiny. See 21 U.S.C. § 333(a); Humanitarian
Law Project, 130 S. Ct. at 2724.
Accordingly, the government's construction of the
FDCA's misbranding provisions to prohibit and criminalize
off-label promotion is content- and speaker-based, and
subject to heightened scrutiny under Sorrell.
-41-
2. Central Hudson
The first two prongs of Central Hudson are easily
satisfied here. First, promoting off-label drug use
concerns lawful activity (off-label drug use), and the
promotion of off-label drug use is not in and of itself
false or misleading.11 See Cent. Hudson, 447 U.S. at 566.
Second, the government's asserted interests in drug safety
and public health are substantial. See id. Specifically,
the government asserts an interest in preserving the
11
In Whitaker, cited by the dissent (Diss. Op. 14), the
D.C. Circuit held that the labeling of a product, which was not
approved by the FDA as a drug, 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. See Whitaker, 353 F.3d at 953.
The government does not contend that off-label
promotion is in and of itself false or misleading. Of course,
off-label promotion that is false or misleading is not entitled
to First Amendment protection. See Cent. Hudson, 447 U.S. at
566. Under 21 U.S.C. § 331(a), a defendant may be prosecuted for
untruthfully promoting the off-label use of an FDA-approved drug,
e.g., making false or misleading statements about a drug.
The government did not argue at trial, nor does it
argue on appeal, that the promotion in question was false or
misleading. (See Trial Tr. 823 (mentioning, in government's
summation, that Caronia "did not give accurate and complete
information in promoting and marketing Xyrem," but focusing on
promotion as misbranding and not pursuing argument that speech
was false or misleading); Gov't Br. 58 (considering whether "the
commercial speech in question clears [the] hurdle" of Central
Hudson's first prong, but not contending that the speech concerns
unlawful activity or is false or misleading)).
-42-
effectiveness and integrity of the FDCA's drug approval
process, and an interest in reducing patient exposure to
unsafe and ineffective drugs. See FDA v. Brown & Williamson
Tobacco Corp., 529 U.S. 120, 133 (2000) ("[O]ne of the
[FDCA's] core objectives is to ensure that any product
regulated by the FDA is 'safe' and 'effective' for its
intended use.").
The third and fourth prongs of Central Hudson
require that the regulation directly advance the
government's interests and be narrowly drawn. See Cent.
Hudson, 447 U.S. at 566. We turn to the third and fourth
prongs below.
a. Direct Advancement
The government's construction of the FDCA as
prohibiting off-label promotion does not, by itself,
withstand scrutiny under Central Hudson's third prong.
First, off-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,
-43-
drugs for off-label purposes. See supra 4-7. 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. See Sorrell, 131
S. Ct. at 2668-69 (holding government interest in protecting
physician privacy not directly served when law made
prescriber-identifying information available to "all but a
narrow class of disfavored speakers").
Second, 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.
See Va. Bd. of Pharmacy v. Va. Citizens Consumer Council,
Inc., 425 U.S. 748, 770 (1976) (discussing "highly
paternalistic approach" of government prohibitions on free
-44-
flow of information); see also Sorrell, 131 S. Ct. at 2670-
72 ("[The] fear that [physicians, sophisticated and
experienced customers,] would make bad decisions if given
truthful information" cannot justify content-based burdens
on speech.") (citing sources); Liquormart, 517 U.S. at 503("[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."). In fact,
in 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 non-misleading scientific and medical information on
unapproved uses" of approved drugs. Dep't of Health and
Human Serv., Good Reprint Practices, supra, at III, V; see
Wash. Legal Found. v. Henney, 202 F.3d 331, 335 (D.C. Cir.
2000) (discussing FDA "safe harbor," where certain forums
for off-label discussion, such as continuing medical
-45-
education programs and scientific publications, would not be
used against manufacturers in misbranding enforcement
actions).
Here, as the FDA recognizes, it is the physician's
role to consider multiple factors, including a drug's FDA-
approval status, to determine the best course of action for
her patient. See FDA Drug Bull., supra, at 5; Buckman, 531
U.S. at 350; Weaver, 886 F.2d at 198-99; 21 U.S.C. § 396;
see also Thompson, 535 U.S. at 367 (discussing the "general
rule" that "the speaker and the audience, not the
government, assess the value of the information presented")
(quoting Edenfield, 507 U.S. at 767); see also Va. Bd. of
Pharmacy, 425 U.S. at 770 ("[T]he choice . . . is not ours
to make or the [legislature's]."). While some off-label
information could certainly be misleading or unhelpful, this
case does not involve false or misleading promotion. See
supra note 11. 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. See Sorrell, 131 S. Ct.
-46-
at 2664, 2671; Thompson, 535 U.S. at 366 (quoting Va. Bd. of
Pharmacy, 425 U.S. at 765).
The government's construction of the FDCA
essentially legalizes the outcome -- off-label use -- but
prohibits the free flow of information that would inform
that outcome. 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. Thus,
the government's construction of the FDCA's misbranding
provisions does not directly advance its interest in
reducing patient exposure to off-label drugs or in
preserving the efficacy of the FDA drug approval process
because the off-label use of such drugs continues to be
generally lawful. Accordingly, the government's prohibition
of off-label promotion by pharmaceutical manufacturers
"provides only ineffective or remote support for the
government's purpose." See Liquormart, 517 U.S. at 504-05(quoting Cent. Hudson, 447 U.S. at 564).
-47-
b. Narrowly Drawn
The last prong of Central Hudson requires the
government's regulation to be narrowly drawn to further the
interests served. Cent. Hudson, 447 U.S. at 566. Here, the
government's construction of the FDCA to impose a complete
and criminal ban on off-label promotion by pharmaceutical
manufacturers is more extensive than necessary to achieve
the government's substantial interests. See id. Numerous,
less speech-restrictive alternatives are available, as are
non-criminal penalties. See Thompson, 535 U.S. at 372-73.
To advance the integrity of the FDA's drug
approval process and increase the safety of off-label drug
use, the government could pursue several alternatives
without excessive First Amendment restrictions. See Cent.
Hudson, 447 U.S. at 564. For example, if the government is
concerned about the use of drugs off-label, it could more
directly address the issue. If the government is concerned
that off-label promotion may mislead physicians, it could
guide physicians and patients in differentiating between
misleading and false promotion, exaggerations and
embellishments, and truthful or non-misleading information.
-48-
See Osborn, Can I Tell You The Truth?, supra, at 306-07.
The government could develop its warning or disclaimer
systems, or develop safety tiers within the off-label
market, to distinguish between drugs. See Coleen Klasmeier
and Martin H. Redish, Off-Label Prescription Advertising,
the FDA and the First Amendment: A Study in the Values of
Commercial Speech Protection, 37 Am. J.L. & Med. 315, 334
(2011). The government could require pharmaceutical
manufacturers to list all applicable or intended indications
when they first apply for FDA approval, enabling physicians,
the government, and patients to track a drug's development.
To minimize off-label use, or manufacturer evasion of the
approval process for such use, the government could create
other limits, including ceilings or caps on off-label
prescriptions. The FDA could further remind physicians and
manufacturers of, and even perhaps further regulate, the
legal liability surrounding off-label promotion and
treatment decisions.12 Finally, where off-label drug use is
12
Physicians and pharmaceutical manufacturers can be held
accountable for off-label drug use through medical malpractice
and negligence theories of liability. See generally Boyle v.
Revici, 961 F.2d 1060 (2d Cir. 1992); Sita v. Danek Med. Inc., 43
-49-
exceptionally concerning, the government could prohibit
the off-label use altogether. See, e.g., Bader, 678 F.3d at
873-75 & n.10 (citing 21 U.S.C. § 333(e) (prohibiting off-
label use of human growth hormone)). The possibilities are
numerous indeed.
"If the First Amendment means anything, it means
that regulating speech must be a last -- not first --
resort." Thompson, 535 U.S. at 373. The government has not
established a "reasonable fit" among its interests in drug
safety and public health, the lawfulness of off-label use,
and its construction of the FDCA to prohibit off-label
promotion. See Fox, 492 U.S. at 480. The government's
interests could be served equally well by more limited and
targeted restrictions on speech. See Cent. Hudson, 447 U.S.
at 565. The government contends that these alternative
means of reducing patient exposure to unsafe, untested drugs
and maintaining the integrity of the FDA-approval process
are "indefensible" (Gov't Br. 70), because they are not
administrable, feasible, or otherwise effective. In the
F. Supp. 2d 245 (E.D.N.Y. 1999); Retkwa v. Orentreich, 584
N.Y.S.2d 710 (N.Y. Sup. Ct. 1992).
-50-
absence of any support, such conclusory assertions are
insufficient to sustain the government's burden of
demonstrating that the proposed alternatives are less
effective than its proposed construction of the FDCA in
furthering the government interests identified. See
Ashcroft v. ACLU, 542 U.S. 656, 665, 669 (2004).
Accordingly, even if speech can be used as
evidence of a drug's intended use, we decline to adopt the
government's construction of the FDCA's misbranding
provisions to prohibit manufacturer promotion alone as it
would unconstitutionally restrict free speech. We construe
the misbranding provisions of the FDCA as not prohibiting
and criminalizing the truthful off-label promotion of FDA-
approved prescription drugs. Our conclusion is limited to
FDA-approved drugs for which off-label use is not
prohibited, and we do not hold, of course, that the FDA
cannot regulate the marketing of prescription drugs. We
conclude simply that the government cannot prosecute
pharmaceutical manufacturers and their representatives under
the FDCA for speech promoting the lawful, off-label use of
an FDA-approved drug.
-51-
CONCLUSION
For the reasons set forth above, we VACATE the
judgment of conviction and REMAND the case to the district
court.
-52-
DEBRA ANN LIVINGSTON, Circuit Judge, dissenting:
Alfred Caronia was convicted of conspiring to introduce a prescription drug
into interstate commerce with the intent that it be used in ways its labeling
neither disclosed nor described. This intent was revealed, inter alia, through his
speech. Because the First Amendment has never prohibited the government
from using speech as evidence of motive or intent, see Wisconsin v. Mitchell, 508
U.S. 476, 489 (1993), I would affirm Caronia's conviction. By holding, instead,
that Caronia’s conviction must be vacated—and on the theory that whatever the
elements of the crime for which he was duly tried, he was in fact convicted for
promoting a drug for unapproved uses, in supposed violation of the First
Amendment—the majority calls into question the very foundations of our
century-old system of drug regulation. I do not believe that the Supreme Court's
precedents compel such a result. I therefore respectfully dissent.
I. Intended Uses
Alfred Caronia was convicted of conspiring to introduce a “misbranded”
drug into interstate commerce. See 18 U.S.C. § 371; 21 U.S.C. § 331(a). Under
the Federal Food, Drug and Cosmetic Act ("FDCA"), one way in which a drug is
misbranded is if its labeling lacks adequate directions for layperson use. See 21
U.S.C. § 352(f)(1); 21 C.F.R. § 201.5. Whether a drug’s directions are
“adequate . . . for use” depends on the drug’s intended uses. This is because the
1
Food and Drug Administration (“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.” 21 C.F.R. § 201.5 (emphasis added). Directions are
adequate only if they include, for example, “[s]tatements of all . . . uses for which
such drug is intended,” and “usual quantities [of dose] for each of the uses for
which it is intended.” 21 C.F.R. § 201.5(a), (b). This labeling provision is in part
merely a disclosure requirement for the benefit of a drug’s lay users. But some
uses of drugs are never safe, at least for a layperson; 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.1
The labeling on the drug at issue in this case, Xyrem, stated that it was
“indicated for the treatment of excessive daytime sleepiness and cataplexy in
patients with narcolepsy.” At all relevant times, the FDA had not approved
Xyrem for any other uses. Xyrem’s labeling did not state any other intended
1
The FDA has exempted certain drugs from the requirement that their labels
contain adequate directions for lay use. See 21 U.S.C. § 352(f); see, e.g., 21 C.F.R.
§ 201.100 (exempting certain prescription drugs); cf. United States v. An Article of
Device, 731 F.2d 1253, 1259 (7th Cir. 1984) (“Obviously there are many medical devices
which would be ineffective at best, and dangerous at worst, if left in the hands of a
layman, and [FDA regulations] appear[] to deem any such devices ‘misbranded’ and
thus subject to seizure. However, the regulations provide several exemptions from the
‘adequate directions for use’ requirement.”). Caronia does not argue that any such
exemption applies here.
2
uses for the drug, nor provide directions for any other intended uses.
Unsurprisingly, then, Caronia did not argue before the jury that Xyrem’s
labeling included adequate directions for the off-label uses that he was alleged
to have promoted. Rather, his trial focused on whether Caronia agreed with his
employer, Orphan Medical, Inc. (“Orphan”), and with others associated with
Orphan, that Xyrem would be distributed for off-label use.
Determining a product’s “intended uses” has long been a central concern
of food and drug law. The concept originated in the Pure Food and Drugs Act of
1906, Pub. L. No. 59-384, 34 Stat. 768, which prohibited introducing any
adulterated or misbranded drug into interstate commerce, id. § 2, 34 Stat. at
768, and which defined “drug” to include “any substance or mixture of
substances intended to be used for the cure, mitigation, or prevention of disease,”
id. § 5, 34 Stat. at 769 (emphasis added). Courts found violations of that statute
where, as in this case, a manufacturer’s speech demonstrated an intended use
that brought it within the scope of the statute such that its label was required
affirmatively to disclose certain information. See, e.g., United States v. Eleven
Cartons of Drug Labeled in Part “Vapex,” 59 F.2d 446 (D. Md. 1932) (holding
that “Vapex” was “intended to be used for the cure, mitigation or prevention of
disease,” and was thus a “drug,” because its label stated that it was “effective to
relieve a head cold instantly,” id. at 447; and further holding that the drug was
3
misbranded, even “assum[ing] that the inhalation of Vapex is innocuous,”
because it was “required to contain a declaration on the label of the alcoholic
content” yet failed to do so, id. at 449).
When Congress expanded the law three decades later in the Food, Drug,
and Cosmetic Act of 1938, Pub. L. No. 75-717, 52 Stat. 1040, its revisions
remained anchored to the concept of “intended uses.” The definition of “drug”
was broadened to also include “articles . . . intended to affect the structure or any
function of the body,” id. § 201(g)(3), 52 Stat. at 1041 (emphasis added), and the
parallel category of “devices” was created and similarly defined in terms of
intended uses, see id. § 201(h), 52 Stat. at 1041. At the same time, Congress
broadened the definition of a “misbranded” drug to include any drug with
labeling not bearing “adequate directions for use.” Id. § 502(f)(1), 52 Stat. at
1051. Under the 1938 Act, courts upheld convictions for introducing drugs into
interstate commerce that lacked adequate labeling for their intended uses, and
routinely relied on “oral representations made by . . . authorized sales
distributors” to determine a product’s intended uses. V.E. Irons, Inc. v. United
States, 244 F.2d 34, 44 (1st Cir. 1957) (upholding a conviction for introducing
into interstate commerce “articles of drug [that] were misbranded in that their
labeling failed to bear ‘adequate directions for use’ for the various diseases and
conditions for which they were intended,” and relying on “both graphic materials
4
distributed and testimony of oral representations to users and prospective
users . . . . show[ing] that the products shipped were to be used as drugs”).
The modern FDCA continues to define “drugs” (and “devices”) on the basis
of an article’s intended uses. See 21 U.S.C. § 321(g)(1)(B), (C); 21 U.S.C.
§ 321(h)(2), (3). The concept of “intended uses” therefore largely defines the
scope of the FDA’s regulatory authority. See FDA v. Brown & Williamson
Tobacco Corp., 529 U.S. 120, 126 (2000). To put the matter in practical terms:
it is because of the “intended uses” principle that 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.”2
According to regulations that have remained essentially unchanged for
sixty years, see 17 Fed. Reg. 6818, 6820 (1952) (codified at 21 C.F.R. § 1.106(o)
(Cm. Supp. 1955)), the FDA defines a drug’s “intended uses” on an objective,
rather than subjective, basis:
The words intended uses or words of similar import . . . refer to the
2
See Wikipedia, Hamlin’s Wizard Oil,
http://en.wikipedia.org/wiki/Hamlin’s_Wizard_Oil (last visited May 30, 2012); cf.
United States v. Rutherford, 442 U.S. 544, 558 (1979) (“Since the turn of the century,
resourceful entrepreneurs have advertised a wide variety of purportedly simple and
painless cures for cancer, including liniments of turpentine, mustard, oil, eggs, and
ammonia; peat moss; arrangements of colored floodlamps; pastes made from glycerin
and limburger cheese; mineral tablets; and ‘Fountain of Youth’ mixtures of spices, oil,
and suet. . . . [H]istorical experience does suggest why Congress could reasonably have
determined to protect . . . patients[] from the vast range of self-styled panaceas that
inventive minds can devise.”).
5
objective intent of the persons legally responsible for the labeling of
drugs. The intent is determined by such persons’ expressions or
may be shown by the circumstances surrounding the distribution of
the article. This objective intent may, for example, be shown by
labeling claims, advertising matter, or oral or written statements by
such persons or their representatives. It may be shown by 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. . . . [I]f a manufacturer
knows, or has knowledge of facts that would give him notice, that a
drug introduced into interstate commerce by him is to be used for
conditions, purposes, or uses other than the ones for which he offers
it, he is required to provide adequate labeling for such a drug which
accords with such other uses to which the article is to be put.
21 C.F.R. § 201.128. As previously noted, Caronia did not contend at trial that
Xyrem’s label (which provided dosage and other instructions for Xyrem’s use in
the treatment of narcolepsy patients who experience cataplexy and excessive
daytime sleepiness) provided adequate instructions for any other use. In this
case, then, Xyrem was “misbranded”—and Caronia could be guilty of conspiring
with others to introduce it into interstate commerce in such a state—if the
conduct and statements of the persons legally responsible for labeling the drug
(or the conduct and statements of their representatives) demonstrated an
objective intent that Xyrem be used for off-label purposes.
II. The First Amendment and Speech as Evidence of Intent
It is well settled that “[t]he First Amendment . . . does not prohibit the
evidentiary use of speech to establish the elements of a crime or to prove motive
or intent.” Wisconsin v. Mitchell, 508 U.S. 476, 489 (1993). To demonstrate that
6
Xyrem was intended for off-label uses (and thus that it was misbranded) the
prosecution in this case relied, inter alia, upon Caronia’s statements that Xyrem
could be used to treat “insomnia, [f]ibromyalgia[,] periodic leg movement,
restless leg, . . . Parkinson’s and . . . MS.”3 Because Caronia’s speech was used
simply as evidence of Xyrem’s intended uses, I agree with the government that
Caronia’s conviction does not run afoul of the First Amendment.
The majority unsurprisingly agrees that speech may be used as evidence
of intent. It even leaves open the possibility that speech may serve as evidence
of intent to introduce a misbranded drug into interstate commerce. See Maj. Op.
at 25. The majority nonetheless concludes that in this particular case “the
government clearly prosecuted Caronia for his words—for his speech” and not
for conspiring to introduce a misbranded drug into interstate commerce. Maj.
3
This was not the only evidence on which the government relied. As the
majority acknowledges, Xyrem is a “powerful central nervous system depressant” that
the FDA requires to bear a “black box” warning (the most serious warning placed on
prescription medicine) in light of its potential side effects, which include seizure,
respiratory depression, coma, and death. Maj. Op. at 11. Yet in the tape-recorded
meeting of October 26, 2005 between Caronia and Dr. Charno, to which the majority
refers, Caronia described Xyrem as “a very safe drug,” with no contraindications. At
Caronia’s second meeting with Dr. Charno on November 2, Dr. Gleason, one of
Caronia’s co-conspirators, described many potential uses for Xyrem, including in the
treatment of obesity and chronic fatigue, and added that “for the problems with
insomnia there’s no better drug, no safer drug, it’s as safe as Ambien and Sonata . . . .”
Caronia later admitted that his employer required him to meet an annual sales quota
of 520 bottles of Xyrem in 2005, the year these conversations took place, and that he
was unable to meet it. In fact, the salaries of Orphan’s sales personnel depended to a
significant degree on meeting sales targets, and in 2005 Caronia was ranked near the
very bottom of Orphan’s national sales force.
7
Op. at 27–28. I disagree that the government prosecuted Caronia for his speech.
I also fail to see how the majority’s reasoning would ever allow such speech to
support a conviction under 21 U.S.C. § 331(a). For this reason, I conclude the
majority’s opinion is fundamentally at odds both with Mitchell and with the
underlying premises behind much of the FDCA’s regulatory scheme.
I do not agree with the majority that Caronia was “prosecuted and
convicted for promoting Xyrem off-label.” Maj. Op. at 26. The district court
correctly instructed the jury as to all the elements necessary to prove a
conspiracy, as well as the additional elements, derived from 21 U.S.C. § 331(a),
to prove the conspiracy’s unlawful purpose:
To sustain the charge of conspiracy to introduce
into interstate commerce a misbranded drug, the
Government must prove the element[s] of conspiracy as
I previously described them for you and must also prove
the following elements of misbranding through the
introduction of a misbranded drug into interstate
commerce.
First, the Government must prove that the
defendant conspired to introduce or conspired to cause
to be introduced a drug into interstate commerce or
conspired to deliver a drug for introduction into
interstate commerce or conspired to cause a drug to be
delivered for introduction into interstate commerce.
Second, the Government must prove that the
drug was misbranded, as I’ve previously defined that
term.
If you find that the Government has satisfied its
burden with respect to each of these elements, along
with satisfying the elements of conspiracy as I have
previously explained them to you, then you should find
8
the defendant guilty of that prong of the conspiracy
count charging him with conspiracy to misbrand in
violation of Section 331(a).
The majority makes much of the fact that the district court also instructed
the jury that “[a] misbranded drug may be shown by a promotion of the drug by
a distributor for an intended use different from the use for which the drug was
approved by the Food and Drug Administration.” But this wholly appropriate
charge was but part of the district court’s explanation of the “objective intent”
standard with respect to “intended uses”:
The intended use of a drug can be determined from its label,
accompanying labels, promotional material, advertising or any other
relevant source that reveals the manner in which the drug’s
distributors expect[ ] the product to be used. A misbranded drug
may be shown by a promotion of the drug by a distributor for an
intended use different from the use for which the drug was approved
by the Food and Drug Administration, the Government agency
charged with the responsibility for approving a drug’s use. Under
21 Code of Federal Regulations, Section 201.128, intended use or
words of a similar import refer to the objective intent of the persons
legally responsible for the labeling of drugs. The intent is
determined by such persons’ expressions or may be shown by the
circumstances surrounding the distribution of the drug. This
objective intent may, for example, be shown by labeling claims,
advertising matter or oral or written statements by such persons or
their representatives. It may be shown by the circumstances that
the drug is, with the knowledge of such persons or their
representatives, offered and used for a purpose for which it is
neither labeled, nor advertised.
Granted, in a single sentence at the conclusion of this instruction the district
court stated that drug manufacturers “are not permitted to promote uses for a
9
drug that have not been cleared by the United States Food and Drug
Administration.” In context, however, the district court was simply instructing
the jury that promotion of an off-label use may demonstrate an objective intent
that a drug be used for off-label purposes—and thus that it is being placed into
interstate commerce without proper labeling. And this, contrary to the
majority’s suggestion, was not error.4 See United States v. Sabhnani, 599 F.3d
215, 237 (2d Cir. 2010) (admonishing that jury instructions are not to be read in
isolation, but in their entirety, to determine whether they communicate the
“essential ideas” to the jury); accord United States v. Tran, 519 F.3d 98, 105 (2d
Cir. 2008); see also Cupp v. Naughten, 414 U.S. 141, 146–47 (1973) (“[A] single
4
Notably, Caronia himself does not argue that the district court’s
instruction was improper. While I disagree with the majority’s conclusion that
the jury was improperly instructed, moreover, I note to be clear that an identical
instruction could be problematic in a different case of alleged
misbranding—where a defendant argued, for example, that the drug’s labeling
included adequate directions for uses that were not FDA-approved. Cf. United
States v. Articles of Drug, 585 F.2d 575, 585 n.20 (3d Cir. 1978) (instructing the
district court, which had “entered no findings of fact as to misbranding” and did
not consider the “argument that the drugs were labeled sufficiently for lay use,”
to “consider these factors” on remand). Provided a drug bears adequate labeling
for an unapproved use, a defendant distributing such a drug cannot be convicted
under 21 U.S.C. § 331(a) for introducing a misbranded drug into interstate
commerce. Labeling a drug with directions for unapproved uses, however, may
violate another provision of the FDCA. See, e.g., Wyeth v. Levine, 555 U.S. 555,
568 (2009) (“The FDA’s premarket approval of a new drug application includes
the approval of the exact text in the proposed label. See 21 U.S.C. § 355; 21
C.F.R. § 314.105(b) (2008). Generally speaking, a manufacturer may only
change a drug label after the FDA approves a supplemental application.”).
10
instruction to a jury may not be judged in artificial isolation, but must be viewed
in the context of the overall charge.”).
The majority also focuses on the prosecution’s summations, arguing that
the government did not use Caronia’s promotion of Xyrem as evidence of
misbranding, but rather “prosecuted Caronia for his off-label promotion.” Maj.
Op. at 19 (emphasis added). Suffice it to say, however, that any claim that
Caronia was convicted for his speech, as opposed to his conspiracy, is belied by
the fact that, as the majority rightly concedes, the district court explained the
elements of conspiracy and misbranding to the jury and instructed that each
element must be shown beyond a reasonable doubt. We presume that juries
follow their instructions. United States v. Williams, 690 F.3d 70, 77 (2d Cir.
2012). Caronia, moreover, objected not at all to the prosecution’s references to
his off-label promotion of Xyrem—and unsurprisingly, since read in context, the
government properly referred to this promotion to prove Caronia’s participation
in a conspiracy to distribute Xyrem for uses that its labeling neither described
nor explained.
At bottom, the majority is troubled that “the simple promotion of a drug’s
off-label use” can lead to criminal liability under the FDCA. Maj. Op. at 30.
That is, where all that a drug manufacturer (or its representative) does is sell
a prescription drug and promote it for an off-label purpose, the majority
11
concludes that prosecution raises serious First Amendment concerns—and
regardless whether the off-label promotion is presented as mere evidence or as
the proscribed conduct itself. The majority’s conclusion, clearly stated, is that
while speech might serve as evidence of other types of mislabeling, such as false
or deficient labeling, see Maj. Op. at 26–27, a mislabeling charge simply may not
rest on off-label promotion.
This is a departure from precedent. My conclusion here—that promotion
of a use may demonstrate an objective intent that the drug be used for that
purpose—has long been endorsed by this Circuit. See United States v. Writers
& Research, Inc., 113 F.3d 8, 11 (2d Cir. 1997) (“We agree with the district court
that, as a matter of law, if 714X was promoted as a treatment or cure for cancer,
AIDS, or other diseases, it is subject to the requirements of the FDCA . . . .”);
United States v. An Article . . . Consisting of 216 Individually Cartoned Bottles,
409 F.2d 734, 739 (2d Cir. 1969) (“It is well settled that the intended use of a
product may be determined from its label, accompanying labeling, promotional
material, advertising, and any other relevant source. . . . Thus, Congress has
made a judgment that a product is subject to regulation as a drug if certain
promotional claims are made for it.”). Such use of speech, moreover, has never
been prohibited by the First Amendment. See Sorrell v. IMS Health Inc., 131 S.
Ct. 2653, 2664–65 (2011) (“[T]he First Amendment does not prevent restrictions
12
directed at commerce or conduct from imposing incidental burdens on speech.
That is why a ban on race-based hiring may require employers to remove ‘White
Applicants Only’ signs; why an ordinance against outdoor fires might forbid
burning a flag; and why antitrust laws can prohibit agreements in restraint of
trade.”) (citations and some internal quotation marks omitted).
It is true that the introduction of Xyrem into interstate commerce by
Caronia’s employer was generally legal so long as the drug was not intended to
be used for purposes that lacked adequate directions on its labeling. It is also
true that, absent Caronia’s speech (and speech by other Orphan
representatives), the jury likely would not have found that Xyrem was intended
for such off-label uses. Consistent with the First Amendment, however,
otherwise permissible conduct may become impermissible if undertaken with a
prohibited motive, and speech may be used as evidence of such a motive. An
employer, for example, is generally free to refuse to promote an employee simply
because he does not like the employee’s attitude, but he may not refuse to
promote the employee because of her sex. See Wisconsin v. Mitchell, 508 U.S. at
487 (“In Hishon[ v. King & Spalding, 467 U.S. 69, 78 (1984)], we rejected the
argument that Title VII infringed employers’ First Amendment rights.”). The
First Amendment does not bar using the employer’s speech to demonstrate his
discriminatory motive. See Wisconsin v. Mitchell, 508 U.S. at 490 (citing Price
13
Waterhouse v. Hopkins, 490 U.S. 228, 251–52 (1989) (plurality opinion)). Indeed,
as the crimes of attempt, conspiracy, and inducement demonstrate, “[w]ords
alone may constitute a criminal offense, even if they spring from the anterior
motive to effect political or social change.” United States v. Freeman, 761 F.2d
549, 551 (9th Cir. 1985) (Kennedy, J.). See generally Kent Greenawalt, Speech,
Crime, and the Uses of Language 6–7 (1989) (enumerating twenty-one crimes
that “critically involve communication,” id. at 7). Simply put, 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.
Caronia attempts to distinguish this line of authority by arguing that he
merely discussed “a perfectly lawful practice: the use of a lawful drug, Xyrem,
for off-label purposes.” Appellant’s Reply Br. at 10. But the fact that a physician
or a patient could legally use Xyrem for an off-label purpose is not enough to
make out Caronia’s First Amendment claim. There might be no law forbidding
the consumption of arsenic. But this would not endow Abby and Martha with
a First Amendment right to offer arsenic-laced wine to lonely old bachelors with
the intent that they drink it. See Arsenic and Old Lace (Warner Bros. Pictures
1944). And any statements Abby or Martha made suggesting their intent—even
if all of the statements were truthful and not misleading—would not be barred
14
from evidence by the First Amendment simply because arsenic might legally be
consumed.5
Although Caronia relies heavily on the Supreme Court’s decision in
Thompson v. Western States Medical Center, 535 U.S. 357 (2002), that case did
not discuss the use of speech as evidence of intent. The statute at issue in
Western States, as the government conceded before the Supreme Court,
regulated speech directly rather than as evidence of intent. See id. at 364–65
(“[T]he pharmacy, licensed pharmacist, or licensed physician compounding the
drug may ‘not advertise or promote the compounding of any particular drug,
class of drug, or type of drug’ . . . .”) (quoting 21 U.S.C. § 353a(c)); Western
States, 535 U.S. at 370–71 (“The Government argues that advertising . . . is ‘a
5
Indeed, speech encouraging others to engage in certain legal conduct has long
been directly regulated or prohibited in a variety of areas. For example, an insider who
is privy to an impending corporate merger is prohibited from telling a friend that one
of those companies is a good buy—even if that statement is truthful and even if the
friend (who does not realize that she has just been made privy to material nonpublic
information) may legally buy stock in that company. See United States v. Gansman,
657 F.3d 85, 92 (2d Cir. 2011) (elements of tipper liability); United States v. Falcone,
257 F.3d 226, 234 (2d Cir. 2001) (elements of tippee liability). Each of two
corporations may be free to raise its prices, but the Sherman Act forbids them from
discussing such a course of action. See In re High Fructose Corn Syrup Antitrust Litig.,
295 F.3d 651, 654 (7th Cir. 2002) (Posner, J.); Louis Kaplow, On the Meaning of
Horizontal Agreements in Competition Law, 99 Calif. L. Rev. 683 (2011). Likewise,
nonlawyers are forbidden from giving legal advice even if the advice is sound, see, e.g.,
People v. Alfani, 125 N.E. 671, 673 (N.Y. 1919), and unlicensed laypersons may not
provide medical diagnoses, regardless of their accuracy, see, e.g., Locke v. Ionia Circuit
Judge, 151 N.W. 623, 625 (Mich. 1915); Commonwealth v. Jewelle, 85 N.E. 858, 859
(Mass. 1908).
15
fair proxy for actual or intended large-scale manufacturing . . . .’”) (emphasis
added). The statute at issue in Sorrell v. IMS Health Inc., 131 S. Ct. 2653(2011), also targeted speech directly. See id. at 2660 (“Pharmaceutical
manufacturers and pharmaceutical marketers shall not use prescriber-
identifiable information for marketing or promoting a prescription drug unless
the prescriber consents . . . .”) (quoting Vt. Stat. Ann., Tit. 18, § 4631(d) (Supp.
2010)). By contrast, Caronia’s conviction required a finding that Xyrem was
intended by those responsible for its labeling for an off-label use—a finding
which “may be shown by 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.” 21 C.F.R. § 201.128. See
generally Krista Hessler Carver, A Global View of the First Amendment
Constraints on FDA, 63 Food & Drug L.J. 151, 187–88 (2008).
Put another way, if the jury had concluded there was a reasonable doubt
as to whether Caronia and Orphan actually intended to sell Xyrem to Caronia's
customers—to introduce it into interstate commerce—then Caronia could not
have been convicted under § 331(a), no matter what he said. By contrast, a
pharmacy would violate the statute in Western States as soon as it advertised the
compounding of particular drugs. See 535 U.S. at 364–65 (citing 21 U.S.C. §
353a(c)). Similarly, a Vermont pharmacy would violate the statute in Sorrell as
16
soon as it disseminated prescriber-identifying information for marketing
purposes. See 131 S. Ct. at 2660. Speech alone was sufficient to trigger
punishment under the challenged statutes in those cases. Speech alone is not,
however, sufficient to sustain a conviction under 21 U.S.C. § 331(a).
My analysis here is not original. The D.C. Circuit reached the same
conclusion in Whitaker v. Thompson, 353 F.3d 947, 953 (D.C. Cir. 2004),6 in
which a plaintiff argued that he had a First Amendment right to label his
product with a drug claim despite its lack of FDA approval. The Whitaker court
disagreed, reasoning that:
Assuming that the government may condition the sale of drugs on
passage through the elaborate testing that the statute requires . . . ,
the key step is the []FDCA principle that classification of a
substance as a ‘drug’ turns on the nature of the claims advanced on
its behalf. That principle, in turn, rests on the idea that claims
about a product by its manufacturer and vendors, including product
labeling, serve as evidence of the sellers’ intent that consumers will
purchase and use the product for a particular purpose—and,
therefore, as evidence whether the product is or is not a drug. The
question is whether this use of speech to infer intent, which in turn
renders an otherwise permissible act unlawful, is constitutionally
valid. In fact, the First Amendment allows ‘the evidentiary use of
speech to establish the elements of a crime or to prove motive or
intent.’ Thus it is constitutionally permissible for the FDA to use
speech, in the form of labeling, to infer intent for purposes of
determining that [the plaintiff’s] proposed sale of saw palmetto
extract would constitute the forbidden sale of an unapproved drug.
Id. (citations and paragraph breaks omitted). Caronia attempts to distinguish
6
Then-Judge Roberts was a member of the unanimous panel.
17
Whitaker by arguing that “the drug itself in Whitaker could not be sold lawfully,
and so there were no lawful off-label uses to promote.” Appellant’s Reply Br. at
15 (internal quotation marks and brackets omitted). But the product in
Whitaker—“‘saw palmetto,’ an extract from the pulp and seed of the dwarf
American palm,” Whitaker, 353 F.3d at 948—could be sold lawfully so long as it
was not a “drug,” and whether it was a drug depended entirely upon the
plaintiff’s speech, as evidence of his intent, when he offered it for sale. That case
is therefore indistinguishable from this case; indeed, even if the FDA had not
approved Xyrem for any medical uses at all, Caronia could presumably have sold
Xyrem as an industrial solvent if it happened to be excellent at removing grease
and grime.
Not every prohibition on conduct undertaken with a certain intent is
necessarily constitutional: the problem posed by a ban on “sending any leaflet
with the intent to influence another’s vote” suggests the limits on the analysis
here. It remains the case, however, that 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
18
and effective.
III. Applying Central Hudson and Sorrell
Finally, even if using Caronia’s speech as evidence of his intent was not
necessarily constitutionally permissible—in other words, even if the protection
afforded to commercial speech requires an analysis of this question where the
customers of a product like Xyrem may lawfully use it for purposes not
addressed in the label, and where the FDA does not purport to regulate the
claims made by unrelated third parties about the efficacy of such uses, see
George W. Evans & Arnold I. Friede, The Food and Drug Administration’s
Regulation of Prescription Drug Manufacturer Speech: A First Amendment
Analysis, 58 Food & Drug L.J. 365, 390 (2003)—I believe the correct application
of commercial speech principles requires us to uphold Caronia’s conviction. I
agree with the majority that our analysis is guided by Central Hudson Gas &
Electric Corp. v. Public Service Commission of New York, 447 U.S. 557 (1980),
and Sorrell v. IMS Health Inc., 131 S. Ct. 2653 (2011). I conclude, however, that
the FDCA’s misbranding provision survives the scrutiny required by those cases
because it directly advances a substantial government interest and is narrowly
drawn to further that interest.
“[O]ne of the [FDCA]’s core objectives is to ensure that any product
regulated by the FDA is safe and effective for its intended use.” Brown &
19
Williamson, 529 U.S. at 133 (2000) (internal quotation marks omitted). The
FDCA is meant to achieve this objective through a rigorous premarket approval
process. See 21 U.S.C. § 355. Under this process, a manufacturer may not sell
a drug without first providing proof to the FDA that the drug is “safe for use”
and “effective in use.” See id. § 355(b). There must be “substantial evidence,”
including evidence from clinical investigations, “that the drug will have the
effect it purports or is represented to have.” Id. § 355(d).
This process is a central, if not the central, feature of the FDCA. Prior to
the passage of the FDCA, the government could combat misleading drug claims
only through post-market enforcement actions. The 1938 Act’s “most substantial
innovation” was to require approval of a drug’s safety before it could enter the
market. Wyeth, 555 U.S. at 566. This innovation became even more important
after Congress amended the FDCA in 1962 to also require premarket approval
of a drug’s effectiveness for its stated uses. See Drug Amendments of 1962, Pub.
L. No. 87-781, § 102, 76 Stat. 780, 781. Behind the 1962 amendments were
concerns that doctors could not adequately evaluate frequently misleading
claims by drug manufacturers without a body of objective, reliable information.
See, e.g., Henry A. Waxman, A History of Adverse Drug Experiences: Congress
Had Ample Evidence to Support Restrictions on the Promotion of Prescription
Drugs, 58 Food & Drug L.J. 299, 301–08 (2003); Alan H. Kaplan, Fifty Years of
20
Drug Amendments Revisited, 50 Food & Drug L.J. 179, 184–85 (1995).
The Supreme Court has accordingly stated that “[p]reserving the
effectiveness and integrity of the FDCA’s new drug approval process is clearly
an important governmental interest.” Western States, 535 U.S. at 369. Given
the benefits of premarket approval, “the Government has every reason to want
as many drugs as possible to be subject to that approval process.” Id.The FDCA’s prohibition on off-label marketing directly advances this
interest. If drug manufacturers were allowed to promote FDA-approved drugs
for non-approved uses, they would have little incentive to seek FDA approval for
those uses. Prohibiting such promotion is thus “one of the few mechanisms
available” to encourage participation in the approval process. Washington Legal
Foundation v. Friedman, 13 F. Supp. 2d 51, 72 (D.D.C. 1998), vacated in part,
Washington Legal Foundation v. Henney, 202 F.3d 331 (D.C. Cir. 2000). And
premarket approval improves drug safety and effectiveness only to the extent
that drugs are not sold without such approval.
In concluding that prohibiting off-label promotion does not directly
advance the government’s interests, the majority places great weight on the fact
that “physicians can prescribe, and patients can use, drugs for off-label
purposes.” Maj. Op. at 39. But this is also true for substances that have not
been approved by the FDA for any medical use at all. The law generally permits
21
a hardware store to sell turpentine, and though such conduct may not be
advisable, the law generally permits a consumer to purchase that turpentine and
use it as a pain reliever. Under the majority’s reasoning, then, any substance
that may be legally sold for some purpose may be promoted by its manufacturer
for any purpose—so long as the manufacturer’s statements are merely
unsubstantiated, rather than demonstrably false or misleading. But this
reasoning would invalidate the very definitions of “drug” and “device” that
undergird the entire FDCA.
The majority also emphasizes that the prohibition on off-label promotion
applies only to a “particular class of speakers”— namely, drug manufacturers.
Maj. Op. at 39. But drug manufacturers are the precise group that the
government must encourage to participate in the new drug approval process.
Indeed, if the prohibition applied to any broader class of speakers, it would likely
fail Central Hudson’s fourth requirement that a regulation be “narrowly drawn.”
The Supreme Court’s decision in Sorrell is thus inapposite in the present
circumstances. The statute there did not directly advance Vermont’s interest in
protecting patient privacy because it applied to only a small subset of those
groups that could possibly compromise patient privacy. See 131 S. Ct. at 2668.
Drug manufacturers, in contrast, form the entirety of those speakers that could
possibly undermine the new drug approval process by not participating in it.
22
Furthermore, allowing drug manufacturers to promote off-label uses would
undermine the FDA’s approval process for not only new uses of pre-approved
drugs, but also for entirely new drugs. As explained above, when determining
whether a drug should be approved, the FDCA requires consideration not only
of the drug’s safety, but also its effectiveness. See 21 U.S.C. § 355; United States
v. Rutherford, 442 U.S. 544, 555 (1979) (“[T]he [FDA] Commissioner generally
considers a drug safe when the expected therapeutic gain justifies the risk
entailed by its use.”). If a drug manufacturer must be allowed to distribute a
drug for any use so long as it is approved for one use, the government’s balancing
of a drug’s benefits against its risks becomes very difficult or even impossible.
Drugs viewed as safe for certain uses might be considered unsafe overall if the
benefits and risks being weighed are not for a specific intended use but rather
for any use at all, whether supported by evidence or not.
The prohibition of off-label promotion is thus not simply a “paternalistic”
attempt to shield physicians and patients from truthful information. See Maj.
Op. at 40. Rather, it is a necessary tool for the effective functioning of a
regulatory system that the Supreme Court has endorsed as legitimate. The
majority implies that prohibiting off-label promotion is unconstitutionally
“paternalistic” regardless whether the drug manufacturer’s claims are addressed
to a physician or to a patient. See, e.g., Maj. Op. at 40 (“[P]rohibiting off-label
23
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 . . . .”) (emphasis added).
But if drug manufacturers have a First Amendment right to distribute drugs for
any use to physicians or even directly to patients, then the entire FDCA may
well be unconstitutional.
Prohibiting off-label promotion by drug manufacturers is also the least
restrictive way of advancing the government’s interests. Although the majority
asserts various alternatives, none would be similarly effective. A disclaimer
system or required listing of intended uses would provide manufacturers much
less incentive to submit their drugs for FDA approval, and in turn encourage
promotion based on data much less reliable than the clinical investigations
required under 21 U.S.C. § 355(d).7 A ceiling on off-label prescriptions would
require collecting data from countless numbers of doctors and patients and,
given the medical uncertainties involved, could needlessly (and simultaneously)
result in the denial of some effective treatments and the overprescription of
7
Indeed, experts have concluded that most prescriptions for off-label use have
little or no scientific support. See Randall S. Stafford, Regulating Off-Label Drug Use:
Rethinking the Role of the FDA, 358 New Eng. J. Med. 1427, 1427 (2008) (“In an
examination of off-label prescribing of 160 common drugs, off-label use was . . . found
to account for 21% of all prescriptions, and most off-label drug uses (73%) were shown
to have little or no scientific support.”) (citing David C. Radley, Stan N. Finkelstein &
Randall S. Stafford, Off-Label Prescribing Among Office-Based Physicians, 166
Archives of Internal Med. 1021 (2006)).
24
ineffective and even dangerous ones. Finally, a ban on off-label prescriptions
would be no better. Indeed, it would constitute an unprecedented intrusion into
the practice of medicine, and would result in perhaps an even greater restriction
on speech. See Central Hudson, 447 U.S. at 563–64 (government free to ban
“commercial speech related to illegal activity”). And again, because a product’s
very definition as a “drug” depends upon its intended use (which is often
established by the manufacturer’s speech), it is unclear why the majority’s less-
restrictive-alternatives analysis is not equally applicable to the FDCA’s entire
scheme of drug regulation.
That the FDCA is both “content- and speaker-based” within the meaning
of Sorrell, 131 S. Ct. at 2663, does not alter the foregoing analysis. Every
commercial speech case, by its very nature, involves both content- and speaker-
based speech restrictions. See Va. State Bd. of Pharmacy v. Va. Citizens
Consumer Council, Inc., 425 U.S. 748, 761 (1976) (“If there is a kind of
commercial speech . . . it must be distinguished by its content.”). Yet the
Supreme Court has long acknowledged—and acknowledged again in
Sorrell—that “the government’s legitimate interest in protecting consumers from
commercial harms explains why commercial speech can be subject to greater
governmental regulation than noncommercial speech.” Sorrell, 131 S. Ct. at
2672 (internal quotation marks omitted). Indeed, the Supreme Court struck
25
down the ban on energy advertising in Central Hudson because a content-based
less-restrictive alternative existed. See Cent. Hudson, 447 U.S. at 571 (“[T]he
Commission could attempt to restrict the format and content of Central
Hudson’s advertising. It might, for example, require that the advertisements
include information about the relative efficiency and expense of the offered
service, both under the current conditions and for the foreseeable future.”).
Sorrell did not purport to overrule the Central Hudson test, which has guided
First Amendment doctrine in this area for thirty years.
Moreover, in Sorrell the Court noted that Vermont did not argue that its
challenged statute “will prevent false or misleading speech.” 131 S. Ct. at 2672.
Rather, Vermont’s “interest in burdening the speech of detailers instead turn[ed]
on nothing more than a difference of opinion.” Id. In contrast, Congress
intended the FDA approval process to prevent dangerous products with false or
misleading labels from entering the market, and also to provide a base of
reliable, objective information about prescription drugs that could help
physicians and patients identify potentially misleading claims. Clearly this is
the type of statute to which Sorrell intended that Central Hudson would still
apply.8
8
Nor does the fact that 21 U.S.C. § 331(a) applies criminal penalties necessarily
mean that it warrants heightened scrutiny. The case that the majority cites for this
proposition, Holder v. Humanitarian Law Project, did not premise its application of
26
It is certainly true that "the 'fear that people would make bad decisions if
given truthful information' cannot justify content-based burdens on speech."
Sorrell, 131 S. Ct. at 2670–71 (quoting Thompson, 535 U.S. at 374). But this
does not mean that conveying non-demonstrably false information to consumers
must take precedence over all competing government interests. Our system of
drug regulation developed to protect consumers from misleading and
unsubstantiated claims about drugs’ safety and efficacy, and the prohibition on
off-label promotion by drug manufacturers is essential to maintaining the
effectiveness of that system. Therefore, even if such a prohibition is considered
a direct regulation of speech, it is a regulation that directly advances a
substantial government interest in a manner not more extensive than necessary
to serve that interest. I would thus find it constitutional under Central Hudson
and Sorrell.
IV. The Verdict Sheet and the Jury’s Verdict
Because I believe that the FDCA’s misbranding provision may
constitutionally be applied to Caronia’s conduct, I next address Caronia’s
heightened scrutiny on the statute’s criminal penalties. See 130 S. Ct. 2705, 2724
(2010). Moreover, the Supreme Court has previously applied Central Hudson to
statutes that provide for or trigger criminal punishment for speech. See Greater New
Orleans Broad. Ass’n, Inc. v. United States, 527 U.S. 173, 177 (1999); 44 Liquormart,
Inc. v. Rhode Island, 517 U.S. 484, 490 n.3 (1996); Bolger v. Youngs Drug Products
Corp., 463 U.S. 60, 61–62 (1983).
27
remaining arguments: (1) that the district court erred in breaking down the
conspiracy charge on the verdict sheet into two subissues; and (2) that the jury
rendered an inconsistent verdict by convicting Caronia of conspiring to introduce
or deliver for introduction into interstate commerce a misbranded drug while
finding him not guilty of conspiring to do an act to a drug that would result in
it being misbranded.
The first count of a two-count information charged Caronia with conspiring
both (1) to introduce into interstate commerce a drug that was misbranded and
(2) to do an act with respect to a drug that would result in that drug being
misbranded.9 With respect to that count, the district court submitted a two-part
verdict sheet to the jury which asked:
1. How do you find the defendant, ALFRED CARONIA, on
Count One of the Information?
(a) Conspiracy to introduce or deliver for introduction into
interstate commerce a drug, Xyrem, that was misbranded?
NOT GUILTY _____ GUILTY _____
(b) Conspiracy to do an act with respect to a drug, Xyrem,
when such drug was held for sale after shipment in interstate
commerce when such act would result in Xyrem being misbranded?
NOT GUILTY _____ GUILTY _____
The jury concluded that Caronia was guilty with respect to question (a) and not
guilty with respect to question (b).
9
The second count charged Caronia with doing an act with respect to a drug that
resulted in that drug being misbranded.
28
Caronia argues that the district court erred by subdividing the conspiracy
charge on the verdict sheet because, he claims, the district court essentially split
the charge into two separate counts. But we have held that a conspiracy charge
may allege an agreement to commit more than one offense, see United States v.
Coriaty, 300 F.3d 244, 250 (2d Cir. 2002) (“We have upheld convictions for
multi-object conspiracies charged in the conjunctive even when there was
insufficient evidence to support one of the objects of the conspiracy.”), and that
a district court does not impermissibly constructively amend a charge by
subdividing an offense into parts, see United States v. McCourty, 562 F.3d 458,
470 (2d Cir. 2009) (“No constructive amendment resulted when the District
Court broke the single offense into two parts to be addressed by the jury.”). I
therefore find no error in the verdict sheet.
Caronia further argues that the jury rendered an inconsistent verdict by
finding him not guilty of conspiring to do an act to a drug that would result in
it being misbranded while finding him guilty of conspiring to introduce or deliver
for introduction into interstate commerce a misbranded drug. But these verdicts
were not inconsistent—for example, the jury may have concluded that the drug
was not being held for sale after shipment in interstate commerce. And even
assuming the verdicts were inconsistent, “the convicted defendant’s protection
against an irrational verdict is his ability to have the courts review the
29
sufficiency of the evidence to support his conviction,” United States v. Acosta, 17
F.3d 538, 545 (2d Cir. 1994). There was ample evidence for a reasonable jury to
conclude beyond a reasonable doubt that Caronia conspired to introduce or
deliver for introduction into interstate commerce a misbranded drug. Indeed,
Caronia was caught on tape with Dr. Gleeson suggesting off-label uses of Xyrem
to doctors. I therefore see no error in the verdict sheet and no inconsistency
requiring reversal or vacatur in the jury’s verdict.
* * *
The majority has chosen to apply heightened scrutiny to this case, though
we have not done so in other cases involving the use of speech as evidence of
intent—for example, in antidiscrimination actions or prosecutions for criminal
inducement, attempt, and conspiracy—cases I cannot meaningfully distinguish
from this one. The majority’s decision today extends heightened scrutiny further
than the Supreme Court ever has, and calls into question a fundamental regime
of federal regulation that has existed for more than a century. I respectfully
dissent.
30