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

The FDCA provides: "No person shall introduce or 1

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 FDAapproved 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 offlabel 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."). The FDA 2

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.

See also James M. Beck & Elizabeth D. Azari, FDA, Off- 2

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. § 201.5.4

FDA 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

A drug is also misbranded if, inter alia: its label is 4

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).

-7-
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.

The facts are drawn primarily from the trial record. 5

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. In contrast, physicians employed by Orphan as 6

promotional speakers for Xyrem were permitted to answer offlabel 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.

In December of 2011, the FDA released recommendations 6

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 onethird 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. Caronia argues that the First Amendment does not 8

permit the government to prohibit and criminalize a

pharmaceutical manufacturer's truthful and non-misleading

promotion of an FDA-approved drug to physicians for offlabel 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. 

Caronia also argues that the verdict sheet was 8

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, that is 9

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 FDAapproved 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 offlabel promotion of Xyrem is highlighted over forty times. 

(See Trial Tr. 819-49, 870-80, 883-85).

See Wisconsin v. Mitchell, 508 U.S. 476, 489 (1993) 9

(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 offlabel 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 offlabel 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 offlabel 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, it affords little support to the 10

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

Although we assume, without deciding, that such use of 10

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 contentbased," 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. at

2667-69 (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 prescriberidentifying 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. See Cent. Hudson, 447 U.S. at 566. 11

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

In Whitaker, cited by the dissent (Diss. Op. 14), the 11

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 FDAapproval 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. Finally, where off-label drug use is 12

Physicians and pharmaceutical manufacturers can be held 12

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 offlabel 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 FDAapproved 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

 The FDA has exempted certain drugs from the requirement that their labels 1

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

S e e W i k i p e d i a , H a m l i n ’ s W i z a r d O i l ,

2

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.” Because Caronia’s speech was used 3

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.

This was not the only evidence on which the government relied. As the 3

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. See United States v. Sabhnani, 599 F.3d 4

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

Notably, Caronia himself does not argue that the district court’s

4

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

Indeed, speech encouraging others to engage in certain legal conduct has long 5

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 prescriberidentifiable 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), in 6

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

 Then-Judge Roberts was a member of the unanimous panel. 6

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 ofthe 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 thatturpentine 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 offlabel 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). A ceiling on off-label prescriptions would 7

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

Indeed, experts have concluded that most prescriptions for off-label use have 7

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 lessrestrictive-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 speakerbased 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

Nor does the fact that 21 U.S.C. § 331(a) applies criminal penalties necessarily

8

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. With respect to that count, the district court submitted a two-part 9

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).

The second count charged Caronia with doing an act with respect to a drug that 9

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