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