Download Post Caronia: Is a new paradigm needed for off-label

Original article
Post Caronia: Is a new paradigm needed
for off-label medication usage?
Journal of Medical Marketing
2013, Vol. 13(4) 212–220
! The Author(s) 2014
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DOI: 10.1177/1745790414526613
mmj.sagepub.com
Martha M Rumore1,2
Abstract
In United States v. Caronia (2012), a criminal misbranding, off-label promotion case, the Second Circuit ruled
that the Food and Drug Administration’s (FDA) enforcement of pharmaceutical manufacturers violates the
First Amendment. Pharmaceutical manufacturers view Caronia as a watershed for the end of deference to
FDA’s oversight role as arbiter of off-label medication usage determinations and perhaps, the beginning of the
demise of preemption. The central constitutional question is can FDA’s off-label promotion prohibition withstand First Amendment scrutiny of free speech in general and commercial speech in particular? Is a new
paradigm required to promulgate a framework of laws and regulations that will minimize healthcare costs
and patient injuries while allowing truthful off-label promotion?
Keywords
Off-label, Caronia, First Amendment, Food and Drug Administration, pharmaceutical promotion
Introduction
Off-label use encompasses unapproved indications,
dosages, delivery systems, administration routes,
patient populations (e.g. pediatric, geriatric, pregnant), or use inconsistent with the labeling. While estimates vary, for certain diseases states, e.g. cancer, the
prevalence of off-label use is about 60%. Table 1 provides examples of widely accepted off-label uses which
may represent the ‘‘standard of care.’’ Medicare,
Medicaid, and private insurance often reimburse for
off-label uses.
FDA’s authority flows from the misbranding provisions of the Food, Drug & Cosmetic Act (FDCA),1
and specifically, Kefauver Harris Amendment provisions of safety and efficacy.2 FDA has argued that
off-label promotion of drugs is evidence of manufacturer intent to sell misbranded medications. That is,
introduction of a medication into interstate commerce
without adequate directions for use for all intended
uses constitutes misbranding. The agency’s policy prohibits pharmaceutical manufacturers from promoting
off-label uses either directly, through labels and package inserts, or indirectly through advertising and promotional activities. FDA’s authority has never
extended to prescribers who remain free to both prescribe and promote approved medications for off-label
uses. In fact, anyone except for pharmaceutical manufacturers can discuss off-label uses.
The federal government has been extremely successful in claiming FDCA violations and the Obama
Administration has been particularly aggressive in prosecuting off-label promotion. The Department of
Justice (DOJ) has repeatedly used the FDCA to
pursue civil and criminal charges. Additionally, government cases increasingly rely on the False Claims
Act with its treble damages provision.3 Off-label promotion is the most commonly asserted Medicaid fraud
allegation in federal enforcement actions.4 Table 2 lists
some settlements with pharmaceutical manufacturers
amounting to billions of dollars.5–7 Throughout
the government contended that its authority over
manufacturer off-label speech presented no First
Amendment issue.
However, the government has been extremely
unsuccessful in actually deterring off-label use and
pharmaceutical manufacturer promotion has been
1
Clinical & Educational Services, Cohen Children’s Medical Center,
New Hyde Park, New York, NY, USA
2
Pharmacy & Health Outcomes, Touro College of Pharmacy, New
York, NY, USA
Corresponding author:
Martha M Rumore, Clinical & Educational Services, Cohen
Children’s Medical Center, 420 Lakeville Road, Room 103, New
York, NY 11042, USA.
Email: [email protected]
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Rumore
213
Table 1. Examples of off-label use
Medication
Off-label use
Tricyclic
antidepressants
SSRIs
Neuropathic pain
Morphine
Magnesium sulfate
Gabapentin
Risperidone
Propranolol
Olanzapine
Coenzyme Q
Azathioprine
Trazodone
Phenytoin
Alcoholism, addictive disorders,
OCD, stuttering
Pain in pediatric patients
Premature labor
Migraines
Eating disorders
Infantile hemangiomas
Nausea and vomiting
Metabolic acidosis
Atopic dermatitis, psoriasis
Insomnia
Gastrointestinal fistulae
Table 2. Federal Government success in claiming FDCA
violations. Select recent off-label promotion cases
Pharmaceutical manufacturer
Cost
GlaxoSmithKline
Pfizer
Eli Lilly
Abbott
Forest
Merck & Co., Inc.
Elan Corporation
US$3 billion, NPA, CIA
US$2.3 billion
US$1.4 billion
US$1.6 billion
US$313 million, NPA
US$950 million, NPA
US$203 million, NPA
NPA: non-prosecution agreement; CIA: corporate integrity
agreement.
effective in expanding off-label use. Additionally, FDA
does not seem to be working in tandem with other
agencies giving complete prescribing discretion for
off-label use while CMS limits Medicare reimbursement for same. Thus, despite increasing application
of federal criminal law to regulate pharmaceutical promotion, a trend toward increased prescription of medications for off-label use exists.
Overview of off-label usage
Off-label use is commonplace and can be evidencebased and life-saving but abuses exist; it can be dangerous (e.g. fen-phen) and costly. For example,
recently a manufacturer re-analyzed study results,
withheld safety findings and continued to aggressively
market the medication.8 Although manufacturers are
not permitted to share promotional informational
about off-label use, FDA does require them to
inform prescribers about safety issues related to same.
The rules of the game for off-label promotion are
found in the PhRMA Code on Interactions with
Healthcare Professionals, Accreditation Council for
Continuing Medical Education Standards, HHS
OIG Compliance Program for Pharmaceutical
Manufacturers,9 FDA’s Good Reprint Practices
Guidance for Industry,10 FDA’s Guidance for
Industry-Supported Scientific and Educational
Activities,11 and FDA’s Responding to Unsolicited
Requests
for
Off-Label
Information
About
Prescription Drug and Medical Devices Guidance
for Industry.12 The patchwork of regulations and guidance’s in and of itself would seem to run afoul of Due
Process requirements of the Fifth Amendment. While
there are at least four safe harbors: scientific exchange,
responses to unsolicited requests, dissemination of
reprints, and financial support for continuing medical
education, the rules for off-label promotion have
inched closer to confounding the First Amendment.
Basic tension with the First Amendment
The premise of the First Amendment is as follows:
‘‘Congress shall make no law . . .. abridging the freedom of speech.’’ The First Amendment does not
permit restriction of communication based on content
but may restrict context. Before the mid-1970s, First
Amendment protection did not extend to commercial
speech such as advertising. However, since Central
Hudson Gas & Electric Co. v. Public Service
Commission, which struck down a state law that prohibited advertisement by a public utility, this is no
longer the case.13 Modern law to assess government
regulation of commercial speech is crystallized in
Central Hudson where the court set out a four prong
test: the speech must concern lawful activity and not
be misleading; the government interest in restricting
the speech must be substantial, the restriction must
directly advance the government interests asserted
and not be more extensive than is necessary to serve
that interest. Once the speech passes the first hurdle,
not promoting sale of an unlawful product or be false
or misleading (e.g. presenting drug superiority without
head-to-head clinical trials or characterizing case
reports or poorly designed studies as definitive evidence supporting an off-label use),14 then it must satisfy the remaining three prongs to be constitutional.
Under Central Hudson, the burden shifts to the government to show its regulation is narrowly tailored to
advance a substantial interest. That is, the party seeking to uphold the restriction carries the burden of justifying it. This intermediate scrutiny test has been used
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Journal of Medical Marketing 13(4)
to overturn FDA’s efforts to restrict pharmaceutical
advertising.
Central Hudson’s third prong has been particularly
troublesome for FDA as it hollows the government’s
argument that in some cases public health danger
could be avoided by the provision of more information
rather than less. It would be unethical for patients to
be deprived of valuable medications because their prescribers were unaware of their existence.1 Moreover,
allowing non-FDA-approved medications (i.e. grandfather and/or DESI) while banning off-label promotion flies in the face of the ‘‘substantial interest’’ of
protecting public safety.1
Where the government is concerned about public
safety, it is free under the Commerce Clause15 and
the Necessary and Proper Clause16 to prohibit the
actual activity itself, not merely the speech advocating
the activity. Once the activity is illegal, the government
is free to prohibit speech advocating that illegal activity. The government, in turn, has argued that off-label
promotion is non-expressive conduct, making the First
Amendment inapplicable. Even if the First
Amendment applies, the government has a substantial
interest in both preventing unsafe or unsupported use
and inducing manufacturers to seek FDA approval for
off-label uses.1
Central Hudson’s fourth prong, however, has been
FDA’s greatest challenge in defending the over inclusiveness and chilling effect of its off-label restrictions
on some on-label speech. While the fourth prong does
not require the least restrictive method to satisfy the
government’s substantial interest, the existence of
alternative non-speech means violates this prong.
Impinging upon protected speech that fails to result
in the harm sought to be prevented (off-label speech
for beneficial or standard of care, albeit not FDAapproved uses) violates that aspect of the fourth
prong.1 In Thompson v. Western States Medical Center,
the Supreme Court in applying Hudson struck down a
restriction on pharmacist advertising of compounded
medications.17 The court found the restriction
unnecessarily broad and noted a number of alternatives to prevent the advertising from undermining the
FDA approval process.
In the 1990s, pharmaceutical companies attempted
to circumvent the prohibition on off-label use by distributing scientific literature and funding continuing
medical education. FDA responded via issuance of
several guidance documents. What followed in 1996
was a challenge to FDA’s jurisdictional authority when
the Washington Legal Foundation (WLF) brought a
First Amendment action.18 WLF won at trial but on
appeal FDA asserted its guidance’s were not mandatory. The D.C. Circuit found no constitutional controversy between the parties, and held the matter was not
ripe for determination. The following year, the FDA
Modernization Act (FDAMA) formalized the supplemental NDA process and permitted distribution of
certain published articles with disclaimers they were
not FDA-approved. However, WLF brought a subsequent case, and the court enjoined the FDAMA provision relating to reprint dissemination.19 Following
this case FDA unleashed a torrent of off-label investigations and actions against the pharmaceutical industry involving numerous settlements and billions in
criminal and civil penalties.
Over the past fifteen years beginning with 44
Liquormart v. Rhode Island and in a number of cases
since, an even more protective version of the Central
Hudson test has emerged.20 Under Sorrell v. IMS
Health, Inc, the precursor to Caronia, data mining,
the purchasing of prescription information and selling
it to pharmaceutical companies, is protected by the
First Amendment.16 The Vermont Prescription
Confidentiality Law of 2007 prohibiting same was
invalidated. Under Sorrell, strict scrutiny applies, i.e.
a restriction on commercial speech that is contentbased (off-label uses) and speaker-based (pharmaceutical manufacturers) is presumptively invalid.21 Sorrell
stands for the proposition that where a law is viewpoint
discriminatory (i.e. burdens particular content-marketing and particular speakers-drug manufacturers) it
will be subject to strict scrutiny, regardless of whether
it affects commercial speech, or not. The Sorrell ruling
prompted additional legal challenges.
Many cases have evoked Central Hudson to contest
FDA’s restrictions on off-label promotion claiming the
agency is stifling commercial speech.22 Allergan filed
one of the earlier First Amendment cases (2009) alleging that by requiring manufacturers of BotoxÕ to
warn users about the risk of serious side-effects, the
FDA was restricting the company’s First Amendment
rights to speak freely and truthfully with prescribers.23
In its complaint, Allergan sought to overturn all FDA
rules restricting off-label promotion and argued the
speech restriction was more extensive than necessary:
(1) with negative public health ramifications by preventing information dissemination, (2) included ‘‘factual’’ information widely implemented by prescribers,
contained in peer-reviewed articles, approved by other
similar regulatory bodies, and translated into payer
decisions, and (3) the communications were to be
communicated in responsible professional forums.5,24
Allergan dropped its claim before the court reached
the First Amendment issue when the case was settled.
In U.S. v. Caputo, several corporate officers were
accused and convicted of promoting off-label uses.25
They argued FDA’s off-label speech restrictions violated their First Amendment rights. Here, the court
applied Central Hudson and not finding less restrictive
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Rumore
215
alternatives, concluded the regulations were not more
restrictive than necessary, and thus, constitutional.
The Caronia case
A recent Second Circuit case, U.S. v. Caronia has now
found FDA’s enforcement regime to be in violation of
the First Amendment.26 The facts surrounding the
case follow: In 2005, the government undertook criminal prosecution of Alfred Caronia for illegal promotion of XyremÕ (sodium oxybate), a central nervous
system depressant for insomnia in pediatric patients
and other off-label uses. In a DOJ sting operation
Caronia met with a physician who was a government
informant and discussed off-label uses which were
caught on audiotape. The statements of Mr. Caronia
were not untruthful or misleading. In fact, the uses
had been studied in clinical trials but were not FDA
approved. The government argued the promotional
activities violated the FDCA misbranding provisions.27 The government further contended that the
First Amendment was a non-issue because Caronia’s
speech was not the basis of its prosecution but merely
provided an ‘‘evidentiary role’’ of ‘‘intended use.’’ The
manufacturer pleaded guilty but Caronia did not. The
Federal District Court in New York found against
Caronia, holding that the marketing constraint was
necessary to prevent circumvention of the FDA’s
new drug requirements.28 The District Court rejected
First Amendment challenges based on overbreath and
ambiguity. Caronia was convicted of conspiracy to
introduce a misbranded drug into interstate commerce, sentenced to 1 year probation, 100 hours community service and fined US$25. He appealed on the
basis that FDA’s speech restriction violates the First
Amendment. Both WLF and the Medical Information
Working Group filed amicus briefs, the former advocating manufacturers should be able to provide information about off-label use if the information is
accompanied by a disclaimer. FDA countered that
this would ‘‘turn back the regulatory clock more than
seventy years. . .before the FDCA was enacted in 1938,
and would radically undermine the incentives for
manufacturers to go through the new drug approval
process.’’29 However, in 1971 FDA made the same
disclaimer suggestion when implementing the 1962
Drug Amendments.30
In a landmark decision, the Second Circuit set aside
Caronia’s conviction reasoning that it violated his right
to freedom of speech, requiring a narrow construction
of the relevant statutes and regulations. The government unsuccessfully argued that off-label promotion
by Caronia was used only to demonstrate intent, not
restrict speech. The majority identified that while the
government can use such speech as evidence of
intended off-label use, a conviction must rest on
more than just speech. The court was persuaded by
the argument that FDA’s regulations do not inhibit
prescribing, only the free flow of information that
would result in a full vetting of uses, limitations and
side effects. The court ruled that the FDCA’s
misbranding provisions cannot be used to prohibit
off-label promotions.
The Caronia majority found that the government
restriction was not content- and speaker-neutral inasmuch as speech about FDA-approved medication use
was encouraged but not speech about off-label use.
Additionally, health professionals are permitted to
speak about off-label use but the same speech is prohibited when delivered by pharmaceutical manufacturers. Consequently, citing Sorrell, the court applied
the strict scrutiny test to the speech restriction – that
is, it must serve a substantial government interest, directly and materially advance that interest, and be no
broader than necessary. While the restriction was
found to serve government interests of drug safety
and public health, the Court found that restricting
off-label speech does not directly advance the government’s interest because: (1) off-label use itself is not
prohibited, (2) others are allowed to promote off-label
use, and (3) it blocks the free flow of information that
could actually improve off-label prescribing decisions.
Not only did the court find the restriction failed to
advance the government’s interest for public safety, it
had the opposite effect, ‘‘. . . such barriers to information about off-label use could inhibit, to the public’s
detriment, informed and intelligent treatment decisions.’’19 According to the Caronia majority, ‘‘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.’’ The Court also found the
restriction overly broad because the government could
achieve its goal without inhibiting speech, for example,
by educating prescribers and patients, requiring disclaimers, and/or capping the number of off-label prescriptions allowed.31 Clearly, regulating speech must
be a last – not first – resort.
The dissent in Caronia agreed with the government’s argument that off-label speech, no matter
how truthful, could be used to prove off-label intent
and declared that the ruling potentially unravels the
entire FDA drug approval process. The dissent
adhered to the view that extreme deference must be
given to FDA. The dissenting opinion provided an
example of conduct which is not prohibited but
which is unlawful to promote – it is not prohibited to
consume arsenic but it is unlawful to advocate its consumption by others, stating ‘‘this would not endow
Abby and Martha with a First Amendment right to
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Journal of Medical Marketing 13(4)
offer arsenic-laced wine to lonely old bachelors with
the intent that they drink it.’’ However, the dissent
failed to note the difference in that Abby and Martha
wanted to kill people (malum in se), not save lives and
Caronia did nothing that offends fundamental social
norms. Further, the dissent did not provide examples
where the activity was legal for some but not others.
Caronia is the ninth First Amendment case where
FDA has been judicially rebuked as violating the free
speech provisions of the First Amendment. Two other
notable cases are: U.S. v. Harkonen32 and three qui
tam cases referred to collectively as U.S. v. Par.33 In
U.S. v Par, Par contended ‘‘right to convey truthful
information to physicians is protected by the First
Amendment’’ and cited data showing legitimacy of
off-label uses, as determined by independent medical
personnel. The case involved on-label promotion in an
off-label setting: a marketing campaign for MegaceÕ
ES (mestrol acetate) for elderly nursing home residents. Par sought to enjoin FDA from prohibiting
both truthful and non-misleading off-label speech
and on-label speech to physicians who may prescribe
for unapproved uses. The Appeal challenged FDA’s
authority to censor truthful pharmaceutical company
speech.34 Par filed for declaratory relief prohibiting
‘‘FDA’s unconstitutional and invalid regulations’’
from restricting truthful non-misleading speech and
stated it was seeking to ‘‘elicit tailored and constitutionally permissible regulatory guidance to ensure that
physicians may be kept abreast of valuable, off-label
information about prescription drugs to aid in their
provision of quality and informed patient care.’’
FDA’s declaration sought to describe its policies and
procedures with respect to communication of off-label
use information. No information was provided
explaining what evidence suffices to render ‘‘truthful
speech’’ illegal. The government then sought to strike
the FDA’s declaration from the public record because
the statement demonstrates the regime for prosecuting
off-label use runs afoul of the First Amendment. Par
filed a motion seeking to depose FDA on the declaration statement stating it raises more questions than it
answers.35 In March 2013, PAR Pharmaceutical Co.
Inc. pled guilty for violating the False Claims Act and
agreed to pay US$45 million and be subject to a 5-year
integrity agreement to resolve its criminal and civil
liability. By the settlement terms, PAR withdrew its
First Amendment challenge, the government thus
avoiding having to litigate the merits of the First
Amendment question in another jurisdiction outside
the Second Circuit post-Caronia. The government’s
interest in avoiding more First Amendment precedent
seems acute.
In U.S. v. Harkonen, a former CEO was convicted
for allegedly making false statements about
ActimmuneÕ, for rare pediatric diseases, in a press
release. He expressed his scientific opinion about the
development of the drug, but overstated the conclusiveness of clinical trial results, especially since FDA
had already reviewed/rejected the data as insufficient
for approval of the new indication. Harkonen concerned both speech and conduct (i.e. dissemination
of speech). In this case, the speech was closer to commercial speech in that the press release was unquestionably disseminated for commercial benefit. As in
Caronia, the statement was not false, a trigger for criminal liability. Harkonen received three years probation,
6 months home detention, community service, and a
US$20,000 fine. The government appealed seeking a
greater sentence and Harkonen sought to reverse the
verdict. An Amicus Brief in support of Harkonen’s
appeal by PhRMA asserted affirmance of the decision
would threaten core First Amendment principles by
establishing that scientific debate over how to interpret
data can constitute a crime. The Ninth Circuit
reviewed the First Amendment challenges, and found
the fraud verdict was supported by the evidence presented. The appeal court did not address the First
Amendment or Due Process issues raised and did
not grant the government’s request to enhance the sentence stating that the government failed to ‘‘articulate
a legal theory that made sense’’. Some thought the
Ninth Circuit in Harkonen would provide the requisite
circuit split to allow for Supreme Court review of the
First Amendment issues raised in Caronia. However,
Harkonen is distinguished from Caronia and Par in that
the speech at issue was debatable (evidence to support
the information in the press release was based upon
interpretation was submitted too late for court consideration). In August 2013, Harkonen filed a petition for
writ of certiorari asking the Supreme Court to review
his case and in November 2013, the DOJ filed a petition in opposition of same. According to Harkonen,
the Ninth Circuit ruling creates a split regarding
First Amendment protection in cases involving scientific interpretation. That is, the Second, Sixth, and
Eighth Circuits would have overturned his conviction
in that debate precludes a fraud conviction. If the
Supreme Court declines to rule, the question remains,
is debatable speech open to government speech
restrictions?
What is the real effect of Caronia?
Caronia may signal the beginning of a new wave of
private litigation. The Court noted that where there
is a right to speak, corresponding duty follows.
Private litigants may replace government prosecution
and off-label promotion state tort claims could pose a
new threat to pharmaceutical manufacturers.36
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Rumore
217
Table 3. Balancing public health goals and commercial speech
Too much flexibility
Too little flexibility
FDA approval involves many highly skilled scientist
reviewers. Not possible for individual prescribers to
conduct the same rigorous review.
All the data may not be available for individual prescribers to review. Nor can sales representatives
effectively meet this need.
Reduction in manufacturer’s incentives to conduct
clinical trials for new indications.
The current process whereby federal prosecutors enter
into ‘‘NPAs’’ and ‘‘CIAs’’ lacks transparency and
judicial oversight.
Adverse impact on public health-limiting ability to
communicate.
Proliferation of poorly documented off-label claims.
Studies not meeting current FDA standards for scientific rigor (e.g. flawed study design).
Selection of studies which meet marketing goals while
ignoring those that do not.
Unraveling of FDA’s process as manufacturers market
products for off-label uses.
Lack of evidence-based information for payers to make
informed reimbursement decisions; lack of insurance
coverage for off-label uses.
Increased pharmaceutical company revenue and reduced
costs because of less rigorous FDA review.
Stifling of manufacturer’s willingness to respond to
unsolicited requests for information about off-label
uses from health care professionals; places barriers
of prescribers and patients to receive relevant
treatment information.
Limited numbers of therapeutic choices for certain
patient populations, e.g. pediatric patient; less identification of medications for orphan disease states.
Shifting of off-label use to investigational use requiring
informed consent.
Diminishing of, or end of, off-label use.
Increased litigation characterizing off-label use as
negligence per se.
Potential valuable treatments tied up in years of red tape
or manufacturers might decide that seeking FDA
approval is not worth the investment.
Increased use of medications with dangerous side effect
profiles or high risk of adverse drug reactions.
Possible distortion of practice away from agents listed in
clinical practice guidelines.
Increased healthcare costs as incentives would exist to
promote newest most expensive products for off-label
uses.
As courts continue to question FDA deference, new
theories are emerging to permit state laws claims to
proceed. For example, a Texas Statute allows the
claimants to rebut preemption (i.e. no liability where
a product liability claim is based on a failure to
warn. . .if the warnings. . .were those approved by
FDA) where the manufacturer promoted the product
for off-label use and the injury was causally related to
that use.37
The FDA and DOJ will need to reformulate their
approach to prosecuting off-label cases- pursue only
cases where they can prove that false or misleading
information was conveyed to healthcare professionals.
For whistleblower cases, the government is seeking
false/misleading evidence that will hold up in court
such as affirmative statements about clinical trial
results or adverse drug reactions, intentionally
misleading ghostwritten articles and sales representative training documents, or examples of clear
misbranding.
The decision raises significant concerns about the
state and federal government’s ability to impose a variety of regulatory programs targeting specific conduct
or a particular industry.38,39 Since manufacturers will
be able to promote their products for truthful off-label
uses, Caronia potentially opens the door for increased
off-label marketing. The question is what will FDA do
in response. FDA decided not to seek a re-hearing
before the appeals court and did not request
Supreme Court review of the decision. However, the
decision only holds for the Second Circuit (i.e. New
York, Connecticut, Vermont) and there is no way to
know if other circuits will follow the ruling. The
Federal government is free to pursue marketing violations in other parts of the country. The decision does
not strike down any FDCA provision, nor does it find
any conflict between the FDCA’s misbranding provisions and the First Amendment, or call into question
the drug approval framework. In fact, even companies
in the Second Circuit can still be pursued if any part of
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the off-label promotion is false or misleading. Free
speech does not extend to activities that include false
or misleading statements. Moreover, since making
truthful off-label statements may not be a safe harbor
as indictment often causes stocks to crash and fraud
convictions preclude companies from participating in
government healthcare programs, industry is currently
taking a wait and see approach.
From Caronia the question emerges – will a new
paradigm for off-label medication usage be required?
FDA critics refer to its off-label regulation and
enforcement as a pendulum – sometimes too lax and
sometimes too strict, simultaneously over-regulating
and under-regulating the practice, reflected in regulatory inconsistency. The Caronia majority called for
Congress/FDA to create less speech restrictive means
to incentivize companies to conduct research for new
indications. However, the situation is complicated.
Often, the costly clinical trials reveal that the new indication does not have the necessary efficacy/safety for
FDA approval or new safety issues with an already
marketed agent are uncovered. Some argue that
FDA’s enforcement is only the tip of the iceberg of
violative off-label promotion as FDA has limited
resources and does not actually get to all promotional
materials submitted by manufacturers (FDA tracks the
number received but not the number reviewed), FDA
attends only a small number of educational programs,
and they cannot possibly monitor communications
from physician’s offices.40 Difficulties in balancing
opposing concerns for off-label use are detailed in
Table 3 – too much enforcement restricts patient
access to best therapeutic treatments; too much flexibility increases the possibility of patient harm and
increases healthcare spending.
Some have advocated moving away from the concept of off-label to one of ‘‘emerging uses’’ with a
warning that the use is not FDA-approved and that
safety and efficacy are still emerging.41 Others advocate the recognition of a continuum of different types
of off-label use ranging from totally new indication to
related indication to dosage variation. This continuum
could be the basis of a scaled oversight or an accelerated approval process rather than the lengthy
Supplemental New Drug Application (NDA) process.
One suggestion is to have this accelerated review occur
when a particular off-label use reaches a certain
threshold.3 Possible FDA next moves, some of which
were set out in Caronia, are found in Table 4.
Mechanisms should be explored to balance medication safety while preventing irrational delay in approving off-label uses which could improve the lives of
millions of Americans on a daily basis.
In the future, as the government seeks to avoid further First Amendment precedent from off-label
Table 4. A new paradigm may be needed for off-label use
Guide the differentiation between misleading and false
promotion and truthful or non-misleading information.
Develop a warning or disclaimer system or develop
safety tiers within the off-label market.
Require manufacturers to list all applicable or intended
indications when they first apply for FDA approval.
Disclaimer.
Mandate safety and effectiveness data for wide-spread
uses (e.g. based on percentage of sales) or those
based on questionable evidence (e.g. based on numbers
of lawsuits).
Allow some private organization to enforce off-label
uses.
Expand Third Party Payer role in off-label regulation.
Better incentives – such as patent extensions or tax
credits or rebates on off-label prescribing to fund offlabel research efforts.
Tax manufacturers on off-label use; use funds for FDA’s
clinical trial efforts.
FDA streamline and expedite the Supplemental NDA
process.
FDA develop a fast track approval process for off-label
uses.
FDA work to facilitate communication of the best science
available to prescribers (safe harbors) – truthful sciencebased off-label use.
To minimize off-label use, FDA could create ceilings or
caps on off-label prescriptions.
Allow supplemental warning that a use is off-label and
that safety and efficacy is still emerging.
Where off-label use is particularly concerning, the government could prohibit it altogether.
FDA could remind prescribers and manufacturers of
legal liability (i.e. medical malpractice and negligence).
Alternatively, FDA could regulate such liability.
Amend the FDCA and its regulations for clarification for
prosecutors.
Better integration of FDA and CMS off-label policies –
develop national Medicare coverage standards for offlabel use.
Require healthcare providers to inform patients when
they are being prescribed an off-label use.
promotions, cases resembling Harkonen involving
false or debatable promotion are more likely to be
pursued than those resembling Par or Caronia. While
it may be too early to predict if Caronia will cause a sea
change in FDA’s off-label policymaking and enforcement efforts, FDA will be unlikely to pursue similar
cases until resolution of the legal issues.
Conclusion
Caronia is consistent with the position that there is, in
fact, no current, express federal law or regulation
that prohibits off-label promotion. At most, there are
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non-binding FDA Guidance documents. Beyond the
52-page opinion and 30-page dissent, Caronia represents a significant development in the enforcement of
pharmaceutical marketing practices. The decision
could serve as a strong defense against FDA enforcement actions since it holds off-label speech restrictions
up to the heightened scrutiny for which the government bears the burden of proof that any such restriction complies with the First Amendment. Whether the
courts apply some form of strict scrutiny, pursuant to
Sorrell or intermediate scrutiny, pursuant to Central
Hudson, the FDA’s off-label restrictions violate
pharmaceutical manufacturer’s First Amendment
rights.
The First Amendment issues in Caronia are very
significant, making eventual Supreme Court review
likely. However, there is no certainty how a Supreme
Court torn between extreme deference to legislation
on economic and commercial issues and a suspicious
attitude toward regulation of commercial speech will
rule. Cases such as Caronia, Par and Harkonen should
be watched closely as they will begin a course of events
that impact how medications are promoted in the
United States. Questions remain – should the government ever be able to block the sale of medication not
tainted by false or misleading information? Can the
government impose a categorical ban on truthful promotion of off-label use without contravening the U.S.
Constitution notion of free speech?
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23.
24.
25.
26.
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Author biography
Martha M Rumore (PharmD, JD) is Assistant
Director of Pharmacy, Cohen Children’s Medical
Center, New Hyde Park, NY and Professor,
Pharmacy & Health Outcomes at Touro College of
Pharmacy in New York, NY. Her research focuses on
Pharmacy and Food, Drug and Cosmetic Law.
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