Presentation to the Compliance Online 2-day course on Ensuring Compliance with FDA Requirements for the Promotion & Advertising of Drugs and Medical Devices, March 23, 2018

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© 2015 ComplianceOnline
This training session is sponsored by
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FDA Regulation of Promotion & Advertising
Part 6: First Amendment, Off-Label
and False Claims; Guidance on Medical Product
Communications Consistent with Labeling
ComplianceOnline Seminar
November 6-7, 2014
Michael A. Swit, Esq.
LAW OFFICES OF MICHAEL A. SWIT

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First Amendment
➢ Adopted December 15, 1791
– Congress shall make no law respecting an establishment of
religion, or prohibiting the free exercise thereof; or abridging
the freedom of speech, or of the press; or the right of the
people peaceably to assemble, and to petition the Government
for a redress of grievances.
➢ “Commercial Speech” – does not get “full” 1st Am.
protection
– Advertising – clearly is commercial speech
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➢ Alfred Caronia –
– Sales rep for Orphan Medical (now Jazz Pharm.)
– convicted of conspiracy to introduce a misbranded drug into
commerce – for an unapproved use (off-label)
– Appealed
• Caronia -- contended that he was prosecuted for his speech
• FDA – his speech was not the issue, it was just used as evidence of his
intent … to misbrand the drug
Caronia and Off-Label Promotion
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➢ The Facts
– Xyrem – powerful central nervous system depressant;
approved (GHB – “date rape” drug) – approved (1) to treat
narcolepsy patients who experience cataplexy and (2) to treat
narcolepsy patients with excessive daytime sleepiness (EDS);
severe side effects
• Black box warning – elderly and pediatric patients under 16
• Limited distribution – single pharmacy in Missouri
– Caronia – started a speaker program for Xyrem
• Caronia – not allowed to answer questions on off-label use; had to send
info into company
• Physician Speakers – could answer off-label questions
Caronia and Off-Label Promotion …
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➢ The Facts …
– “The Conspiracy”
• Caronia taped
– 10/26 – Dr. Charno – promoted Xyrem for uses such as fibromyalgia,
insomnia, “muscle disorders and chronic pain”
– 11/2/05 – Dr. Charno and Gleason
• Caronia and Peter Gleason – pushed Xyrem for children under 16
– Pled guilty originally; moved to have plea dismissed, claiming
that the application of the misbranding theory essentially
violated his 1st Am rights to speech
Caronia and Off-Label Promotion …
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➢ The “Misbranding Theory”
– Misbranding theory of off-label promotion – that there are not
adequate directions for use for the off-label use, but that the
off-label use has become an “intended use” as defined in FDA
regulations and directions for use, under 21 CFR 201.5, must
cover all “intended uses” (even off-label)
• 21 CFR 201.128 – objective intent of person -- allows “intended use” to
be shown by oral or written statement 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.”
• Government – not possible to write adequate directions for use for an
off-label use
Caronia and Off-Label Promotion …
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Caronia and Off-Label Promotion …
➢ Decision …
– First, 2nd Circuit concluded that the trial record made clear that
the govt prosecuted Caronia for the speech – the off-label
promotion
– On appeal, Caronia argued that the misbranding provisions, by
prohibiting off-label promotion, impinge the 1st Am.
– Court – took a slightly narrower approach –
• concluded that he was prosecuted for “mere off-label promotion”
(speech) and that was improper
– no proof offered at trial of deficient labeling, for example
• also concluded that the misbranding provisions don’t criminalize speech
per se
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Caronia and Off-Label Promotion …
➢ Court – 1st Am. violated in several ways
– Sorrell case – Heightened scrutiny
• Content based –distinguishes between “favored” and “unfavored”
speech based on the ideas expressed
– favored = approved use
– unfavored = unapproved use
• Speaker based – distinguished between types of speakers
– docs – could talk about off-label use
– drug companies – could NOT
– Central Hudson – Intermediate Scrutiny
• ….continued …
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“Central Hudson” 4-Prong Test
➢ 1 -- Is the expression protected by the First
Amendment and not misleading and related to
lawful activity?
– Yes, speech; related to lawful activity (off-label use) and not
misleading (if true)
➢ 2 -- Is the asserted government interest substantial?
– Yes, drug safety and public health
➢ 3 -- Does the regulation directly advance the
governmental interest asserted?
– No, because off-label use is acceptable and this ban on
promotion actually inhibits that use by docs
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➢ 3 -- Does the regulation directly advance the
governmental interest asserted? …
• besides, FDA actually allows distribution of off-label info under draft
Good Reprint Guidance
➢ 4 – Is the restriction narrowly drawn to further gov’t
interest
– No, there are other ways to address that FDA and government
are not pursuing. For example, the law actually bars off-label
use of HGH – Section 303(f) of Act
– Regulating speech should be last resort
“Central Hudson” 4-Prong Test
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Future after Caronia?
➢ Wild West? Snake Oil?
– 2nd Circuit -- is just NY, VT, & CT
– Government – will probably focus on:
• failure to provide adequate directions for use, because the product is
being promoted for an off-label use, in future actions
• unapproved drug actions
– Off-label promotion – must essentially be in writing
– 21 CFR 801.4 – device maker required to provide info on
labeling if it learns that its product is being used off-label
• See Dexcom Warning Letter; May 2010, where FDA asked for
labeling changes on off-label uses (pediatrics; incision location)
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➢ Very unique set of facts
– Drug: Vascepa (icosapent ethyl) – “fish oil”
• Approved originally for to reduce triglyceride levels in adults with severe
– or “very high” -- hypertriglyceridemia (≥ 500 mg/dl) – 2012
• SPA – new indication – “persistently high” triglycerides (≥ 200 to ≤500)
– ANCHOR trial, to be followed by the REDUCE-IT trial (which would
study Vascepa impact on reducing CV events)
• ANCHOR study – statistically significant results on primary endpoint
• sNDA in 2013 based on ANCHOR trial
• FDA – convened AdCom – called into question whether ANCHOR
endpoint of reducing triglycerides = lowering of CV events (which the
REDUCE-IT was supposed to address)
• FDA – complete response letter, which also included a warning not to
publicize the ANCHOR study.
• Other factor – Fish Oil supplements can make a qualified health claim
about benefits of fish oil on CV events
Amarin
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➢ Lawsuit
– Preemptive strike by Amarin
– Court decision on preliminary injunction:
• “Real and imminent fear” of prosecution present due to threat in
Complete Response Letter of misbranding if Amarin publicized
• Applied Caronia (same circuit)
• True -- what Amarin was saying was true as was clear by an extensive
record
• Not misleading – Amarin offered to distribute the info with clear
disclaimers that:
– No approval for the persistently high indication
– Amarin had proposed a qualified cardioprotective claim which was very
similar to the one FDA allows for Fish Oil supplements
• Did note that Amarin had duty to ensure that changes in science did not
alter its conclusions and disclosures
Amarin
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➢ Settlement:
– FDA -- to be bound by the Court’s conclusion that Amarin may
engage in truthful and non-misleading speech promoting the off-
label use of Vascepa®, . . . and . . . such speech may not form the
basis of a prosecution for misbranding.
– Amarin is entitled to use a procedure for the review of
promotional pieces for VASCEPA
• Amarin may obtain FDA feedback on two proposed communications each
calendar year until December 31, 2020, by submitting them to FDA for
comment prior to dissemination to doctors.
• FDA will then have 60 days to raise any concerns or objections; Amarin
must respond within 45 days.
• If FDA and Amarin do not reach an agreement 30 days later, either party
may file a motion for judicial resolution with the court.
– Does not address concept of lack of adequate directions for use
Amarin
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Draft Guidance
Medical Product Communications
Consistent with Labeling

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➢ Medical Products Communications That Are
Consistent with the FDA-Required Labeling –
Questions and Answers [Hot Link]
– Draft Guidance, January 2017
➢ Purpose – to state how FDA evaluates “medical
product” communications that present information
not contained in the FDA-required labeling to
determine if that info is consistent with the required
labeling
Medical Products Communications –
Draft Guidance -- Q&A
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➢ Medical Products covered by DG
– Drugs
– Biologics
– Medical Devices
– Animal Drugs
➢ FDA Labeling
– Approved or cleared labeling
– Exempt products – that which is relied upon to provide
adequate directions for use and other required information
➢ Bottom line – if your communications are
consistent with the labeling, fact that not in the
labeling “not alone considered evidence of a new
intended use”
Basics
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➢ 1. How Information Compares to Labeling; if answer
“yes” to any of these questions, NOT consistent:
– Indication – Do statements in the communication relate to a
different indication than the one(s) reflected in labeling?
– Patient Population – Are patient population statements in the
communication outside the approved/cleared patient population
in the labeling?
– Limitations and Directions for Handling/Use – Do
statements conflict with use limitations, or directions for
handling, preparing, and/or using the product, in the labeling?
– Dosing/Administration – Do representations/suggestions
about the product conflict with the recommended dosage or use
regimen, route of administration, or strength(s) (if applicable) in
labeling?
3 Factors FDA Uses To Decide if Consistent
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➢ 2. Whether statements in the communication increase
potential for harm to health relative to FDA labeling –
– If a communication alters the benefit-risk profile of a product in
a way that may result in increased harm to health, the
communication is not consistent with the FDA-required labeling.
– Example:
• If a firm’s communication claims that its drug has superior effectiveness
compared to another drug, but its drug is reserved for third-line use due to
severe risks associated with its use while the comparator drug is approved
for first-line use as a result of its more favorable overall benefit-risk
profile, such a communication has the potential to increase harm to the
health of patients by suggesting use in a broader patient population (e.g.,
all patients with the disease/condition instead of just patients for whom
first- and second-line therapies are not suitable) than the drug’s benefit-risk
profile justifies.
3 Factors FDA Uses To Decide if Consistent
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➢ 3. Whether the directions for use in the FDA-required
labeling enable the product to be safely and effectively used
under the conditions represented/suggested in the
communication —
➢ If the answer to #3 is “no,” the communication is not
consistent with the FDA-required labeling.
– Note: no examples given in the DG
➢ If you are consistent, the DG also says that FDA will not
regard the fact that the communication does not match the
approved labeling as evidence of the lack of adequate
directions for use
➢ Devil is in the details – analyses are very fact-specific
3 Factors FDA Uses To Decide if Consistent
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➢ Comparisons of safety or efficacy of a product for
its labeled use vs. another product with same labeled
use. For example, from a head-to-head study.
➢ Information that provides additional context about
adverse reactions.
– Example – nausea is a labeled adverse reaction.
Communication informs how taking product with food might
reduce nausea
➢ Information about long-term safety or efficacy of
products with chronic use labeling
– Example – firm provides postmarketing info showing 18
months efficacy when approval was based on 24 weeks.
Examples of Communications Consistent
with Labeling
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➢ Info on patient subgroups that are consistent with
the overall patient population in labeling
– Example – info provided on number of women studied in the
pivotal clinical studies and the treatment effects in women
➢ Patient-reported outcomes from the labeled uses
– Example – report on patients’ perceptions of product’s impact
(while used for labeled indication) on their daily activities
➢ Information on additional context about the
mechanism of action
– Example – labeling states product works by binding on a
receptor and the information provides info on why the product
selects for that receptor
Examples of Communications Consistent
with Labeling …
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➢ Information about use of a product to treat/diagnose
a disease not in labeling
– Yes, that is an example …
➢ Information for use in patients not covered by
labeling
– Example – animal drug is OK’d for feedlot cattle; information
discusses use in dairy cattle
➢ Information for use in a different stage, severity, or
manifestation of disease than in labeling
– Example – drug for mild asthma; communication if about severe
asthma
Inconsistent Communications Examples
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➢ Information about use as monotherapy when product
approved only in conjunction with another product
➢ Information about different route of administration
➢ Information about different dosage, strength, or use
regimen
– Example: labeling is for B.I.D. dosing; communication covers
once a day
➢ Information about different dosage form
– Example – drug is capsule; communication is about an oral
solution.
Inconsistent Communications Examples
…
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False Claims Act and Off-Label Promotion
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False Claims Act
➢ Enacted during Civil War; creates a bounty for
anyone who blows whistle on unscrupulous
government contractors
– Qui Tam – actions filed under seal; government can later join
– Recovery – percentage (varies) – can go to the “relator” (the
whistleblower)
➢ Late 1990’s – began to emerge in FDA-regulated
violations
– Neurontin – one of the first big ones -- $430,000,000
• (whistleblower got about $25 mil.)

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➢ Orphan Medical – Xyrem -- $20 million
➢ BMS/Otsuka – Abilify – $50 million
– Pediatric and to treat dementia (approved for MDD, PD, etc.)
➢ Cephalon -- $375 million for three drugs
– Actiq – pain in non-cancer patients (approved in cancer)
– Gabitril – anxiety, insomnia, pain (approved for partial seizures)
– Provigil – fatique and other “stimulant” uses(approved for
narcolepsy)
➢ Lilly – Zyprexa -- $1.4 Billion – anti-psychotic
marketed for numerous off-label uses
False Claims Act Settlements
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➢ Pfizer I – Bextra, Geodon, Lyrica -- $2.3 billion
– six whistleblowers shared $102 million
➢ Allergan – Botox -- $600 million – chronic migraines
(later approved for use)
➢ Abbott – Depakote -- $1.6 billion
➢ GSK – Paxil, etc. -- $3 billion
False Claims Act Settlements
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FCA – What's’ Involved
➢ Civil monetary penalties – range from $5,500 to $11G
per violation; up to 3 times amount of damage
sustained by government
➢ Focus of off-label liability – Federal healthcare
programs -- not responsible for paying for unapproved
uses
➢ Filed under seal – although you likely know if you’re
under investigation
➢ Whistleblower – protected from retaliation
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End of Part 6 –
First Amendment, Off-Label and False
Claims

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Questions?
➢ Call or e-mail:
Michael A. Swit, Esq.
LAW OFFICES OF MICHAEL A. SWIT
San Diego, California
m: 760-815-4762
e: mswit@fdacounsel.com
web: www.fdacounsel.com
➢ Follow me on:
– LinkedIn: http://www.linkedin.com/in/michaelswit
– Twitter: https://twitter.com/FDACounsel

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About Your Speaker
Michael A. Swit, Esq., has been addressing critical FDA legal and regulatory issues
since 1984. Before returning to private law practice in late 2017, he served for 3 years
at Illumina, Inc. as Senior Director, Legal, Regulatory. Prior to that, Swit was a
special counsel at the global law firm of Duane Morris LLP in its San Diego
office. Before joining Duane Morris in March 2012, Swit served for seven years as a
vice president at The Weinberg Group Inc., a preeminent scientific and regulatory
consulting firm in the Life Sciences. His expertise includes product development,
compliance and enforcement, recalls and crisis management, submissions and
related traditional FDA regulatory activities, labeling and advertising, and clinical
research efforts for all types of life sciences companies, with a particular emphasis
on drugs, biologics and therapeutic biotech products. His FDA legal and regulatory
work also has included tenures in private practice with McKenna & Cuneo (now
Dentons) and Heller Ehrman, and as vice president, general counsel and secretary
of Par Pharmaceutical, a top public generic and specialty drug firm. He also was,
from 1994 to 1998, CEO of FDANews.com, a premier publisher of regulatory
newsletters and other specialty information products for FDA-regulated firms. He
has taught and written on many topics relating to FDA regulation and associated
commercial activities and is a past member of the Food & Drug Law Journal
Editorial Board. He earned his A.B., magna cum laude, with high honors in history,
at Bowdoin College, and his law degree at Emory University.