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Presented by:
Mark DuVal, J.D., is president and managing
partner of DuVal & Associates. DuVal counsels
pharmaceutical, medical device, biotech, food and
nutritional supplement companies and regularly
advises clients in all areas of FDA law and
regulation.
Bradley Merrill Thompson, Esq. is a shareholder
in the law firm of Epstein, Becker & Green.
P.C. There Thomson counsels medical device and
drug companies on a wide range of FDA
regulatory, reimbursement and clinical trial issues.
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Agenda: Off-label Promotion—
Avoiding Off-label Pitfalls
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The Big Picture and a brief overview of advertising
& promotion law
Permissible forms of off-label promotion
Foundations for lawful off-label
dissemination
Permissible forms of off-label
communication
The BIG Picture: The Real Promotional
Issues Are Here Today
Antikickback
False
Claims Act
Off-label
information
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“…Mr. Louck’s [U.S.
Attorney Boston] team is
interested in whether
Schering-Plough pushed
doctors to prescribe
its drugs for unapproved,
or ‘off-label’, purposes by
offering the doctors
clinical trial grants or
other incentives.”
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Spotlight on
CME
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The Neurontin
Whistleblower Case
False Claims Act theories: alleged marketing of
off-label uses through medical science
liaisons, medical education, clinical trials etc.
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“It is reasonable to anticipate that the same kinds
of cases brought against pharmaceutical
manufacturers for kickback are going to be out
there for device manufacturers because
the industries are similar.”
—Jim Sheehan, Associate U.S. Attorney
May 2005
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FDLI’s UPDATE magazine
Jan./Feb. 2004
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Subpeonas issued:
October 27, 2005
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General vs. Specific Use Issues

The Biliary Stent FDA Compliance
Meeting—Spring 2007
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The Spineology Warning
Letter—Fall 2007
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Hot off the press:
Still further pressure
on off-label uses by
Senator Grassley
Letter to Comm’r FDA
Nov. 30, 2007
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FDA’s New Guidance document
October/September 2007
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“[This] does not mean that people will never be
mislead or offended even by truthful
advertisements. Nor does such a principle
guarantee that people will always make the right
decisions. But…the American people must be
trusted with a free flow of ‘commercial information’
unhindered by concern about government
interference.”
—Dan Troy, Former Chief Counsel, FDA
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Brief Overview of
Advertising &
Promotion Law
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FDA Regulatory Authority
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At base, FDA regulates information about
products, i.e. “claims”
Claims must truthful, not misleading, fairly
balanced and substantiated
The areas of general vs. specific
indication/claims and dissemination
of off-label information present
special issues
Concept of “Intended Use”
Under 21 CFR 801.4,
the words “intended uses” … refer to
the objective intent of the persons legally responsible for the labeling
of devices. 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. …
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Off-Label Use Rules
If promoted off-label, a device may be
deemed “misbranded” or “adulterated”
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The uses promoted are “intended uses”
under 21 CFR 801.4
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If an intended use is for other than the approved
indication, the lack of approval and inadequate
labeling make device “adulterated” and “misbranded”
Three Types of Information Flow
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Lawful on-label promotion
“Dissemination” of scientific
information
Off-label “communication”
Off-Label Promotion
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The legal basis for FDA’s objection
The evolution of the law over the
last decade
Evolution of the Legal Landscape
Where FDA was:
of Strict regulation off-label promotion
FDA
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Guidances
Guidance on Dissemination of Reprints and
Reference Texts (1996)
Guidance on Industry Supported Scientific and
Educational Activities (1997)
Then First Amendment Litigation
Washington Legal Foundation
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WLF brought action challenging 1996/1997
Guidances (and later, FDAMA) as
unconstitutional under the First Amendment
WLF won at trial
On appeal, when FDA asserted they were not
mandatory, but created only safe harbors,
the court held the matter was not ripe for
determination—a technicality
WLF Trial Court Holding
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Trial court suggested restrictions of its own,
which many manufacturers have adopted
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Articles from bona fide peer-reviewed journals or text
books published by a bona fide independent publisher
 Product must be cleared or approved for at least one
indication
 False and misleading materials still open to FDA
enforcement
 Must disclose off-label nature of a use
 Must disclose any relationship between
the company and product or authors
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FDAMA Section 401 (1997)
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Set forth process for disseminating
off-label information
Required disclosure statements & labeling
Required later filing for approval of any
unapproved uses in the materials
Set forth audience restrictions
Limited to dissemination of certain
reference journals
Codified in regulations (Part 99)
First Amendment Status

US Supreme Court decided Western States case
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FDA cannot infringe on the right of medical device
companies to promote their products if other, less
restrictive measures can achieve FDA's objectives,
such as:
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Involved pharmacy compounding provisions of FDAMA
Disclaimers and warning labels
Disclosures
Limitations on non-speech related activity
Narrowing of speech restrictions
On May 16, 2002, FDA requested comments
on its authority to regulate communications —
more than 730 comments received
What the Law is NOW—a Void
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FDCA sections on misbranding are
still in effect
FDAMA 401 provisions on dissemination of offlabel materials and regulations sunset
CME guidance is still in effect
Constitutionally speaking, FDA cannot infringe
on promotion of products if it has other options
FDA’s proposed Guidance document is in the
works
Types of Promotion
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Sales activity
Trade shows
Company controlled medical education
(non-CME)
Contracts for the sale of unapproved
equipment
Promotion before approval
Sales
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Should be controlled by “Good Promotional
Practices”
Training essential to managing risk and ensuring
compliance
Sales pitches and materials need to
be on label
Companies need to tightly control what
sales reps hand out
Trade Shows
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What standards apply to information
disseminated at trade shows?
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Labeling regulations do apply
FDA frequently cites companies for
their trade show activities.
Trade Shows (cont’d)
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Best practices:
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Train marketing personnel extensively in
permitted disclosures
 Consider having clinical personnel present to
respond to questions that are off-label
 Maintain a separate space for
international uses
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Trade Shows (cont’d)
Special Rules—510(k) Pending
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For 510(k) pending devices, special accommodation to
account for infrequent trade shows
Show demo model, with conspicuous statement that not
cleared, 510(k) pending
No performance claims
Can explain intended use and existence of basic features
Can collect business leads
But do not take orders, or be prepared to take orders, that
might result in contracts of sale for the device unless limited to
research or investigational use (e.g. no discussion of
commercial price)
Meetings – Two Types
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“Controlled” - speakers under the control of the
manufacturer (e.g., employees, consultants)
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Company-organized educational sessions
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Speaker’s bureaus
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Trade show booths
“Supported” - speakers are not under the
manufacturer’s control but manufacturer
provides financial support, i.e. grants, for the
program speakers
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Commercially supported, accredited CME, e.g., ACCME
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Mark will address CME later
Promotional Meetings
Controlled Communications
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Regulated as promotional material
Remarks should:
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Be consistent with approved intended use
Conform to rules applicable to unsolicited requests
Also consider rules applicable to:
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Written promotional materials
 Appropriate locations
 Interactions with healthcare professionals
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Meetings
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Best practices: Controlled speakers
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Respond to questions openly, but follow
guidelines for responding to unsolicited
questions on off-label uses
 Focus prepared remarks and materials on
cleared or approved uses, or disease state
 No “back-up” slides on off-label uses
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Contracts for Future Generations
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Some provisions marketers may want:
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Option to purchase at unspecified price
Option to purchase as specified price
Commitment to provide by certain date
Commitment as to features or performance of next
generation
Commitment to notify when available
Commitment to upgrade as part of the contract price
Lease agreement that includes any future generations
over the course of the lease
Clause subject to obtaining regulatory
approval/clearance
Contracts for Future Generations
(cont’d)
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FDA’s policy concerns
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Rush to develop/design, less quality
Temptation to ship before approval/clearance
Company loss of control
Promise that the company can’t fulfill
Premature promotion that creates intended uses that
may not be suitable
Freedom of choice among healthcare
providers/patients
Rationale—this is where interstate
commerce begins
Contracts for Future Generations
(cont’d)
The Law, or Some Rules of Thumb
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Can’t sign, or perhaps even negotiate, a contract
where successful performance (e.g. delivery) would
require FDA approval/clearance
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Some believe this is true even if the contract conditions
performance on FDA clearance or approval (penalty free)
Note that exempt devices or changes that do not require a new
510(k) would not be included
Can’t pre-promote except in compliance with the
rules for pre-approval communication
Contracts for Future Generations
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Some provisions marketers get
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Option to purchase at unspecified price
Option to purchase as specified price
Commitment to provide certain features by certain
date
Commitment as to features or performance of next
generation
Commitment to notify when available
Commitment to upgrade as part of the contract price
Lease agreement that includes any future
(unspecified) generations over the course
of the lease
Development Phases
Regulatory
Category
Requirements Related to Promotion
1
Early
Development
As a legal technicality, none on promotion until introduced into interstate
commerce. See CPG 300.600. Remember design control requirements
that will apply to labeling. But customers and FDA will remember what is
said.
2
Investigational
allowed beyond what is necessary for its use in investigations (e.g.
(Human use) recruiting subjects). Here, no clinical performance claims are permitted.
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According to FDA CPG section 300.600:
“Although a firm may advertise or display a device that is the subject of a
pending 510(k)--in the hope that FDA will conclude that the device is
510(k) pending
substantially equivalent to a pre-amendments device--a firm may not take
orders, or be prepared to take orders, that might result in contracts of sale
for the device unless limited to research or investigational use.”
4
Cleared or
approved
5
Cleared and
A blend of both phase 2 and 4.
investigational
Phase
IDE regulation places explicit restrictions. For example, no promotion is
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A whole slew of restrictions apply, including limits on off-label promotion,
truth in labeling, adequate directions for use, and a number of affirmative
requirements related to name, quantity, etc...
Basic Rules For Pre-approval
Promotion—Go Back to First Principles
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Thou Shall Not Promote Beyond the
anticipated Approved Label
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Whatever the company says now about its upcoming
product will create an impression in the minds of the
customers who may ultimately be asked to purchase
that product.
If the company describes uses that do not ultimately
get approved, the company will be creating an
off-label promotion situation once the product is
introduced into commercial distribution.
Basic Rules For Pre-approval
Discussion
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Thou Shall Tell the Truth in Promotional
Materials
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Both FDA and FTC would have difficulty proceeding
against the company for statements made in advance
of any product being placed in commercial
distribution. (But other laws may still be relevant.)
However, once the opportunity to acquire the product
exists, any prior statements made would be evaluated
for their truthfulness. Being truthful means, among
other things, the statements made are adequately
supported by valid scientific evidence at the
time they are made.
Issues by Development Phase
Phase
1
2
3
4
5
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Regulatory
Category
Special settings and issues
Development
1. Investor communications about research
Investigational
(Human use)
1.
2.
3.
4.
Trade shows
Investor communications about clinical trials
Medical meeting discussions of clinical trials
Peer reviewed articles about marketed devices
510(k)
pending
1.
2.
3.
4.
Trade shows
Investor communications about clinical trials
Medical meeting discussions of clinical trials
Peer reviewed articles about marketed devices
Cleared or
approved
1.
2.
3.
4.
Contracts for future generations
Investor communications about clinical trials
Medical meeting discussions of clinical trials
Peer reviewed articles about marketed devices
Cleared and
investigational
1.
2.
3.
4.
Contracts for future generations
Investor communications about clinical trials
Medical meeting discussions of clinical trials
Peer reviewed articles about marketed devices
Three Types of Information Flow
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Lawful on-label promotion
“Dissemination” of scientific
information
Off-label “communication”
Dissemination of Scientific Information
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Unsolicited requests
Dissemination of peer reviewed articles
Unsolicited Requests
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When may off-label information be provided?
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In response to an unsolicited request of a health care
provider
Best Practices: Unsolicited Requests
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Make sure unsolicited
 Keep the discussion objective, non-promotional in
nature, and fairly balanced
 Confine responses to the specific question asked,
narrowing broad questions before responding
 Clearly disclose that the device has not been
cleared or approved for the discussed use
 Document all responses to unsolicited requests
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Medical Affairs
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Long recognized by FDA as a position that has
additional freedom to engage in medical and
scientific exchange
Must not report to marketing or sales—must
remain independent
Must maintain its credibility
May affirmatively disseminate off-label
information
Proactively Disseminating
Peer Reviewed Articles About
Marketed Devices
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FDAMA Process—Part 99
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Common law process
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Dozens of requirements, including a commitment to
file a supplement
Although it has sunset, it does provide a conceptual
approach
Undefined by FDA, relies heavily on WLF
FDA seems to give it some deference
Factors to Consider
For Peer Reviewed
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Regulatory Status—510(k)
or PMA or investigational
Type of Off-Label
Content:
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Any new indications for
use, or intended use?
Any difference in directions
for use?
Any difference in
performance claims made?
Public Health Value
Ability to Avoid Off Label
Content
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Regulatory History
Health Risk
Evidence Quality
Author Ties
Peer Review Process
Robustness
Fair Balance
Disclosures and
Disclaimers
Other marketing practices
Level Of Restriction For Peer
Reviewed
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Don’t use
Medical fulfillment of unsolicited request
Sales fulfillment of unsolicited request
Sales dissemination with restrictions
Sales dissemination without restriction
Remember all options require training
to do well
Three Types of Information Flow
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Lawful on-label promotion
“Dissemination” of scientific
information
Off-label “communication”
What is Role of CME
Programs?
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Three Types of Medical Education
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Company-sponsored promotional
programs
Independent educational programs
Hybrid programs
Independent Educational Programs
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Accreditation is key
Company is “commercial interest” or
“commercial supporter”
Independent needs assessment done
No control over content, speakers, venue
Does not run program, control invitations
No selling or marketing in meeting
Hybrid Programs
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Tougher analysis—has aspects of independent and
promotional programs
These are symposia at credible institutions, grand
rounds, medical society meetings, etc.
Accreditation may or may not be involved
If speaker sponsored, must advise about making offlabel remarks, Q&A is ok
No control over content, speakers, venue
Does not run program
Often commercial supporters sponsor meal
No selling or marketing in meeting
Supporting Medical Education
Major Issues
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CME as a “safe harbor”—ACCME accreditation,
AdvaMed Code of Conduct; but ACCME not the
only way—new ACCME rules out since Sept. 2004
Can support non-CME too—symposia, round table
discussions, medical society meetings, grand
rounds, etc.—level and type of support is fact
intensive, usually stay on-label
Company speaker’s bureaus—the main message
belongs to the company (Q&A treated differently)
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ACCME on CME
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The standards are:
1.
2.
3.
4.
5.
6.
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Independence
Resolution of Personal Conflicts of Interest
Appropriate Use of Commercial Support
Appropriate Management of Associated
Commercial Promotion
Content and Format without
Commercial Bias
Disclosures Relevant to Potential
Commercial Bias
North American Association of Medical
Education Communication Companies
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CME and Non-CME—Life
As We Know It Will Change
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60
How does the organization support the inquiring
needs of customers and the advancement of
medicine through CME and non-CME programs?
How are ideas for CME initiated? Does the CME
provider work only with the company? Have you
audited their performance (adherence to ACCME)?
What role does the company play (e.g., financial
sponsorship, invitations, speaker materials, presence
of employees, availability of marketing materials)?
Does the organization have a standard procedure
on how to handle this topic? Has it been updated?
Clinical Trial Recruitment
of Physicians Under Notices
of Availability (NOAs)
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Can place ads in appropriate scientific and
medical journals; calculated to reach
qualified potential investigators
Do not make claims
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No comparisons
 Limit information to FDA guidance
 State investigational nature of product
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Must direct to an audience of appropriate
size and qualifications
Direct Advertising: Be Creative
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For example, while you can’t talk about
safety and effectiveness of a product preapproval, in a recruiting ad you can describe
the study protocol and what you hope the
trial will demonstrate
Investigator-Initiated Trials
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Supporting Investigator-Initiated
Trials—Major Issues
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Can support off-label studies
Anti-kickback issue is big
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Is it bona fide or a “seeding” trial
Is it a way to compensate a high-volume prescriber?
What is a “study”
False Claims Act issue is bigger —
reimbursement for off-label investigational
uses
Cannot be end-run around IDE regs—issue
who is truly the “sponsor”
Wall Street Journal, Feb. 2005
ANS argued the $1000 they paid physicians
was an initiative to collect data to compare
the efficacy of competing devices
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Indicia of Sponsorship
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Initiation of idea
Providing the protocol or paying someone else to write
the protocol
Reserving the right to exercise some control over study,
e.g. acceptance of the trial design (design input,
suggested edits
to the protocol), payment milestones, requiring right to
review publication, etc.
“Loaning” employees to work on study, e.g., monitoring,
auditing, data management, analysis, etc.
Requiring the physician to use a particular CRO,
regulatory group
Investigator-Initiated Trials
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How are grant requests handled? What is included
and excluded (mostly from an anti-kickback
standpoint)?
Has the company established criteria for the support
of trials? Is the trial calculated to generate
meaningful, actionable clinical information? Is it
overly duplicative of other studies?
How is financial disclosure handled?
Does the organization have a standard procedure
on how to handle this topic?
Patient Registries
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Beware of them—FDA advertising, Anti-kickback
and False Claims Act issues too
Did the government ask you to collect
the data
Why are you collecting it, what use will it
be and how much are you paying for it?
Publication Planning—
What Can We Do?
We Can Conduct/Probably Cannot Disseminate—
Permissible “Background Noise” Activities
Non-peer reviewed articles
Physician-initiated trials
Abstracts
CME outflow
MD newsletters
Consumer newsletters
Opinion editorials
Lay media articles
Third party letters to editor
Press releases
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Website/Investor Relations
Website/internet strategies—
“Research Focus” section on
Company site; “hot links” to other sites
Private sector (e.g. Mayo) or
Government (NIH, CDC, WHO, VA)
treatment protocol, algorithm or practice
guidelines
Product/technology assessment
committees, newsletters, and mailings
Non-CME programs
Consultancies
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Provides good feedback on clinical trials,
marketing messages, development priorities,
new product ideas, etc.
Comes in many formats: advisory boards,
focus panels, speaker’s bureaus, etc.
Anti-kickback Statute/OIG Safe Harbor

Bona fide services
 Fair market value
 Are you extracting or imparting information?
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Physician Training
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FDA tolerates some training pre-approval
FDA now allows specific uses to be taught
when clearance is general
Cannot train on off-label uses

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Difficulty is knowing the difference between legitimate
specific use within a general clearance and off-label
use
Consult FDA guidance documents:
“General/Specific Intended Use” and “Determination of Intended
Use for 510 (k) Devices”
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Market Research
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Are you extracting or imparting
information?
How many do you have involved to get
necessary feedback?
Legitimate exercise under FDA regulations
and anti-kickback statute—follow Personal
services Safe Harbor
Co-Marketing Practice/Product
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Anti-kickback issues predominate—cannot
underwrite business expenses for physician
Cannot pick just high volume prescribers
Physician must have “skin in the game”
Cannot promote off-label
Can answer unsolicited/unscripted off-label
questions
Company must view this as promotional channel for
itself
Meet personal services safe harbor/review ads
Compliance—Process and Procedure
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Appoint a compliance person
Putting Policy and Standard Operating
Procedures (SOPs) and policies in place
and someone in charge of them
Establish and use a promotional
review process
Training our sales reps, medical science
liaisons, reimbursement personnel and
marketers on the company’s:
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Position on off-label dissemination
SOP’s/policies/approval procedures
Compliance—Process and Procedure
(cont’d)
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Education on the law—rights and
responsibilities
Compliance—ensuring adherence to
policies, SOPs and procedures by dealing
swiftly and fairly with offenders
Audits—in-house and the field
Regular management review
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