American Medical Association

Confidential For Internal Use Only Not To Be Distributed

Four out of five doctors say that if they were stranded on a deserted island with no lawyers, they wouldn’t need any aspirin.

American Medical Association


DeviceLabeling and Promotion

presented by

Bradley Merrill Thompson Epstein Becker & Green, P.C.

February 27, 2009


Topics

Part One Regulatory RequirementsPart Two Claim SubstantiationPart Three Off-Label PromotionPart Four Marketing in a

Regulated EnvironmentPart Five Case Studies

I feel like Zsa Zsa Gabor’s fifth husband. I know what I'm supposed to do

but I don't know if I can make it interesting. Al Gore


Part One: Regulatory Requirements

Topics• Definitions• Fundamental prohibition• Special labeling rules • Risks in interactions with physicians

Actual Trial Question

What happened then?

He told me, he says, “I have to kill you because you can identify me.”Did he kill you?


It’s good to know the basics

politicalhumor.about.com


Definitions

• “Label" is a:

display of written, printed, or graphic matter upon the immediate container of any article....

• “Labeling" is:

all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article.


Definitions

• “Accompanying":– Is interpreted liberally to mean more than physical

association with the product– Extends to posters, tags, pamphlets, circulars,

booklets, brochures, instruction books, direction sheets, fillers, etc., depending how they are used

– Includes labeling that is brought together with the device after shipment or delivery for shipment in interstate commerce.

• But what of an oral sales pitch?


Definitions

Advertising

• Not defined in the FFDCA• FDA likes to treat advertising as labeling

– According to an appellate court decision: "Most, if not all advertising, is labeling.… Congress did not, and we cannot, exclude from the definition printed matter which constitutes advertising.”

• But consider radio and TV ads– Where do magazine ads fit

• FTC has jurisdiction over device advertising other than for restricted devices


Fundamental Prohibition

• The term misbranded means:– “False or misleading in any particular.”

• False generally is understood to mean a statement that in any material respect is untrue.

• Misleading is less clear– Twin goals of—

• Safety and effectiveness• Preventing economic fraud


Truth in Advertising

Funky.co.uk


More Truths



• Examples of false labeling include:– Incorrect, inadequate or incomplete

identification– Unsubstantiated claims of therapeutic value– Substitution of parts or material – Inaccuracies concerning condition, state,

treatment, size, shape or style


Good Accuracy

4.bp.blogspot.com


Mixed Disclosure

www.txrollergirls.com



• Examples of misleading labeling include:– Ambiguity, half-truths, and trade puffery– Expressions of opinion or subjective

statements– Failure to reveal material facts, consequences

that may result from use, or the existence of difference of opinion


Adequate Disclosure?

Photoshoptalent.com



• Examples of other objectionable labeling practices include

– Deceptive pictorial matter– Misleading testimonials– Misleading list of parts or components– Use of brand or trade names instead of

"established names"

Often the surest way to convey misinformation is to tell the strict truth.

Mark Twain


Misleading testimonial?

A6.vox.com


Good Use of Brand Name


Could be deceptive

Img.ffffound.com


What else is misbranded?

• FDA specifically requires certain information, prominently displayed (unless exempt):– Established name of the product– Name and place of business of the

manufacturer, packer, or distributor– Net quantity of contents – Adequate directions for use and

adequate warnings


Make sure materials are clear

www.gdarguad.net


Exemptions from Adequate Directions for Use

• Prescription devices• Commonly-known directions• IVDs• Products intended for further

processing• Teaching, law enforcement and

research


FTC Regulation of Advertising

• FTC has jurisdiction over advertising for a non-restricted device

• FTC applies three requirements– Adequate substantiation– No deception, from the standpoint of the

reasonable consumer– Fairness

• Agency influenced by lawyers who focus on consumers and how they are affected


Lanham Act

• Action against a competitor in federal court • Liability arises from deceptive statements

about either the competitor’s or the company’s own product alleged to harm the other party, including:– False or misleading claims– Unsubstantiated comparative claims– Overstatements of efficacy– Minimization of risks

• Damages & injunctive relief are available


State Regulation of Advertising

• State Food Drug & Cosmetic Acts• State consumer protection laws

– Enforcement by state attorneys general– Consumer class actions

Politics gives guys so much power that they tend to behave badly

around women. And I hope I never get into that.

Bill Clinton


Risks in Interactions with Physicians

Applicable law– Federal Anti-kickback statute– Fraud and Abuse provisions of the

Social Security Act (Medicare/Medicaid statute)

– Federal False Claims Act– State Anti-kickback statutes– State False Claims Acts– State statutes requiring disclosure of

gifts to prescribers


Risks in Interactions with Physicians

Government enforcement risks arise in the context of:

– Business courtesies • Ensure sales personnel follow applicable guidance with

respect to gifts, meals and entertainment– Consulting arrangements

• Consulting arrangements must be for necessary services pursuant to written agreements in compliance with regulatory requirements

– Research grants• Grants should be administered outside marketing

function, based on objective criteria– Educational activities & meetings

• Sponsored meetings must take place in locations conducive to educational activities, without providing entertainment and with only modest meals and accommodations


Part Two: Claim Substantiation

Topics• Generally• Comparative claims• Establishment claims

The pure and simple truth is rarely pure and never simple.

Oscar Wilde


Claim Substantiation Generally

• Refers to the evidence needed to support a claim regarding some feature or performance of the device– Must support both express and implied claims– In labeling, revolves around the FDCA “false and

misleading” language– In advertising, revolves around the FTC standard

requiring a reasonable basis in objective evidence before the claim is made

• Unlike with drugs, there is no explicit FDA guidance yet on device claim substantiation


FTC Factors for Adequate Substantiation

• Type of product• Type of claim• Benefits of a truthful claim• Cost/feasibility of developing substantiation for

the claim• Consequences of a false claim• Amount of substantiation that experts in the

field believe is reasonable


Comparative claims

• These compare the device to another device• FDA considers them inherently misleading

– Requires that such claims be supported by sound scientific data, usually a rigorous study that directly compares the devices

• FTC does not have that same predisposition, instead favoring useful comparisons

– But likewise requires rigorous scientific evidence, again a study or studies comparing the devices


Establishment claims

• These are claims that declare or even suggest that a device’s superiority has been scientifically proven

• Both FDA and FTC require the company to have at least the level of evidence stated or implied in the claim– There is also a baseline of support required– Studies must be able to withstand criticism


Part Three: Off-Label Promotion

• Off-Label Use Rules– Basic Intended Use Framework– Evolution of the Legal Landscape– Promotion Dos & Don’ts

• First Amendment Issues

Winter related injuries occur more often in the winter.-newswoman for WHIZ-TV, Zanesville Ohio


Basic Intended Use Framework

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. …


Off-Label Use Rules: Basic Framework

• The uses promoted are “intended uses” under 21 CFR 801.4– If an intended use is for other than the

approved indication, the lack of approval and inadequate labeling make device “adulterated” and “misbranded”

If promoted off-label, a device may be deemed “misbranded” or “adulterated”


Evolution of the Legal Landscape

Where FDA was:

Strict regulation of off-label promotion• FDA Guidances

– Guidance on Dissemination of Reprints and Reference Texts (1996)

– Guidance on Industry Supported Scientific and Educational Activities (1997)



Then FDAMA Section 401 (1997)• Sets forth process for disseminating off-

label information• Requires disclosure statements & labeling• Requires later filing for approval of any

unapproved uses in the materials• Sets forth audience restrictions• Limited to dissemination of certain reference

journals• Now sunset

Gofethiye.com



The Next Change• FDA’s authority to regulate off-label promotion has

been limited by the courts► Washington Legal Foundation

► Western States Medical Center

► More on those later

• Result: FDA cannot infringe on the right of medical device companies to promote their products – on-label or off-label – if other, less restrictive measures can achieve FDA's goals



What the Law is NOW• FDCA sections on misbranding are still in effect

• FDAMA 401 provisions on dissemination of off-label materials and regulations have sunset

• CME guidance is still in effect

• New Guidance on journal reprints

• FDA cannot infringe on promotion of products if it has other options


First Amendment

• FDA’s authority to regulate off-label promotion has been limited by the courts – any such regulation must be narrowly tailored to achieve FDA's purpose

• Cases:– Washington Legal Foundation v. Henney

(2000)– Thompson v. Western States Medical Center

(2002)


Washington Legal Foundation

• 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


Washington Legal Foundation

Trial court suggested restrictions of its own, which many manufacturers have adopted.– 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 use – Must disclose any relationship between the

company and product or authors


Western States

• Background: FDAMA exempted "compounded drugs" (mixed by pharmacist) if, among other things:– Drug is compounded by licensed pharmacist– Providers don't advertise or promote

compounding of a particular drug, drug class or drug type

• Challenge:– Compounding provision challenged by group of

pharmacies arguing provisions prohibiting advertising violated First Amendment


Western States

• U.S. Supreme Court held FDAMA compounding provision unconstitutional

• Lesson learned: – Government must use the least

restrictive means possible to achieve its objectives

– If government can achieve its purpose without restricting speech, or by restricting less speech, it must do so


Impact of the Litigation

• 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:– Disclaimers and warning labels– Disclosures– Limitations on non-speech related activity– Narrowing of speech restrictions

• FDA is reassessing its own authority• On May 16, 2002, FDA requested comments on its

authority to regulate communications; More than 730 comments received


SEC Disclosure Requirements

• SEC’s requirement that companies disclose material information to the investment community, including both positive and negative results of clinical trials, is often inconsistent with FDA’s limitations on disclosure– Clash of pro-speech policy with FDA’s speech

restrictions– First Amendment typically does not permit

regulation of speech based on audience• SEC has brought enforcement actions against

companies for failure to disclose important information about products in clinical trials


Conclusions

• Basic principle: Truthful speech should be allowed• Many argue that “truthful” should be judged in the

eye of the audience– Doctors are sophisticated; they can be told the

truth– Patients should be protected

• Begs the question, what level of substantiation is required to establish the truthfulness of a statement?

• But is handing a doctor a peer-reviewed article untruthful? Does it matter who hands it?

• FDA needs to protect the integrity of its clearance/approval process


Part Four: Marketing in a Regulated Environment

• The Stages of Promotion• General Risk Areas

– Good Reprint Practices– Unsolicited Requests– Contracts for future generations– Investor Communications– Websites– Trade Shows– Scientific Meetings

• Trends in Enforcement• Good Promotional Practices

The voters have spoken—the bastards.

Richard M. Nixon


A lot of the rules are obvious

www.okaponds.com


A blend of both phase 2 and 4.Cleared and investigational5

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...

Cleared or approved4

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 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.”

510(k) pending3

IDE regulation places explicit restrictions. For example, no promotion is allowed beyond what is necessary for its use in investigations (e.g. recruiting subjects). Here, no clinical performance claims are permitted.

Investigational (Human use)2

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.

Early Development1

Requirements Related to PromotionRegulatory Category

Phase

Development Phases


1. Contracts for future generations2. Investor communications about clinical trials3. Medical meeting discussions of clinical trials4. Peer reviewed articles about marketed devices

Cleared and investigational5

1. Contracts for future generations2. Investor communications about clinical trials3. Medical meeting discussions of clinical trials4. Peer reviewed articles about marketed devices

Cleared or approved4

1. Trade shows2. Investor communications about clinical trials3. Medical meeting discussions of clinical trials4. Peer reviewed articles about marketed devices

510(k) pending3

1. Trade shows2. Investor communications about clinical trials3. Medical meeting discussions of clinical trials4. Peer reviewed articles about marketed devices

Investigational (Human use)2

1. Investor communications about researchDevelopment1

Special settings and issuesRegulatory CategoryPhase

Issues by Development Phase


Basic Rules For Pre-approval Promotion

• Thou Shall Not Promote Beyond the Anticipated Approved Label– 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

• Thou Shall Tell the Truth in Promotional Materials– 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.


FDA Guidance: Good Reprint Practices

• Publishing Organizations must: – Utilize an independent editorial review board; and– Have a publicly stated policy regarding full disclosure of any

conflicts of interest• Channels of Distribution. A reference publication:

– May not be primarily distributed by the manufacturer; and – Must be generally available.

• Influence of the Manufacturer. Reference publications and reprints may not be disseminated if:– Written, edited, excerpted, or published for, or at the

request of, a product manufacturer – Edited or significantly influenced by the product

manufacturer or any party in a financial relationship with the manufacturer

– They are special supplements or publications that a manufacturer funded in whole or in part.



• Content of Disseminated Information. A reprint or reference publication:– Must not pose a significant risk to the public health. – Must address adequate, well-controlled, scientifically sound

clinical investigations include historically controlled studies, pharmacokinetic and pharmacodynamic studies and meta-analyses if they are testing a specific clinical hypothesis.

– Must be truthful and not misleading. Examples of misleading information include:

• Information that is inconsistent with the weight of credible evidence,

• A withdrawn journal article or disclaimed reference publication, or

• Information based on studies FDA deemed inadequate or not well-controlled.

– Must be disseminated in its original state.



Manner of Dissemination. – The information must be accompanied by :

• a copy of the approved product labeling;• a comprehensive bibliography; and• a publication representative of any articles

reaching different conclusions. – Dissemination must take place separate and apart

from promotional activities. For example:• a reprint may not be physically attached to any

promotional materials;• sales representatives may not discuss the

content; and• reprints may not be distributed at promotional

exhibitions or speaker programs.



Disclaimers. – The article or text must bear permanent and prominent

disclaimers.• That the uses described in the information have not been

approved or cleared by FDA • The manufacturer's interest in the drug or medical device

that is the subject of the journal reprint or reference text; • Any author known to the manufacturer as having a

financial interest in the product or manufacturer or who is receiving compensation from the manufacturer, along with the nature and amount of any such financial interest of the author

• Any person known to the manufacturer who has provided funding for the study; and

• All significant risks or safety concerns known to the manufacturer concerning the unapproved use that are not discussed in the journal article or reference text


Unsolicited Requests

• When may off-label information be provided?– In response to an unsolicited request of a health care

provider• Best Practices: Unsolicited Requests

– 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


Investor Communications

• What legal standard applies to information regarding investigational uses?

– Labeling regulations apply, unless disclosure can be classified as purely business or a scientific exchange

– Pre-approval off-label information, including study announcements, will be tolerated by FDA if segregated in the investor or news section of a website and/or distributed to the press concurrently with a newsworthy event


Contracts for Future Generations

The Law, or Some Rules of Thumb• Can’t sign, or perhaps even negotiate, a contract

where successful performance (e.g. delivery) would require FDA approval/clearance– 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


Websites

• Who regulates medical device website content?– FTC and FDA

• Is a website labeling or advertising?– “FDA considers written, printed, or graphic material

placed on a manufacturer’s or own label distributor’s Internet website to be labeling.”

– “We suggest that you review your current labeling, including … any internet advertising ….”

– Source: FDA, CDRH, Letter Re Medical Claims on Labeling and Promotional Materials of Infant Mattresses and Infant Positioners Distributed in the U.S.

• FDA uses conduct prohibited in any medium as a basis of enforcement actions related to websites– New intended use – Promotion of investigational devices


Website Enforcement Examples

Warning Letters to:– Laser Therapeutics (Despite disclaiming U.S.

medical claims, website caused device to be adulterated and misbranded)

– Medical Device Resource Corp (Claims made on website caused device to be adulterated)

– Diomed (U.S. website headlines and links to industry and general media articles cause device to be misbranded and adulterated)

– Ximed (Link to "gene therapy" page and pictorial caption implies unapproved use in gene therapy)


FDA Monitoring of Websites

•FDA watches web closely for off-label promotion

•From FDA’s page on buying medicines online:


Best Practices: Websites

• Avoid discussion of investigational or OUS uses on sites targeting a US audience– Physical location of server hosting the site is

irrelevant, accessibility is key – Use “gateway” page to select location

– Indications only approved abroad must be segregated from the US site, with no links between them

– Disclaimers are insufficient


Best Practices: Websites

• Monitor linked sites for off-label/ unapproved information – “What you link becomes yours”– Provide notice that viewer is leaving your site– Observe the “two click” rule for off-label

information– Avoid links to chat rooms or sites known to discuss

off-label use of the product


Trade Shows

• What standards apply to information disseminated at trade shows? – Labeling regulations apply

• FDA frequently cites companies for their trade show activities.


Best Practices: Trade Shows

• 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

• Control disclosures regarding pending 510(k)


Scientific Meetings – Two Types

• “Controlled” - speakers under the control of the sponsor (e.g., employees, consultants) – Investigator meetings – Speaker training – Trade show booths

• “Supported” - speakers are not under the sponsor’s control but sponsor provides support for the program (speakers without employment/consultant relationships with the sponsor)– Sponsored CME


Meetings – Controlled Communications

• Regulated as promotional material• Remarks should:

– Be consistent with intended use – Conform to rules applicable to unsolicited

requests • Also consider rules applicable to:

– Dissemination of written materials – Appropriate locations – Interactions with healthcare professionals – Speaker agreements


Meetings – Supported Communications

• Unregulated scientific exchange, unless sponsor is in a position to influence the presentation of information about its products

• In determining independence, FDA will consider:– Sponsor's control over content and speakers– Meaningful disclosure of sponsor support,

relationships with speakers, regulatory status of any unapproved uses discussed

– Focus of the program (e.g., on a single product or single company’s products when alternatives are available)

– Relationship between provider and sponsor– Etc. in 1997 Guidance


Trends in Enforcement

• FDA focus is on “low hanging fruit”– Trade show exhibits and booths – Website advertising and links– Broadcast and print advertising– Promotional materials

• FDA Creativity– Connection of off-label promotion to Medicaid

or Medicare reimbursement claims (Parke-Davis)


Trends in Enforcement

• OIG continues to investigate off- label promotion– Abbott– Amgen– Boston Scientific

• FCA actions have alleged off-label promotion– Cephalon ($425M) – Eli Lilly ($1.4B)– Pfizer ($2.3 B)

• State AG Investigations of off-label promotion are on the rise


Compliance isn’t always easy

www.mustreadblogs.blogspot.com


Good Promotional Practices

• Many leading companies are developing their own GPPs

• Essentially a risk management tool—sets the company’s preferred path forward in a gray area

• Looked favorably upon by regulators if done well.

• Become the basis for training and auditing


Part Five: Case Studies

Topics• Definition of Device/Intended Use• Meetings• Sales Scenarios• Promotional Materials

Actual Trial QuestionHow far apart were the vehicles

at the time of collision?


Definition of Device/Intended Use

Democracy used to be a good thing, but now it has gotten into the wrong hands.

-Senator Jesse Helms


Definitional Case Studies

Which of the following are regulated as medical devices?

1. Popsicle stick

2. Exercise treadmill

3. Computer software for a standard PC. Doctors type in symptoms, and an algorithm suggests the most likely diagnosis.

4. An off-the-shelf modem that connects to a blood glucose monitor. The modem transmits data over the internet to the doctor’s office, so the doctor can stay informed.

5. A website on which a patient can enter information such as height, weight, family health history and existing medical conditions. The website makes recommendations for life style improvements such as diet, exercise and dietary supplements.


Meetings

Actual Trial Question

Was it you or your brother that was

killed in the war?


Case Study - Meetings

• Speaker: Thought-leader physician who has a consulting agreement with the company

• Motivation: Speaking at CME for educational purposes.

• Content: Discussing an off label use of the generic category of devices that includes the manufacturer’s product

• Audience: Doctors attending CME• Setting: Aspen Hotel

Actual Trial QuestionDoctor, did you say he was shot in the woods?

No, I said he was shot in the lumbar region.



• Speaker: Company Medical Director• Motivation: CME Seminar, education purpose, but

an official company spokesman who gets paid partly based on stock performance

• Content: Primary remarks are on label, but an audience member asks about an off label use

• Audience: Physicians• Setting: Aspen Hotel

Actual Trial QuestionWere you acquainted with the deceased?

Yes, sir. Before or after he died?



• Speaker: Physician who serves as an investigator in a company-sponsored clinical trial

• Motivation: Publishes an article in a peer reviewed journal for prestige

• Content: The journal discusses an off label use for the company’s product under investigation.

• Audience: Physicians• Setting: The journal is subscription based, so they

get it through the mail.

Actual Trial QuestionDo you know how far pregnant you are now?

I’ll be three months on November 8.Apparently, then, the date of conception was August 8?

Yes.What were you doing at that time?


Sales Scenarios

Actual Trial QuestionHow far apart were the vehicles

at the time of collision?


Case Study – Sales Scenarios

• Background: Your joint replacement device is labeled for use in individuals 65 years and older while your competitor’s device is designed and labeled for a younger population.

• Scenario: By way of comparison with its device, your competitor is disseminating case studies demonstrating failures of your device when implanted in younger, more physically active patients.

• Is this a violation of:

A. Lanham Act?B. FD&CA?C. FTC Act?

D. State FD&C Acts?E. State Unfair Trade Practices

Acts?


Case Study – Sales Scenarios

• A peer reviewed journal article describes an independent clinical trial comparing on-label, lumbar spine uses of your bone screw device with your biggest competitor. Superior efficacy of your product is clearly demonstrated.

• In the introductory paragraph describing the devices, authors note in a single paragraph the off-label use of these devices in the cervical spine.

• Can you disseminate this article to prescribers?


Arguing with a lawyer is like mud wrestling with a pig: after a while

you realize that the pig actually enjoys it.

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