Off Label Promotion of Medical Devices

presented by

Bradley Merrill Thompson Epstein Becker & Green P.C.

June 21, 2006

Topics

Part One Statutory Basics

Part Two Off-Label Use RulesPart Three First Amendment IssuesPart Four Two Views on Scientific

ExchangePart Five Case Studies

Part One: Statutory Basics

Topics Definitions Intended Use Framework How the Internet fits

into the statutory scheme

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 statute 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.”

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.…

How the Internet Fits into the Regulatory Scheme

Is a web page regulated?What is FDA’s jurisdictional reach?Can you have US and foreign pages with

different content?Are links to and from a device company

website regulated?Is the content of chat rooms and news

groups regulated? Practical observation—FDA is watching the

web closely for off-label promotion—but not pushing the jurisdictional envelope

Part Two: Off-Label Use Rules

Topics Basic Framework Evolution of the Legal Landscape Trends in Enforcement

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)

Evolution of the Legal Landscape

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

referencejournals

Now codified in regulations

Evolution of the Legal Landscape

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

Evolution of the Legal

Landscape What the Law is NOW

FDCA sections on misbranding are still in effect

FDAMA 401 provisions on dissemination of off-label materials and regulations are still in effect

CME guidance is still in effect

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

Trends in Enforcement

FDA focus is on “low hanging fruit”Trade show exhibits and booths Website advertising and linksBroadcast and print advertisingPromotional materials

FDA CreativityConnection of off-label promotion to

Medicaid or Medicare reimbursement claims (Parke-Davis)

Part Three: First Amendment Issues

Topics Recent Court Cases Where does FDA go from here?

First Amendment

Overview 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)

First Amendment

Washington Legal Foundation Background: WLF brought action

challenging 1996/1997 Guidances (and later, FDAMA) as unconstitutional under the First Amendment

U.S. District Court: FDAMA 401, regulations and FDA guidances on CME and off-label promotion are unconstitutional

First Amendment

Washington Legal Foundation On appeal, U.S. Court of Appeals lifted the

district court’s injunction making FDAMA 401, FDA regulations, and CME guidance valid once again

In Appeals Court, FDA took position FDAMA and CME Guidance only create “safe harbors,” not automatic violations, so the court felt the challenge was not “ripe”

First AmendmentWashington 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

First Amendment

Western States Background: FDAMA exempted "compounded

drugs" (mixed by pharmacist) if, among other things:

Drug is compounded by licensed pharmacistProviders 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

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

First AmendmentImpact 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

First Amendment

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: Two Views on Scientific

Exchange

First Amendment View

Vs.

FDA View

Co. Disseminated Reprints

Unsolicited Requests Unrestricted CME

Sponsored Research

Commercial Speech

Sales Influenced CME

First Amendment View

Pure Speech

FDA View

Unregulated Scientific Exchange

UnrestrictedCME

InfluencedCME

CompanyDisseminatedReprints

Sponsored Research

UnsolicitedRequests

Sales

Regulated Promotional Activity

First Amendment View

Two Levels of Protection

Pure SpeechCommercial

Speech

Highest Protection

Modest Protection

Definition of Commercial Speech

Speech that proposes a commercial transaction. See Supreme Court cases like Central

Hudson Test for commercial speech under

Supreme Court Decision in Bolger (1983):1. Whether the speech is concededly an

advertisement2. Whether the speech refers to a specific

product3. Whether the speaker has an economic

interest in disseminating the speech

More Recent View

At least one Supreme Court Justice reads the test for commercial speech a little more narrowly.

Nike (2003) Justice Breyer dissenting:Nike communications defending its labor

practices should be subject to the greater First Amendment protection.

The speech was not traditional advertisingThe speech did not focus on specific

productsMotivated by public controversy

Bottom Line

To distinguish promotion from scientific exchange for purposes of determining the level of First Amendment protection, consider:

1. Is the speech an advertisement?

2. Does the speech refer to a specific product?

3. Does the speaker have an economic interest in disseminating the speech?

But remember, even promotional speech is entitled to some protection

FDA View

Scope of FDA Regulation

FDA regulates drug and device promotion, including:LabelLabelingCertain advertising (Rx drugs and restricted

devices)Words and actions that convey intended

use So ask yourself if the activity fits one of

those categories

Types of Speech that Can Establish

Off Label Violation

Any type

So where does FDA draw the line?

What is the difference between promotion that must be on label vs. scientific

exchange that can be off label?

FDA has not published a view on general rules of thumb, preferring instead to deal with the specific settings

General Rules

My advice, consider:Speaker: scientist or salesmanMotivation

Not just spin (objective or appearance) Including company control issues for outside

speakersContent

Relation to specific product Fair balance Disclosure/disclaimer

Audience: scientist or lay personSetting

Part Five - Case Studies

Case Study Questions

Is the speech at issue regulated by FDA?If so, how would FDA treat it?

Is the speech at issue “commercial speech” as opposed to “pure speech”?

What more do you need to know? How clear is the answer?

Are there arguments on the other side?

Case Study 1

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 drugs that includes the manufacturer’s product

Audience: Doctors attending CME Setting: Aspen Hotel

Case Study 2

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

Case Study 3 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.

Comments or Questions?

Marketing in a Regulated Environment

General Risk Areas Sales Practices Promotional Materials Internet Trade Shows Meetings

Marketing in a Regulated Environment

Sales Practices Legal Standard: Response to off-label question is

allowed in certain cases, if request is unsolicited Industry Practices:

Discuss off-label uses of a device only if in response to an unsolicited question from a healthcare practitioner.

Only answer the specific question asked. If question is broad, narrow the question before responding.

Marketing in a Regulated Environment

Sales Practices Industry Practices:

Keep the discussion objective, non-promotional in nature, and fairly balanced

Tell practitioner the device has not been cleared or approved for the discussed use

If healthcare practitioner requests copies of articles about off-label use, record the request, and follow-up with corporate office medical staff

Marketing in a Regulated Environment

Promotional Materials Legal Standard: Labeling regulations apply,

unless a scientific exchange Industry Practices: Investor Relations and

Media Materials:May announce news-worthy scientific data

from studies, but raise risk if become promotional

Sticking to "real news" mitigates the risk; avoid the trickle-out approach

Marketing in a Regulated Environment

Promotional Materials If the materials are about a clinical trial,

stay close to study data; avoid conclusory statements or interpretations

Avoid comments on safety and effectiveness

Stay objective and balanced Include boilerplate language regarding

approved or cleared uses Disclose material information required

by SEC but avoid promotional “spin”

Marketing in a Regulated Environment

The Internet Legal Standard

FDA governs websites under the labeling regulations; FTC governs website advertising

Industry Practices: May link to releases to financial community that

include off-label information, but cannot remain on the site for extended period

May link to news releases or articles; avoid off-label or promotional-sounding articles

Limit access to OUS uses: separate links for U.S. and foreign visitors

Marketing in a Regulated Environment

The Internet Enforcement Examples:

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

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

Marketing in a Regulated Environment

Trade Shows One of FDA's favorite places to "catch" companies

in violation. Same standards applicable to promotional materials and sales practices apply.

Train your people well Keep international section separate Consider having scientific personnel there

for referring questions that are off-label Pending 510(k)s can be described within

certain limits

Marketing in a Regulated Environment

Meetings Speaking engagements: Company people may

speak at symposia or participate on panels, but off-label discussions increase risk

R Respond to questions openly, but follow guidelines for responding to unsolicited questions on off-label uses

R Focus prepared remarks and materials on cleared or approved uses, or disease state