Advanced Issues in Labeling and Promotion presented by Bradley Merrill Thompson Epstein Becker & Green, P.C. August 7, 2007

Advanced Issues inLabeling and Promotion

presented by

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

August 7, 2007

Topics

Part One Regulatory Requirements

Part Two Off-Label Promotion

Part Three Marketing in a Regulated Environment

Part Four Case Studies

Regulatory RequirementsTopics Definitions Fundamental prohibitions

FDAFTCLanham ActStates

Investigational device rules Risks in interactions with physicians

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


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


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

Fundamental Prohibition 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"

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

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

Investigational Device Labeling Rules Promotion and commercialization of devices subject to

an IDE is prohibited Disclosure of commercial price Taking or being prepared to take orders Prolonging the investigation

Price charged may not be greater than necessary to recover costs of manufacture, research, development and handling FDA may seek justification Medicare reimbursement special rules

Investigational Device Labeling Rules Sponsors may publicize the availability of the device for

the purpose of obtaining clinical investigators Directed at appropriate audience (publication in scientific

publications only, mailings only to qualified professionals

Expressly stating purpose to obtain investigators

Limiting disclosure to the proposed use of the device, sponsor contact information, how to apply to be an investigator & obtain the device, and responsibilities of investigators

Prominently displaying the investigational device caution

Avoiding claims or comparisons with other devices

Avoiding volume discounts

Investigational Device Labeling Rules

Sponsors may publicize the availability of the device for the purpose of recruiting study subjects Only IRB-approved advertisements Neither coercive or containing express or implied safety or

efficacy claims Clearly indicating the investigational nature of the device Including:

– Investigator/institution name and location– Condition/intended use under study– Summary entry criteria– Benefits of participation – Time or other commitment required of subjects– Contact information for additional information

Risks in Interactions with PhysiciansApplicable 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

Basic risk areas Federal law prohibits companies from giving anything of

value to a health care provider if any purpose of the remuneration is to induce referral of the company’s product

Extending business courtesies common in other industries (e.g. meals, gifts, entertainment) puts drug and device companies at risk for substantial enforcement liability

OIG has established guidance, and AdvaMed and PhRMA have established guidelines for interactions with health care providers

Risks in Interactions with PhysiciansGovernment 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

Topics





Off-Label Promotion Off-Label Use Rules

Basic Intended Use Framework Evolution of the Legal Landscape Promotion Dos & Don’ts

First Amendment Issues

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 codified in regulations (Part 99)


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 are still in effect

CME guidance is still in effect

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

Promotion Dos & Don’ts

Do: Promote products for cleared indications Describe product features Tell customers generally that the company

continues to invest in future innovation Respond to unsolicited, specific questions

customers may have on specific products under development, and international products

Promotion Dos & Don’tsDon’t: Encourage off-label questions, or assume a question

relates to an off-label use Make any statements about clinical performance related

to an off-label use unless you are merely providing data for the doctor to assess

Forget to disclose the FDA status of such unapproved uses

Provide any instructions for use for an off-label use, unless merely referring the doctor to a published IFU, for example, in Europe.

Answer a question without clarifying any misleading aspects, such as “Which is the most common dose?” (Common for what? Each dose fits a different use.)

First Amendment Issues

First Amendment

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

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

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

Topics





Marketing in a Regulated Environment

General Risk Areas1. Pre-approval phases

2. Unsolicited requests

3. Contracts for future generations

4. Peer reviewed articles

5. Press Releases

6. Trade shows

7. Meetings

Trends in Enforcement Good Promotional Practices

Development Phases

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

5

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 approved

4

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

Arguably none on promotion until introduced into interstate commerce. See CPG 300.600. Remember design control requirements that will apply to labeling. And remember customers and FDA will remember what is said.

Early Development

1

Requirements Related to PromotionRegulatory Category

Phase

Basic Rules For Pre-approval Promotion

1. Thou Shall Not Promote Beyond the 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 Promotion

2. 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 the appropriate evidence (a reasonable basis) at the time they are made.

Issues by Development Phase

PhaseRegulatory Category

Special settings and issues

1Development 1. Investor communications about research

2Investigational (Human use)

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

3510(k)

pending

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

4Cleared or approved

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

5Cleared and

investigational

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

2. 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

3. Contracts for Future GenerationsSome Provisions Marketers May Want:

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

3. Contracts for Future Generations

FDA’s Policy Concerns 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

3. Contracts for Future GenerationsThe 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

3. Contracts for Future Generations

Some Provisions Marketers GetOption to purchase at unspecified priceOption to purchase as specified priceCommitment to provide certain features by certain

dateCommitment as to features or performance of next

generationCommitment to notify when availableCommitment to upgrade as part of the contract priceLease agreement that includes any future

(unspecified) generations over the course of the lease

4. Peer Reviewed Articles About Marketed Devices

FDAMA Process—Part 99 Dozens of requirements, including a

commitment to file a supplement

Common law process Undefined by FDA, relies heavily on WLF

4. Factors to Consider for Peer Reviewed

1. Regulatory Status-- 510(k) or PMA or investigational2. Type of Off Label Content

a. Any new indications for use, or intended use?b. Any difference in directions for use?c. Any difference in performance claims made?

3. Public Health Value4. Ability to Avoid Off Label Content5. Regulatory History6. Health Risk7. Evidence Quality8. Author Ties9. Peer Review Process Robustness10. Fair Balance11. Disclosures and Disclaimers

4. Level Of Restriction For Peer Reviewed

1. Don’t use

2. Medical fulfillment of unsolicited request

3. Sales fulfillment of unsolicited request

4. Sales dissemination with restrictions

5. Sales dissemination without restriction

5. Press Releases What legal standard applies to information for

investors regarding investigational uses?

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

BUT, 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

5. Press Releases Best Practices:

Be truthful, accurate and objective

Present information in a fair & balanced manner

Avoid investor information that is promotional in tone or makes claims of safety or effectiveness for an unapproved use

Be consistent with prior truthful releases & PI Disclose material information required

by SEC but avoid promotional “spin”

5. Press ReleasesBest Practices:

When discussing clinical trials, limit discussions to study data -- avoid conclusory statements or interpretations

Attach product insert to press releases & provide reference to website in presentations

Unless reporting results of a head-to-head trial, avoid referencing competitors

Redistribution of press releases to actual or potential customers will be deemed promotional

5. Press Releases

Best Practices: Media Communications – IDEs and Pending PMAs

Issue a press release only for the purpose of recruiting clinical investigators or study subjects

Make only objective statements about the physical nature of the product

Make no claims about the product Include no pricing information

5. Press Releases Best Practices: Media Communications –

IDEs and Pending PMAs

Disclose the regulatory status of the product and that the product is limited by Federal law to investigational use

Limit distribution to medical and scientific media if the goal is to recruit clinical investigators, and to appropriate other media to recruit patients

6. Trade Shows

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

FDA frequently cites companies for their trade show activities.

6. Trade Shows

Best Practices: 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

6. Trade Shows Special Rules—510(k) Pending1. For 510(k) pending devices, special accommodation to

account for infrequent trade shows2. Show demo model, with conspicuous statement that not

cleared, 510(k) pending3. No performance claims4. Can explain intended use and existence of basic

features5. Can collect business leads6. 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)

7. 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

7. 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

7. Meetings

Supported Communications Unregulated scientific exchange, unless

sponsor is in a position to influence the presentation of information about its products by, for example:

Selection of speakers Control of content

7. Meetings

Supported Communications In determining independence, FDA will consider:

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 Provider involvement in sales or marketing

7. Meetings

Supported Communications FDA also will consider:

Provider’s demonstrated failure to meet standards Multiple presentations Audience selection Opportunities for discussion Dissemination Ancillary promotional activities Complaints Written agreement between provider and sponsor

7. Meetings

Best Practices: Controlled Speakers 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

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 Warner-Lambert Serono Bristol-Myers Squibb

FCA actions have alleged off-label promotion Parke-Davis Eli Lilly Pharmacia

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

Topics





Part Four: Case Studies

Topics Meetings Sales Scenarios Promotional Materials

Meetings

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

Case Study - Meetings 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

Sales Scenarios

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. FDCA?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?

Promotional Materials

Case Study – Promotional Material? 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?

Documents

Advanced Issues in Labeling and Promotion presented by Bradley Merrill Thompson Epstein Becker & Green, P.C. August 7, 2007