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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.

Presented by:

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Agenda: Off-label Promotion—Avoiding Off-label Pitfalls

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

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The BIG Picture: The Real Promotional

Issues Are Here Today

Off-label information

False Claims Act

Anti-kickback

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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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False Claims Act theories: alleged marketing of off-label uses through medical science liaisons, medical education, clinical trials etc.

The Neurontin Whistleblower Case

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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

The Spineology Warning Letter—Fall 2007

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Hot off the press:Still further pressure on off-label uses by Senator GrassleyLetter 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

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

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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. …

Concept of “Intended Use”

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Off-Label Use Rules

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

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”

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Three Types of Information Flow

Lawful on-label promotion “Dissemination” of scientific

information Off-label “communication”

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Off-Label Promotion

The legal basis for FDA’s objection The evolution of the law over the

last decade

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Evolution of the Legal Landscape

Where FDA was:of Strict regulation off-label promotionFDA Guidances

Guidance on Dissemination of Reprints and Reference Texts (1996)

Guidance on Industry Supported Scientific and Educational Activities (1997)

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Then First Amendment Litigation

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

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WLF Trial Court Holding

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 nature of a use Must disclose any relationship between

the company and product or authors

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FDAMA Section 401 (1997)

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)

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First Amendment Status

US Supreme Court decided Western States case Involved pharmacy compounding provisions of FDAMA

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

On May 16, 2002, FDA requested comments on its authority to regulate communications — more than 730 comments received

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What the Law is NOW—a Void

FDCA sections on misbranding are still in effect

FDAMA 401 provisions on dissemination of off-label 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

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Types of Promotion

Sales activity Trade shows Company controlled medical education

(non-CME) Contracts for the sale of unapproved

equipment Promotion before approval

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Sales

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

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Trade Shows

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

FDA frequently cites companies for their trade show activities.

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Trade Shows (cont’d)

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

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Trade Shows (cont’d)

Special Rules—510(k) Pending 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)

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Meetings – Two Types

“Controlled” - speakers under the control of the manufacturer (e.g., employees, consultants) Company-organized educational sessions Speaker’s bureaus Trade show booths

“Supported” - speakers are not under the manufacturer’s control but manufacturer provides financial support, i.e. grants, for the program speakers Commercially supported, accredited CME, e.g., ACCME Mark will address CME later

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Promotional Meetings

Controlled Communications Regulated as promotional material Remarks should:

Be consistent with approved intended use Conform to rules applicable to unsolicited requests

Also consider rules applicable to: Written promotional materials Appropriate locations Interactions with healthcare professionals

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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

No “back-up” slides on off-label uses

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Contracts for Future Generations

Some 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

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Contracts for Future Generations (cont’d)

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

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Contracts for Future Generations (cont’d)

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

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Contracts for Future Generations

Some provisions marketers get 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

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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

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Basic Rules For Pre-approval Promotion—Go Back to First Principles

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.

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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.

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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 Category

Phase

Issues by Development Phase

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Three Types of Information Flow

Lawful on-label promotion “Dissemination” of scientific

information Off-label “communication”

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Dissemination of Scientific Information

Unsolicited requests Dissemination of peer reviewed articles

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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

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Medical Affairs

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

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Proactively Disseminating Peer Reviewed Articles About Marketed Devices

FDAMA Process—Part 99 Dozens of requirements, including a commitment to

file a supplement Although it has sunset, it does provide a conceptual

approach Common law process

Undefined by FDA, relies heavily on WLF FDA seems to give it some deference

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Factors to Consider For Peer Reviewed Regulatory Status—510(k)

or PMA or investigational Type of Off-Label Content:

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

Regulatory History Health Risk Evidence Quality Author Ties Peer Review Process

Robustness Fair Balance Disclosures and

Disclaimers Other marketing practices

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Level Of Restriction For Peer Reviewed

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

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Three Types of Information Flow

Lawful on-label promotion “Dissemination” of scientific

information Off-label “communication”

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What is Role of CME Programs?

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Three Types of Medical Education

Company-sponsored promotional programs

Independent educational programs Hybrid programs

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Independent Educational Programs

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

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Hybrid Programs

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 off-

label 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

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Supporting Medical EducationMajor Issues

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

The standards are:1. Independence2. Resolution of Personal Conflicts of Interest3. Appropriate Use of Commercial Support4. Appropriate Management of Associated

Commercial Promotion5. Content and Format without

Commercial Bias6. Disclosures Relevant to Potential Commercial

Bias

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North American Association of Medical Education Communication Companies

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CME and Non-CME—Life As We Know It Will Change 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?

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Clinical Trial Recruitment of Physicians Under Notices of Availability (NOAs)

Can place ads in appropriate scientific and medical journals; calculated to reach qualified potential investigators

Do not make claims No comparisons Limit information to FDA guidance State investigational nature of product

Must direct to an audience of appropriate size and qualifications

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Direct Advertising: Be Creative

For example, while you can’t talk about safety and effectiveness of a product pre-approval, in a recruiting ad you can describe the study protocol and what you hope the trial will demonstrate

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Investigator-Initiated Trials

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Supporting Investigator-Initiated Trials—Major Issues

Can support off-label studies Anti-kickback issue is big

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”

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ANS argued the $1000 they paid physicians was an initiative to collect data to compare the efficacy of competing devices

Wall Street Journal, Feb. 2005

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Indicia of Sponsorship

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

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Investigator-Initiated Trials

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?

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Patient Registries

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?

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We Can Conduct/Probably Cannot Disseminate— Permissible “Background Noise” Activities

Non-peer reviewed articlesPhysician-initiated trialsAbstractsCME outflowMD newslettersConsumer newslettersOpinion editorialsLay media articlesThird party letters to editorPress releases

Publication Planning— What Can We Do?

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

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Consultancies

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

FDA tolerates some training pre-approval FDA now allows specific uses to be taught

when clearance is general Cannot train on off-label uses

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

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

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Co-Marketing Practice/Product

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

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Compliance—Process and Procedure

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: Position on off-label dissemination SOP’s/policies/approval procedures

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Compliance—Process and Procedure (cont’d)

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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