Managing Communication Before Device Approval Bradley Merrill Thompson Epstein Becker & Green, P.C.

Managing Communication Before Device Approval

Bradley Merrill ThompsonEpstein Becker & Green, P.C.

• The Law

• General Risk Areas

• Good Promotional Practices

• Case Studies

Topics

• The Law– Basics at FDA– IDE Rules– FTC– Lanham Act– States– Interaction with Physicians

Topics

4

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

5

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”

6

Off-Label Use Rules

• 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”

7

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)

8

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

9

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

10

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)• Now sunset

11

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

12

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 for peer reviewed articles

13

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

14

IDE 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

15

IDE 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

16

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

17

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

18

State Regulation of Advertising

• State Food Drug & Cosmetic Acts

• State consumer protection laws

– Enforcement by state attorneys general

– Consumer class actions

19

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

20


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

21


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

• The Law• General Risk Areas

–Pre-approval phases– Unsolicited requests– Peer reviewed articles– Contracts for future generations– Meetings– Publication Planning– Physician Training– Market Research– Press Releases–Trade Shows

• Good Promotional Practices• Case Studies

Topics

23

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

3

2

1

Regulatory Category

Phase

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Basic Rules For Pre-approval Discussion—Go Back to First

PrinciplesThou 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.

25

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.

26

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

Cleared and investigational

5

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

Cleared or approved

4

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

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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

• Should not report to marketing or sales—must remain independent

• Must maintain its credibility

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FDA Guidance on Peer Reviewed Articles

• 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.

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• 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. – 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.

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

disclaimers.– 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.

32

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

33

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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• 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

35


(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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• 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

37

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

• “Independent” - 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.,

Accreditation Council for Continuing Medical

Education

38

Meetings

Controlled Communications• Regulated as promotional material• Remarks should:

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

requests– Avoid back up slides

• Also consider rules applicable to:– Dissemination of written materials – Appropriate locations – Interactions with healthcare professionals – Speaker agreements

39

Meetings

Independent 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

40

Meetings

Independent 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

41

Meetings

Independent 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

42

ACCME on CME

The standards are:1. Independence

2. Resolution of Personal Conflicts of Interest

3. Appropriate Use of Commercial Support

4. Appropriate Management of Associated Commercial Promotion

5. Content and Format without Commercial Bias

6. Disclosures Relevant to Potential Commercial Bias

43

Published but not disseminated—

Publication Planning— What Can We Do?

• 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

• Non-peer reviewed articles

• Physician-initiated trials

• Abstracts• CME outflow• MD newsletters• Consumer

newsletters• Opinion editorials• Lay media articles• Third party letters to

editor• Investor Relations

44

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

45

Market Research

• Are you extracting or imparting information?

• How many do you have to involve to get necessary feedback?

• Legitimate exercise under FDA regulations and anti-kickback statute—follow Personal services Safe Harbor

46

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

51

Trade Shows

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

• FDA frequently cites companies for their trade show activities.

52

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

53

Trade Shows

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)

• The Law



• Case Studies

Topics

55

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

• The Law



• Case Studies

Topics

57

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

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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

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Case Study – Publications

• 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.

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Managing Communication Before Device Approval Bradley Merrill Thompson Epstein Becker & Green, P.C.

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