American Medical Association

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

Managing Communication Before Device Approval Bradley Merrill Thompson June 4, 2009

Topics Part One Regulatory Requirements Part Two Communicating in a regulated environment Part Three Compliance 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 • Basics at FDA • IDE Rules • FTC • Lanham Act • States • Interaction 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

FDA Regulatory Authority • At base, FDA regulates information about products, i.e. “claims” • Claims must truthful, not misleading, fairly balanced and substantiated • Recent FDA Draft Guidance describes FDA's evaluation of risk information in labeling and advertising, including factors for assessing content and format • FDA asserts that factors described in prescription drug advertising regulations apply to the evaluation of all labeling and advertising of drugs and devices under FDA's jurisdiction • Comments are due August 25 • The areas of general vs. specific indication claims and dissemination of off-label information present special 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)

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 sunset Gofethiye.com

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 First Amendment right of medical device companies to disseminate truthful, non-misleading informationregarding 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 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 My mother never saw the irony in calling me a son-of-a-bitch.Jack Nicholson

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 • On May 16, 2002, FDA requested comments on its authority to regulate communications; More than 730 comments received • Led to Good Reprint Practices described below

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

Investigational Device Labeling Rules • Promotion and commercialization of devices subject to an IDE is prohibited • Promotion of clinical trial results (needs to be bona fide scientific exchange) • Tone • Context • Disclosure of commercial price • Taking or being prepared to take orders • Prolonging the investigation

Recruiting Clinical Investigators • 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

Recruiting Study Subjects • 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

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

Make sure materials are clear www.gdarguad.net

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 and payments to prescribers

Risks in Interactions with Physicians Government enforcement risks arise in the context of: • Business courtesies, for example • Ensure sales personnel follow applicable guidance with respect to gifts, meals and entertainment • Consulting arrangements, for example • Consulting arrangements must be for necessary services pursuant to written agreements in compliance with regulatory requirements • Research and charitablegrants, for example • Grants should be administered outside marketing function, based on objective criteria • Educational activities & meetings, for example • Sponsored meetings must take place in locations conducive to educational activities, without providing entertainment and with only modest meals and accommodations

Part Two: Communicating in 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 • Publication Planning • Physician Training • Market Research • Press Releases The voters have spoken—the bastards. Richard M. Nixon

A lot of the rules are obvious www.okaponds.com

Phase Regulatory Category Requirements Related to Promotion 1 Early Development 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. 2 Investigational (Human use) 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. 3 510(k) pending 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.” 4 Cleared or approved 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... 5 Cleared and investigational A blend of both phase 2 and 4. Development Phases

Issues by Development Phase Phase Regulatory Category Special settings and issues 1 Development • Investor communications about research 2 Investigational (Human use) • Trade shows • Investor communications about clinical trials • Medical meeting discussions of clinical trials • Peer reviewed articles about marketed devices 3 510(k) pending • Trade shows • Investor communications about clinical trials • Medical meeting discussions of clinical trials • Peer reviewed articles about marketed devices 4 Cleared or approved • Contracts for future generations • Investor communications about clinical trials • Medical meeting discussions of clinical trials • Peer reviewed articles about marketed devices 5 Cleared and investigational • Contracts for future generations • Investor communications about clinical trials • Medical meeting discussions of clinical trials • Peer reviewed articles about marketed devices

Basic Rules For Pre-approval Promotion • Thou Shall Not Promote Beyond Anticipated Label, therefore: • 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.

FDA Guidance: Good Reprint Practices • 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 including 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.

FDA Guidance: Good Reprint Practices 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.

FDA Guidance: Good Reprint Practices 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

Level Of Restriction For Peer Reviewed Materials • 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

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 truly unsolicited (i.e., no leading questions) • 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

The rules don’t always make sense

Medical Affairs • Long recognized by FDA as a position that has additional freedom to engage in bona fidemedical and scientific exchange • Should not report to marketing or sales—must remain independent • Must maintain its credibility • Must have medical/scientific credentials, • Education • Experience

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. Must avoid-- • Promotional tone • Claims re safety or effectiveness • Redistribution • Undue prolonging

Contracts for Future Generations • Some provisions marketers may want: • Option to purchase at unspecified price • Option to purchase at 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

Contracts for Future Generations • 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

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:

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