1. Off Label Promotion of Medical Devices presented by Bradley Merrill Thompson Epstein Becker & Green P.C. June 21, 2006

2. Topics Part OneStatutory Basics Part TwoOff-Label Use Rules Part ThreeFirst Amendment Issues Part FourTwo Views on Scientific Exchange Part FiveCase Studies

3. Part One: Statutory Basics Topics Definitions Intended Use Framework How the Internet fits into the statutory scheme

4. 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.

5. 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?

6. Definitions Advertising Not defined in the statute FDA likes to treat advertising as labeling  According to an appellate court decision: "Most, if not all advertising, is labeling.… Congress did not, and we cannot, exclude from the definition printed matter which constitutes advertising.”

7. 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.…

8. How the Internet Fits into the Regulatory Scheme Is a web page regulated?  What is FDA’s jurisdictional reach?  Can you have US and foreign pages with different content?  Are links to and from a device company website regulated?  Is the content of chat rooms and news groups regulated? Practical observation—FDA is watching the web closely for off-label promotion—but not pushing the jurisdictional envelope

9. Part Two: Off-Label Use Rules Topics Basic Framework Evolution of the Legal Landscape Trends in Enforcement

10. 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”

11. 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)

12. 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 reference journals Now codified in regulations

13. Evolution of the Legal Landscape The Next Change FDA’s authority to regulate off-label promotion has been limited by the courts  Washington Legal Foundation  Western States Medical Center  More on those later Result: FDA cannot infringe on the right of medical device companies to promote their products – on- label or off-label – if other, less restrictive measures can achieve FDA's goals

14. Evolution of the Legal Landscape What the Law is NOW FDCA sections on misbranding are still in effect FDAMA 401 provisions on dissemination of off-label materials and regulations are still in effect CME guidance is still in effect FDA cannot infringe on promotion of products if it has other options

15. 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)

16. Part Three: First Amendment Issues Topics Recent Court Cases Where does FDA go from here?

17. First Amendment Overview FDA’s authority to regulate off-label promotion has been limited by the courts – any such regulation must be narrowly tailored to achieve FDA's purpose Cases:  Washington Legal Foundation v. Henney (2000)  Thompson v. Western States Medical Center (2002)

18. First Amendment Washington Legal Foundation Background: WLF brought action challenging 1996/1997 Guidances (and later, FDAMA) as unconstitutional under the First Amendment U.S. District Court: FDAMA 401, regulations and FDA guidances on CME and off-label promotion are unconstitutional

19. First Amendment Washington Legal Foundation On appeal, U.S. Court of Appeals lifted the district court’s injunction making FDAMA 401, FDA regulations, and CME guidance valid once again In Appeals Court, FDA took position FDAMA and CME Guidance only create “safe harbors,” not automatic violations, so the court felt the challenge was not “ripe”

20. First Amendment 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

21. First Amendment 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

22. 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

23. 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

24. First Amendment Conclusions Basic principle: Truthful speech should be allowed Many argue that “truthful” should be judged in the eye of the audience  Doctors are sophisticated; they can be told the truth  Patients should be protected Begs the question, what level of substantiation is required to establish the truthfulness of a statement? But is handing a doctor a peer-reviewed article untruthful? Does it matter who hands it? FDA needs to protect the integrity of its clearance/approval process

25. Part Four: Two Views on Scientific Exchange First Amendment View Vs. FDA View

26. Co. Disseminated Reprints Unsolicited Requests Unrestricted CME Sponsored Research Commercial Speech Sales Influenced CME First Amendment View Pure Speech

27. FDA View Unregulated Scientific Exchange Unrestricted CME Influenced CME Company Disseminated Reprints Sponsored Research Unsolicited Requests Sales Regulated Promotional Activity

28. First Amendment View

29. Two Levels of Protection Pure SpeechCommercial Speech Highest Protection Modest Protection

30. Definition of Commercial Speech Speech that proposes a commercial transaction.  See Supreme Court cases like Central Hudson Test for commercial speech under Supreme Court Decision in Bolger (1983): 1.Whether the speech is concededly an advertisement 2.Whether the speech refers to a specific product 3.Whether the speaker has an economic interest in disseminating the speech

31. More Recent View At least one Supreme Court Justice reads the test for commercial speech a little more narrowly. Nike (2003) Justice Breyer dissenting:  Nike communications defending its labor practices should be subject to the greater First Amendment protection.  The speech was not traditional advertising  The speech did not focus on specific products  Motivated by public controversy

32. Bottom Line To distinguish promotion from scientific exchange for purposes of determining the level of First Amendment protection, consider: 1.Is the speech an advertisement? 2.Does the speech refer to a specific product? 3.Does the speaker have an economic interest in disseminating the speech? But remember, even promotional speech is entitled to some protection

33. FDA View

34. Scope of FDA Regulation FDA regulates drug and device promotion, including:  Label  Labeling  Certain advertising (Rx drugs and restricted devices)  Words and actions that convey intended use So ask yourself if the activity fits one of those categories

35. Types of Speech that Can Establish Off Label Violation Any type

36. So where does FDA draw the line? What is the difference between promotion that must be on label vs. scientific exchange that can be off label? FDA has not published a view on general rules of thumb, preferring instead to deal with the specific settings

37. General Rules My advice, consider:  Speaker: scientist or salesman  Motivation  Not just spin (objective or appearance)  Including company control issues for outside speakers  Content  Relation to specific product  Fair balance  Disclosure/disclaimer  Audience: scientist or lay person  Setting

38. Part Five - Case Studies

39. Case Study Questions Is the speech at issue regulated by FDA?  If so, how would FDA treat it? Is the speech at issue “commercial speech” as opposed to “pure speech”? What more do you need to know? How clear is the answer?  Are there arguments on the other side?

40. Case Study 1 Speaker: Thought-leader physician who has a consulting agreement with the company Motivation: Speaking at CME for educational purposes. Content: Discussing an off label use of the generic category of drugs that includes the manufacturer’s product Audience: Doctors attending CME Setting: Aspen Hotel

41. Case Study 2 Speaker: Company Medical Director Motivation: CME Seminar, education purpose, but an official company spokesman who gets paid partly based on stock performance Content: Primary remarks are on label, but an audience member asks about an off label use Audience: Physicians Setting: Aspen Hotel

42. Case Study 3 Speaker: Physician who serves as an investigator in a company-sponsored clinical trial Motivation: Publishes an article in a peer reviewed journal for prestige Content: The journal discusses an off label use for the company’s product under investigation. Audience: Physicians Setting: The journal is subscription based, so they get it through the mail.

43. Comments or Questions?

44. Marketing in a Regulated Environment General Risk Areas Sales Practices Promotional Materials Internet Trade Shows Meetings

45. Marketing in a Regulated Environment Sales Practices Legal Standard: Response to off-label question is allowed in certain cases, if request is unsolicited Industry Practices:  Discuss off-label uses of a device only if in response to an unsolicited question from a healthcare practitioner.  Only answer the specific question asked. If question is broad, narrow the question before responding.

46. Marketing in a Regulated Environment Sales Practices Industry Practices:  Keep the discussion objective, non-promotional in nature, and fairly balanced  Tell practitioner the device has not been cleared or approved for the discussed use  If healthcare practitioner requests copies of articles about off-label use, record the request, and follow-up with corporate office medical staff

47. Marketing in a Regulated Environment Promotional Materials Legal Standard: Labeling regulations apply, unless a scientific exchange Industry Practices: Investor Relations and Media Materials :  May announce news-worthy scientific data from studies, but raise risk if become promotional  Sticking to "real news" mitigates the risk; avoid the trickle-out approach

48. Marketing in a Regulated Environment Promotional Materials If the materials are about a clinical trial, stay close to study data; avoid conclusory statements or interpretations Avoid comments on safety and effectiveness Stay objective and balanced Include boilerplate language regarding approved or cleared uses Disclose material information required by SEC but avoid promotional “spin”

49. Marketing in a Regulated Environment The Internet Legal Standard  FDA governs websites under the labeling regulations; FTC governs website advertising Industry Practices:  May link to releases to financial community that include off- label information, but cannot remain on the site for extended period  May link to news releases or articles; avoid off-label or promotional-sounding articles  Limit access to OUS uses: separate links for U.S. and foreign visitors

50. Marketing in a Regulated Environment The Internet Enforcement Examples:  Warning Letter to Diomed (U.S. website headlines, and links to industry and general media articles, cause device to be misbranded and adulterated)  Warning Letter to Ximed (Link to "gene therapy" page and pictorial caption implies unapproved use in gene therapy)

51. Marketing in a Regulated Environment Trade Shows One of FDA's favorite places to "catch" companies in violation. Same standards applicable to promotional materials and sales practices apply.  Train your people well  Keep international section separate  Consider having scientific personnel there for referring questions that are off-label  Pending 510(k)s can be described within certain limits

52. Marketing in a Regulated Environment Meetings Speaking engagements: Company people may speak at symposia or participate on panels, but off-label discussions increase risk ̶ 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