Presented by:

3. Presented by: 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.

4. 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

5. The BIG Picture: The Real Promotional Issues Are Here Today Anti- kickback False Claims Act Off-label information

6. “…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.”

7. Spotlight on CME

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

9. “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

10. FDLI’s UPDATE magazine Jan./Feb. 2004

11. Subpeonas issued: October 27, 2005

12. General vs. Specific Use Issues • The Biliary Stent FDA Compliance Meeting—Spring 2007 • The Spineology Warning Letter—Fall 2007

13. Hot off the press: Still further pressure on off-label uses by Senator Grassley Letter to Comm’r FDA Nov. 30, 2007

14. FDA’s New Guidance document October/September 2007

15. “[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

16. Brief Overview of Advertising & Promotion Law

17. 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

18. Concept of “Intended Use” 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. …

19. 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”

20. Three Types of Information Flow • Lawful on-label promotion • “Dissemination” of scientific information • Off-label “communication”

21. Off-Label Promotion • The legal basis for FDA’s objection • The evolution of the law over the last decade

22. Evolution of the Legal Landscape Where FDA was:of Strict regulation off-label promotion • FDA Guidances • Guidance on Dissemination of Reprints and Reference Texts (1996) • Guidance on Industry Supported Scientific and Educational Activities (1997)

23. 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

24. 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

25. 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)

26. 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

27. 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

28. Types of Promotion • Sales activity • Trade shows • Company controlled medical education (non-CME) • Contracts for the sale of unapproved equipment • Promotion before approval

29. 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

30. Trade Shows • What standards apply to information disseminated at trade shows? • Labeling regulations do apply • FDA frequently cites companies for their trade show activities.

31. 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

32. 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)

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. Development Phases 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.

41. 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.

42. 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.

43. 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 Issues by Development Phase

44. Three Types of Information Flow • Lawful on-label promotion • “Dissemination” of scientific information • Off-label “communication”

45. Dissemination of Scientific Information • Unsolicited requests • Dissemination of peer reviewed articles

46. 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

47. 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

48. 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

49. 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 Factors to Consider For Peer Reviewed

50. 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