1. Advanced Issues in Labeling and Promotion presented by Bradley Merrill Thompson Epstein Becker & Green, P.C. August 7, 2007

2. Topics Part OneRegulatory Requirements Part TwoOff-Label Promotion Part ThreeMarketing in a Regulated Environment Part FourCase Studies

3. Regulatory Requirements Topics Definitions Fundamental prohibitions  FDA  FTC  Lanham Act  States Investigational device rules Risks in interactions with physicians

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 FFDCA 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.” But consider radio and TV ads  Where do magazine ads fit FTC has jurisdiction over device advertising other than for restricted devices

7. Fundamental Prohibition The term misbranded means:  “False or misleading in any particular.” – False generally is understood to mean a statement that in any material respect is untrue. –Misleading is less clear  Twin goals of— – Safety and effectiveness – Preventing economic fraud

8. Fundamental Prohibition Examples of false labeling include:  Incorrect, inadequate or incomplete identification  Unsubstantiated claims of therapeutic value  Substitution of parts or material  Inaccuracies concerning condition, state, treatment, size, shape or style

9. Fundamental Prohibition Examples of misleading labeling include:  Ambiguity, half-truths, and trade puffery  Expressions of opinion or subjective statements  Failure to reveal material facts, consequences that may result from use, or the existence of difference of opinion

10. Fundamental Prohibition Examples of other objectionable labeling practices include  Deceptive pictorial matter  Misleading testimonials  Misleading list of parts or components  Use of brand or trade names instead of "established names"

11. What Else is Misbranded? FDA specifically requires certain information, prominently displayed (unless exempt):  Established name of the product  Name and place of business of the manufacturer, packer, or distributor  Net quantity of contents  Adequate directions for use and adequate warnings

12. Exemptions from Adequate Directions for Use Prescription devices Commonly-known directions IVDs Products intended for further processing Teaching, law enforcement and research

13. 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

14. 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

15. State Regulation of Advertising State Food Drug & Cosmetic Acts State consumer protection laws  Enforcement by state attorneys general  Consumer class actions

16. 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 Price charged may not be greater than necessary to recover costs of manufacture, research, development and handling  FDA may seek justification  Medicare reimbursement special rules

17. Investigational Device 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

18. Investigational Device 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

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. Risks in Interactions with Physicians 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. Risks in Interactions with Physicians 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

22. Topics Part OneRegulatory Requirements Part TwoOff-Label Promotion Part ThreeMarketing in a Regulated Environment Part FourCase Studies

23. Off-Label Promotion Off-Label Use Rules  Basic Intended Use Framework  Evolution of the Legal Landscape  Promotion Dos & Don’ts First Amendment Issues

24. 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. …

25. 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”

26. 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)

27. 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 (Part 99)

28. 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

29. 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

30. Promotion Dos & Don’ts Do:  Promote products for cleared indications  Describe product features  Tell customers generally that the company continues to invest in future innovation  Respond to unsolicited, specific questions customers may have on specific products under development, and international products

31. Promotion Dos & Don’ts Don’t: Encourage off-label questions, or assume a question relates to an off-label use Make any statements about clinical performance related to an off-label use unless you are merely providing data for the doctor to assess Forget to disclose the FDA status of such unapproved uses Provide any instructions for use for an off-label use, unless merely referring the doctor to a published IFU, for example, in Europe. Answer a question without clarifying any misleading aspects, such as “Which is the most common dose?” (Common for what? Each dose fits a different use.)

32. First Amendment Issues

33. First Amendment 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

34. 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

35. 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

36. Topics Part OneRegulatory Requirements Part TwoOff-Label Promotion Part ThreeMarketing in a Regulated Environment Part FourCase Studies

37. Marketing in a Regulated Environment General Risk Areas 1. Pre-approval phases 2. Unsolicited requests 3. Contracts for future generations 4. Peer reviewed articles 5. Press Releases 6. Trade shows 7. Meetings Trends in Enforcement Good Promotional Practices

38. Development Phases A blend of both phase 2 and 4.Cleared and investigational 5 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 approved 4 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 Arguably none on promotion until introduced into interstate commerce. See CPG 300.600. Remember design control requirements that will apply to labeling. And remember customers and FDA will remember what is said. Early Development 1 Requirements Related to PromotionRegulatory Category Phase

39. Basic Rules For Pre-approval Promotion 1. Thou Shall Not Promote Beyond the 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.

40. Basic Rules For Pre-approval Promotion 2. 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 the appropriate evidence (a reasonable basis) at the time they are made.

41. Issues by Development Phase Phase Regulatory Category Special settings and issues 1 Development1. Investor communications about research 2 Investigational (Human use) 1.Trade shows 2.Investor communications about clinical trials 3.Medical meeting discussions of clinical trials 4.Peer reviewed articles about marketed devices 3 510(k) pending 1.Trade shows 2.Investor communications about clinical trials 3.Medical meeting discussions of clinical trials 4.Peer reviewed articles about marketed devices 4 Cleared or approved 1. Contracts for future generations 2. Investor communications about clinical trials 3. Medical meeting discussions of clinical trials 4. Peer reviewed articles about marketed devices 5 Cleared and investigational 1. Contracts for future generations 2. Investor communications about clinical trials 3. Medical meeting discussions of clinical trials 4. Peer reviewed articles about marketed devices

42. 2. 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

43. 3. 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

44. 3. Contracts for Future Generations 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

45. 3. 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

46. 3. 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

47. 4. Peer Reviewed Articles About Marketed Devices FDAMA Process—Part 99  Dozens of requirements, including a commitment to file a supplement Common law process  Undefined by FDA, relies heavily on WLF

48. 4. Factors to Consider for Peer Reviewed 1.Regulatory Status-- 510(k) or PMA or investigational 2.Type of Off Label Content a. Any new indications for use, or intended use? b. Any difference in directions for use? c. Any difference in performance claims made? 3.Public Health Value 4.Ability to Avoid Off Label Content 5.Regulatory History 6.Health Risk 7.Evidence Quality 8.Author Ties 9.Peer Review Process Robustness 10.Fair Balance 11.Disclosures and Disclaimers

49. 4. Level Of Restriction For Peer Reviewed 1. Don’t use 2. Medical fulfillment of unsolicited request 3. Sales fulfillment of unsolicited request 4. Sales dissemination with restrictions 5. Sales dissemination without restriction

50. 5. 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. 5. Press Releases Best Practices:  Be truthful, accurate and objective  Present information in a fair & balanced manner  Avoid investor information that is promotional in tone or makes claims of safety or effectiveness for an unapproved use  Be consistent with prior truthful releases & PI  Disclose material information required by SEC but avoid promotional “spin”

52. 5. Press Releases Best Practices :  When discussing c linical trials, limit discussions to study data -- avoid conclusory statements or interpretations  Attach product insert to press releases & provide reference to website in presentations  Unless reporting results of a head-to-head trial, avoid referencing competitors  Redistribution of press releases to actual or potential customers will be deemed promotional

53. 5. Press Releases Best Practices: Media Communications – IDEs and Pending PMAs  Issue a press release only for the purpose of recruiting clinical investigators or study subjects  Make only objective statements about the physical nature of the product  Make no claims about the product  Include no pricing information

54. 5. Press Releases Best Practices: Media Communications – IDEs and Pending PMAs  Disclose the regulatory status of the product and that the product is limited by Federal law to investigational use  Limit distribution to medical and scientific media if the goal is to recruit clinical investigators, and to appropriate other media to recruit patients

55. 6. Trade Shows What standards apply to information disseminated at trade shows?  Labeling regulations apply FDA frequently cites companies for their trade show activities.

56. 6. 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

57. 6. Trade Shows Special Rules—510(k) Pending 1. For 510(k) pending devices, special accommodation to account for infrequent trade shows 2. Show demo model, with conspicuous statement that not cleared, 510(k) pending 3. No performance claims 4. Can explain intended use and existence of basic features 5. Can collect business leads 6. 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)

58. 7. Meetings – Two Types “Controlled” - speakers under the control of the sponsor (e.g., employees, consultants)  Investigator meetings  Speaker training  Trade show booths “Supported” - speakers are not under the sponsor’s control but sponsor provides support for the program (speakers without employment/consultant relationships with the sponsor)  Sponsored CME

59. 7. Meetings Controlled Communications Regulated as promotional material Remarks should:  Be consistent with intended use  Conform to rules applicable to unsolicited requests Also consider rules applicable to:  Dissemination of written materials  Appropriate locations  Interactions with healthcare professionals  Speaker agreements

60. 7. Meetings Supported 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

61. 7. Meetings Supported 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

62. 7. Meetings Supported 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

63. 7. 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

64. 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)

65. Trends in Enforcement OIG continues to investigate off-label promotion  Warner-Lambert  Serono  Bristol-Myers Squibb FCA actions have alleged off-label promotion  Parke-Davis  Eli Lilly  Pharmacia

66. 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

67. Topics Part OneRegulatory Requirements Part TwoOff-Label Promotion Part ThreeMarketing in a Regulated Environment Part FourCase Studies

68. Part Four: Case Studies Topics Meetings Sales Scenarios Promotional Materials

69. Meetings

70. 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

71. 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

72. Sales Scenarios

73. Case Study – Sales Scenarios Background: Your joint replacement device is labeled for use in individuals 65 years and older while your competitor’s device is designed and labeled for a younger population. Scenario: By way of comparison with its device, your competitor is disseminating case studies demonstrating failures of your device when implanted in younger, more physically active patients. Is this a violation of: A. Lanham Act? B. FDCA? C. FTC Act? D. State FD&C Acts? E. State Unfair Trade Practices Acts?

74. Case Study – Sales Scenarios A peer reviewed journal article describes an independent clinical trial comparing on-label, lumbar spine uses of your bone screw device with your biggest competitor. Superior efficacy of your product is clearly demonstrated. In the introductory paragraph describing the devices, authors note in a single paragraph the off-label use of these devices in the cervical spine. Can you disseminate this article to prescribers?

75. Promotional Materials

76. Case Study – Promotional Material? 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.

77. Comments or Questions?