1. 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

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

3. 3 Topics Part OneRegulatory Requirements Part TwoCommunicating in a regulated environment Part ThreeCompliance 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

4. 4 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?

5. 5 It’s good to know the basics politicalhumor.about.com

6. 6 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about products, i.e. “claims” Claims must truthful, not misleading, fairly balanced and substantiated –Recent FDA Draft Guidance describes FDA's evaluation of risk information in labeling and advertising, including factors for assessing content and format –FDA asserts that factors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

7. 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. 8 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”

9. 9 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)

10. 10 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 sunset Gofethiye.com

11. 11 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 information regarding their products – on-label or off-label – if other, less restrictive measures can achieve FDA's goals

12. 12 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

13. 13 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)

14. 14 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

15. 15 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

16. 16 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

17. 17 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

18. 18 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

19. 19 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

20. 20 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

21. 21 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

22. 22 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

23. 23 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

24. 24 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

25. 25 Make sure materials are clear www.gdarguad.net

26. 26 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

27. 27 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

28. 28 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

29. 29 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 charitable grants, 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

30. 30 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

31. 31 A lot of the rules are obvious www.okaponds.com

32. 32 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) pending 3 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 Development 1 Requirements Related to Promotion Regulatory Category Phase Development Phases

33. 33 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 Cleared and investigational 5 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 Cleared or approved 4 1.Trade shows 2.Investor communications about clinical trials 3.Medical meeting discussions of clinical trials 4.Peer reviewed articles about marketed devices 510(k) pending 3 1.Trade shows 2.Investor communications about clinical trials 3.Medical meeting discussions of clinical trials 4.Peer reviewed articles about marketed devices Investigational (Human use) 2 1. Investor communications about research Development 1 Special settings and issues Regulatory Category Phase Issues by Development Phase

34. 34 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.

35. 35 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.

36. 36 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.

37. 37 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.

38. 38 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.

39. 39 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

40. 40 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

41. 41 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

42. 42 The rules don’t always make sense

43. 43 Medical Affairs Long recognized by FDA as a position that has additional freedom to engage in bona fide medical and scientific exchange Should not report to marketing or sales— must remain independent Must maintain its credibility Must have medical/scientific credentials, –Education –Experience

44. 44 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

45. 45 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

46. 46 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

47. 47 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

48. 48 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

49. 49 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)

50. 50 FDA Monitoring of Websites FDA watches web closely for off-label promotion From FDA’s page on buying medicines online:

51. 51 Best Practices: Websites Avoid discussion of investigational or OUS uses on sites targeting a US audience –Physical location of server hosting the site is irrelevant, accessibility is key – Use “gateway” page to select location –Indications only approved abroad must be segregated from the US site, with no links between them –Disclaimers are insufficient

52. 52 Best Practices: Websites Monitor linked sites for off-label/ unapproved information –“What you link becomes yours” –Provide notice that viewer is leaving your site –Observe the “two click” rule for off-label information –Avoid links to chat rooms or sites known to discuss off-label use of the product Search engine enforcement letters

53. 53 Trade Shows What standards apply to information disseminated at trade shows? –Labeling regulations do apply FDA frequently cites companies for their trade show activities. Actual Trial Question How far apart were the vehicles at the time of collision?

54. 54 Trade Shows Best practices: –Train marketing personnel extensively in permitted disclosures –Consider having medical affairs personnel present to respond to questions that are off-label But at a separate place/booth if possible –Maintain a separate space for international uses

55. 55 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)

56. 56 Scientific 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

57. 57 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

58. 58 Meetings – Supported Communications Unregulated scientific exchange, unless sponsor is in a position to influence the presentation of information about its products In determining independence, FDA will consider: –Sponsor's control over content and speakers –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 –Etc. in 1997 Guidance

59. 59 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

60. 60 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

61. 61 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 ATTORNEY: Now doctor, isn't it true that when a person dies in his sleep, he doesn't know about it until the next morning? WITNESS: Did you actually pass the bar exam?

62. 62 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

63. 63 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

64. 64 Part Three: Compliance Enforcement trends Good Promotional Practices I have always wanted to be somebody. I guess I should have been more specific. -Lily Tomlin

65. 65 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)

66. 66 Trends in Enforcement OIG continues to investigate off- label promotion –Abbott –Amgen –Boston Scientific FCA actions have alleged off-label promotion –Cephalon ($425M) –Eli Lilly ($1.4B) –Pfizer ($2.3 B) State AG Investigations of off-label promotion are on the rise

67. 67 Compliance isn’t always easy www.mustreadblogs.blogspot.com

68. 68 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

69. 69 Arguing with a lawyer is like mud wrestling with a pig: after a while you realize that the pig actually enjoys it. Comments or Questions?