1. Managing Communication Before Device Approval Bradley Merrill Thompson Epstein Becker & Green, P.C.

2. The Law General Risk Areas Good Promotional Practices Case Studies Topics

3. The Law –Basics at FDA –IDE Rules –FTC –Lanham Act –States –Interaction with Physicians Topics

4. 4 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

5. 5 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…. Concept of “Intended Use”

6. 6 Off-Label Use Rules 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”

7. 7 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)

8. 8 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

9. 9 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

10. 10 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) Now sunset

11. 11 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

12. 12 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 for peer reviewed articles

13. 13 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

14. 14 IDE 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

15. 15 IDE 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

16. 16 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

17. 17 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

18. 18 State Regulation of Advertising State Food Drug & Cosmetic Acts State consumer protection laws –Enforcement by state attorneys general –Consumer class actions

19. 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. 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. 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. The Law General Risk Areas –Pre-approval phases – Unsolicited requests – Peer reviewed articles – Contracts for future generations – Meetings – Publication Planning – Physician Training – Market Research – Press Releases –Trade Shows Good Promotional Practices Case Studies Topics

23. 23 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 3 2 1 Regulatory Category Phase

24. 24 Basic Rules For Pre-approval Discussion—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.

25. 25 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.

26. 26 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

27. 27 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

28. 28 Medical Affairs Long recognized by FDA as a position that has additional freedom to engage in medical and scientific exchange Should not report to marketing or sales— must remain independent Must maintain its credibility

29. 29 FDA Guidance on Peer Reviewed Articles 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.

30. 30 FDA Guidance on Peer Reviewed Articles 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. –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.

31. 31 FDA Guidance on Peer Reviewed Articles 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. –The article or text must bear permanent and prominent disclaimers. –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.

32. 32 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

33. 33 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

34. 34 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

35. 35 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

36. 36 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

37. 37 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 “Independent” - 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., Accreditation Council for Continuing Medical Education

38. 38 Meetings Controlled Communications Regulated as promotional material Remarks should: –Be consistent with intended use –Conform to rules applicable to unsolicited requests –Avoid back up slides Also consider rules applicable to: –Dissemination of written materials –Appropriate locations –Interactions with healthcare professionals –Speaker agreements

39. 39 Meetings Independent 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

40. 40 Meetings Independent 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

41. 41 Meetings Independent 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

42. 42 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

43. 43 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

44. 44 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

45. 45 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

46. 46 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

47. 47 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” Press Releases

48. 48 Press Releases Best Practices: –When discussing clinical 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

49. 49 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

50. 50 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

51. 51 Trade Shows What standards apply to information disseminated at trade shows? –Labeling regulations do apply FDA frequently cites companies for their trade show activities.

52. 52 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

53. 53 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)

54. The Law General Risk Areas Good Promotional Practices Case Studies Topics

55. 55 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

56. The Law General Risk Areas Good Promotional Practices Case Studies Topics

57. 57 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

58. 58 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

59. 59 Case Study – Publications 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.

60. 60 Comments or Questions?