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2 3 Mark DuVal, J.D., is president and managing partner of DuVal & Associates. DuVal counsels pharmaceutical, medical device, biotech, food and nutritional.

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Presentation on theme: "2 3 Mark DuVal, J.D., is president and managing partner of DuVal & Associates. DuVal counsels pharmaceutical, medical device, biotech, food and nutritional."— Presentation transcript:

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3 3 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. Presented by:

4 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 5 The BIG Picture: The Real Promotional Issues Are Here Today Off-label information False Claims Act Anti- kickback

6 6 …Mr. Loucks [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 7 Spotlight on CME

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

9 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 10 FDLIs UPDATE magazine Jan./Feb. 2004

11 11 Subpeonas issued: October 27, 2005

12 12 General vs. Specific Use Issues The Biliary Stent FDA Compliance MeetingSpring 2007 The Spineology Warning LetterFall 2007

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

14 14 FDAs New Guidance document October/September 2007

15 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 16 Brief Overview of Advertising & Promotion Law

17 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 18 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

19 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 20 Three Types of Information Flow Lawful on-label promotion Dissemination of scientific information Off-label communication

21 21 Off-Label Promotion The legal basis for FDAs objection The evolution of the law over the last decade

22 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 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 determinationa technicality

24 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 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 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 27 What the Law is NOWa 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 FDAs proposed Guidance document is in the works

28 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 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 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 31 Trade Shows (contd) 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 32 Trade Shows (contd) Special Rules510(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 33 Meetings – Two Types Controlled - speakers under the control of the manufacturer (e.g., employees, consultants) Company-organized educational sessions Speakers bureaus Trade show booths Supported - speakers are not under the manufacturers 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 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 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 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 37 Contracts for Future Generations (contd) FDAs policy concerns Rush to develop/design, less quality Temptation to ship before approval/clearance Company loss of control Promise that the company cant fulfill Premature promotion that creates intended uses that may not be suitable Freedom of choice among healthcare providers/patients Rationalethis is where interstate commerce begins

38 38 Contracts for Future Generations (contd) The Law, or Some Rules of Thumb Cant 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 Cant pre-promote except in compliance with the rules for pre-approval communication

39 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 40 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

41 41 Basic Rules For Pre-approval PromotionGo 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 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 43 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

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

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

46 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 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 salesmust remain independent Must maintain its credibility May affirmatively disseminate off-label information

48 48 Proactively Disseminating Peer Reviewed Articles About Marketed Devices FDAMA ProcessPart 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 49 Factors to Consider For Peer Reviewed Regulatory Status510(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

50 50 Level Of Restriction For Peer Reviewed Dont 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

51 51 Three Types of Information Flow Lawful on-label promotion Dissemination of scientific information Off-label communication

52 52 What is Role of CME Programs?

53 53 Three Types of Medical Education Company-sponsored promotional programs Independent educational programs Hybrid programs

54 54 Independent Educational Programs Accreditation is key Company is commercial interest or commercial supporter Independent needs assessment done No control over content, speakers, venue Does not run program, control invitations No selling or marketing in meeting

55 55 Hybrid Programs Tougher analysishas aspects of independent and promotional programs These are symposia at credible institutions, grand rounds, medical society meetings, etc. Accreditation may or may not be involved If speaker sponsored, must advise about making off- label remarks, Q&A is ok No control over content, speakers, venue Does not run program Often commercial supporters sponsor meal No selling or marketing in meeting

56 56 Supporting Medical Education Major Issues CME as a safe harborACCME accreditation, AdvaMed Code of Conduct; but ACCME not the only waynew ACCME rules out since Sept. 2004 Can support non-CME toosymposia, round table discussions, medical society meetings, grand rounds, etc.level and type of support is fact intensive, usually stay on-label Company speakers bureausthe main message belongs to the company (Q&A treated differently)

57 57

58 58 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

59 59 North American Association of Medical Education Communication Companies

60 60 CME and Non-CMELife As We Know It Will Change How does the organization support the inquiring needs of customers and the advancement of medicine through CME and non-CME programs? How are ideas for CME initiated? Does the CME provider work only with the company? Have you audited their performance (adherence to ACCME)? What role does the company play (e.g., financial sponsorship, invitations, speaker materials, presence of employees, availability of marketing materials)? Does the organization have a standard procedure on how to handle this topic? Has it been updated?

61 61 Clinical Trial Recruitment of Physicians Under Notices of Availability (NOAs) Can place ads in appropriate scientific and medical journals; calculated to reach qualified potential investigators Do not make claims No comparisons Limit information to FDA guidance State investigational nature of product Must direct to an audience of appropriate size and qualifications

62 62 Direct Advertising: Be Creative For example, while you cant talk about safety and effectiveness of a product pre- approval, in a recruiting ad you can describe the study protocol and what you hope the trial will demonstrate

63 63 Investigator-Initiated Trials

64 64 Supporting Investigator-Initiated TrialsMajor Issues Can support off-label studies Anti-kickback issue is big Is it bona fide or a seeding trial Is it a way to compensate a high-volume prescriber? What is a study False Claims Act issue is bigger reimbursement for off-label investigational uses Cannot be end-run around IDE regsissue who is truly the sponsor

65 65 ANS argued the $1000 they paid physicians was an initiative to collect data to compare the efficacy of competing devices Wall Street Journal, Feb. 2005

66 66 Indicia of Sponsorship Initiation of idea Providing the protocol or paying someone else to write the protocol Reserving the right to exercise some control over study, e.g. acceptance of the trial design (design input, suggested edits to the protocol), payment milestones, requiring right to review publication, etc. Loaning employees to work on study, e.g., monitoring, auditing, data management, analysis, etc. Requiring the physician to use a particular CRO, regulatory group

67 67 Investigator-Initiated Trials How are grant requests handled? What is included and excluded (mostly from an anti-kickback standpoint)? Has the company established criteria for the support of trials? Is the trial calculated to generate meaningful, actionable clinical information? Is it overly duplicative of other studies? How is financial disclosure handled? Does the organization have a standard procedure on how to handle this topic?

68 68 Patient Registries Beware of themFDA advertising, Anti-kickback and False Claims Act issues too Did the government ask you to collect the data Why are you collecting it, what use will it be and how much are you paying for it?

69 69 We Can Conduct/Probably Cannot Disseminate Permissible Background Noise Activities Non-peer reviewed articles Physician-initiated trials Abstracts CME outflow MD newsletters Consumer newsletters Opinion editorials Lay media articles Third party letters to editor Press releases Publication Planning What Can We Do? Website/Investor Relations 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

70 70 Consultancies Provides good feedback on clinical trials, marketing messages, development priorities, new product ideas, etc. Comes in many formats: advisory boards, focus panels, speakers bureaus, etc. Anti-kickback Statute/OIG Safe Harbor Bona fide services Fair market value Are you extracting or imparting information?

71 71 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 Difficulty is knowing the difference between legitimate specific use within a general clearance and off-label use Consult FDA guidance documents: General/Specific Intended Use and Determination of Intended Use for 510 (k) Devices

72 72 Market Research Are you extracting or imparting information? How many do you have involved to get necessary feedback? Legitimate exercise under FDA regulations and anti-kickback statutefollow Personal services Safe Harbor

73 73 Co-Marketing Practice/Product Anti-kickback issues predominatecannot underwrite business expenses for physician Cannot pick just high volume prescribers Physician must have skin in the game Cannot promote off-label Can answer unsolicited/unscripted off-label questions Company must view this as promotional channel for itself Meet personal services safe harbor/review ads

74 74 ComplianceProcess and Procedure Appoint a compliance person Putting Policy and Standard Operating Procedures (SOPs) and policies in place and someone in charge of them Establish and use a promotional review process Training our sales reps, medical science liaisons, reimbursement personnel and marketers on the companys: Position on off-label dissemination SOPs/policies/approval procedures

75 75 ComplianceProcess and Procedure (contd) Education on the lawrights and responsibilities Complianceensuring adherence to policies, SOPs and procedures by dealing swiftly and fairly with offenders Auditsin-house and the field Regular management review

76 76 Please type your questions into text chat at this time. Find the CHAT box located on the lower left corner of your screen. Click where you see the words Type Message Here, then type your message and click the Send button. SAMPLE Question & Answer

77 77 Thank You!

78 78 This concludes todays program. Thank you for attending! Please click the EXIT button in the upper left-hand corner of your screen to exit and be directed to the post-event survey.


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