REGULATORY AFFAIRS PROFESSIONAL SOCIETY Advertising, Promotion & Labeling Conference May 2, 2006 Denver

1. Using Clinical Studies to Support Claims for510(k) Devices REGULATORY AFFAIRS PROFESSIONAL SOCIETY Advertising, Promotion & Labeling ConferenceMay 2, 2006Denver Michael A. Swit, Esq.Vice President, Life Sciences

2. What We Will Cover • Clinical Literature to Support Claims in Labeling and Advertising – FDA’s Views • Clinical Investigations – using to Support Claims in Labeling and Advertising • “Intended Use” – the Lynchpin of Device Promotional Analysis vis-à-vis Clinical Studies • Case studies -- Advertising/Promotional Claims Impacted by Deviations from Intended Use • A Final Word of Caution – Be Careful if You Are Publicly Traded on what you say on clinicals 2

3. Use of Clinical Literature to Support Device Marketing • Statutory Provisions -- Federal Food, Drug, and Cosmetic Act (FFDCA) • § 513(a)(3)(B) – FDA may use “valid scientific evidence” [other than clinical investigations] to find a device is effective [note: does not say “safety”] • § 515(c)(1)(A) – PMA -- to contain “full reports of all information, published or known to or which should reasonably be known to the applicant, concerning investigations which have been made to show whether or not such device is safe and effective;”… 3

4. Use of Clinical Literature … • Statutory Provisions … • § 906 of FFDCA -- PRACTICE OF MEDICINE. ``Nothing in this Act shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship. This section shall not limit any existing authority of the Secretary to establish and enforce restrictions on the sale or distribution, or in the labeling, of a device that are part of a determination of substantial equivalence, established as a condition of approval, or promulgated through regulations. Further, this section shall not change any existing prohibition on the promotion of unapproved uses of legally marketed devices.'' • Added by FDAMA in 1997 4

5. Use of Clinical Literature … • § 552(a) of FFDCA -- AUTHORIZED INFORMATION.— A manufacturer may disseminate information under section 551 on a new use only if the information— • (1) is in the form of an unabridged— • (A) reprint or copy of an article, peer-reviewed by experts qualified by scientific training or experience to evaluate the safety or effectiveness of the drug or device involved, which was published in a scientific or medical journal (as defined in section 556(5)), which is about a clinical investigation with respect to the drug or device, and which would be considered to be scientifically sound by such experts; or • (B) reference publication, described in subsection (b), that includes information about a clinical investigation with respect to the drug or device that would be considered to be scientifically sound by experts qualified by scientific training or experience to evaluate the safety or effectiveness of the drug or device that is the subject of such a clinical investigation; 5

6. Use of Clinical Literature … • Regulatory Provisions • 510(k) Regulations – 21 CFR 807.87(g) – if a major change from predicate device (e.g., impacting safety, effectiveness, or indication): • “…the premarket notification submission must include appropriate supporting data…” 6

7. Use of Clinical Literature … • Regulatory Provisions • PMA Regulations -- 21 CFR 860.7 – “Although the manufacturer may submit any form of evidence … to substantiate the safety and effectiveness of a device, the agency relies upon only valid scientific evidence to determine whether there is a reasonable assurance that the device is safe and effective. • Unapproved Uses Dissemination -- 21 CFR Part 99 – Implements § 552(a) of Federal Food, Drug, and Cosmetic Act 7

8. Use of Clinical Literature … • Guidance Documents -- • Deciding When to Submit a 510k for a Change to an Existing Device– 510k Memorandum #K97-1 • Materials changes – “A 510(k) may not be needed if the manufacturer has satisfactory results from the testing indicated by ISO 10993­1 in its files for the material in question or if such results are available to the manufacturer, e.g., are available in the open published literature or have been provided to the 510(k) holder by the material supplier.” • Seehttp://www.fda.gov/cdrh/ode/510kmod.html • General/Specific Use Guidance – November 1998 – does not address clinical literature or trials directly, but is key to when further studies may be needed • Seehttp://www.fda.gov/cdrh/modact/genspec.pdf 8

9. Use of Clinical Literature … • FDA Does Not Like Clinical Literature • Questions applicability of data to specific device when study done on another manufacturer’s • Quality of data is suspect – • Cursory summaries – often underlying data not available • Not enough access to how the trial was structured • Possible where used to support claim you already have • Generally, will not allow a specific use when only a general previously cleared 9

10. Actual Clinical Investigations • Substantial Equivalence clinical studies are only required in ~10% of all Class II 510(k) submissions • When no reliable method is available to validate substantial equivalence to a predicate device • Product-related issues • Novel design • New technology • New indications for use • Upon request by FDA 10

11. Actual Clinical Investigations … • Why done: • Superiority and economic data not required for FDA clearance of a 510(k) submission. . . . . .but these data are required to support reimbursement applications with CMS or private payers • Data to support FDA clearance may not be the data needed for reimbursement; marketing goals 11

12. Actual Clinicals -- Regulatory Considerations • FDA • Remember – main focus is substantial equivalence • How to determine if you need a clinical study: • Comparison to predicate – technology • Comparison to predicate – intended use • Comparison to requirements for similar devices • Any factor raising new questions of safety or effectiveness that cannot be alleviated through bench testing points towards a clinical trial 12

13. Actual Clinicals -- Regulatory Considerations • CMS • Primary focus is effectiveness • Requires systematic evaluation of the performance and properties of the technology: • All available clinical and outcomes data • Comprehensive review of relevant literature (published and unpublished) • If marketed, opinions/data from leaders in the field on real-world use • Analysis of competitive advantage • Overall economic impact including costs offsets 13

14. Understanding “Intended Use” • 21 CFR 801.4 – “…This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives….” • General/Specific Guidance -- A change from a general to a specific indication for use is defined as: Any proposed increase in the level of specificity of the indication for use of a medical device. A change in a device’s indication for use from general to specific usually results in an indication for use that is narrower than the approved or cleared general use. Such a change or additional indication generally will narrow the indication for use with respect to function, target population, organ or organ system, tissue type, disease entity, or analyte. 14

15. Case Study – Thoratec Warning Letter -- 1999 • Thoratec’s Devices – Ventricular Assist Device & TLC-II • Type of Promo – Video circulated at Am. Assn. of Thoracic Surgery conference • FDA alleged video contained: • Misleading comparative claims • Claims for unapproved use – viral myocarditis • Claims for uses beyond those approved in PMA 15

16. Case Study – Thoratec … • Thoratec PMA Approved Use: 16

17. Case Study – Thoratec … • Improper use of clinical literature • “Thoratec’s video quotes portions of information from two articles , appearing in the Annals of Thoracic Surgery in 1995 and 1996. However, neither article reflects results from a controlled clinical trial conducted by either Thoratec or ABIOMED. Both articles instead reflect European clinical experience with circulatory support devices. The portions of the articles quoted are taken out of context and provide only the briefest statements of comparison between devices. Although such presentations may encapsulate the appearances of superiority for the Thoratec device that Thoratec apparently wishes to create, they are misleading presentations of clinical experience and conclusions.” 17

18. Case Study – Thoratec … • Other alleged errors in using clinical literature • Selective quotation – Thoratec left out quotes that might provide alternative explanations for results achieved in the study that did not favor Thoratec 18

19. Case Study – Diomed Warning Letter -- 2001 • Device: Photodynamic Therapy Lasers for various surgical uses • FDA allegation – website promoting unapproved use to treat varicose veins [a 510(k) was pending, but not yet cleared] • Unacceptable literature sources – links to: • New York Times article on varicose vein treatments • Good Morning America article 19

20. Case Study – OmniCorder Tech. -- 2000 • Device: Bioscan System -- QuantumWell Infrared Photodector and the Dynamic Area Telethermometry (DAT) • Intended use: • The intended use of the BioScan designated K990416 is “for viewing and recording heat patterns generated by the human body in the hospital, acute care settings, outpatient surgery, healthcare practitioner facilities or in an environment where patient care is provided by qualified healthcare personnel. The patient populations include adult, pediatric and neonatal. The device is for adjunctive diagnostic screening for detection breast cancer and diseases affecting the blood perfusion or reperfusion of tissue or organs. This device is intended for use by qualified healthcare personnel trained in its use.” 20

21. Case Study – OmniCorder … • FDA allegation: links on website to clinical studies that suggested the use of the Bioscan system alone to detect breast cancer • Note: FDA also claimed this was an inappropriate unsolicited dissemination of an off-label use 21

22. Final Note – Remember Your Goal with a 510(k) is Substantial Equivalence 22

23. Clinical Study Disclosures and the SEC • For a disclosure to be actionable, it usually must be both false or misleading and “material” – thus, these are fact-specific scenarios • “Material” – info would have “actual significance in the deliberations of the reasonable shareholder” 23

24. Life Sciences Companies Disclosures and the SEC … • Clinical Trial Results – • If disclosure involves an interpretation of the results, will only be actionable if not within the range of reasonable science • No duty to disclose all facts about a study, as long as those selected are done in a reasonable way and any omissions would not render the disclosure “so incomplete as to mislead” • Negative trial results • You have a reasonable time to evaluate – until you do, you lack “material information” • No overt duty to disclose, except if: • Your officers are trading in the stock • Public statements are misleading if the results are NOT disclosed 24

25. Questions? Call, e-mail, fax or write: Michael A. Swit, Esq. Vice President, Life Sciences THE WEINBERG GROUP INC. 336 North Coast Hwy. 101 Suite C Encinitas, CA 92024 Phone 760.633.3343 Fax 760.633.3501 Cell 760.815.4762 D.C. Office 202.730.4123 michael.swit@weinberggroup.com www.weinberggroup.com 25

26. About the speaker … Michael A. Swit, Esq., who is Vice President, Life Sciences at THE WEINBERG GROUP INC., has extensive experience in all aspects of FDA regulation with a particular emphasis on drugs and medical device regulation. In addition to his private legal and consulting experience, Mr. Swit also served for three and a half years as vice president and general counsel of Pharmaceutical Resources, Inc. (PRI) a prominent generic drug company and, thus, brings an industry and commercial perspective to his representation of FDA-regulated companies. While at PRI from 1990 to late 1993, Mr. Swit spearheaded the company’s defense of multiple grand jury investigations, other federal and state proceedings, and securities litigation stemming from the acts of prior management. Mr. Swit then served from 1994 to 1998 as CEO of Washington Business Information, Inc. (WBII) a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA publishing company. Before joining THE WEINBERG GROUP, he served in the FDA Regulatory Law Practices at both Heller Ehrman and McKenna & Cuneo, first in that firm’s D.C. office and then in its San Diego office. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius from 1984 to 1988. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law including, since 1989, co-directing a three-day intensive course on the generic drug approval process, serving on the Editorial Board of the Food & Drug Law Journal, and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved, published by WBII. Mr. Swit holds an A.B., magna cum laude, with high honors in history, in 1979, from Bowdoin College, and earned his law degree from Emory University in 1982. He is a member of the California, Virginia and District of Columbia bars. 26

27. For more than twenty years, leading companies have depended on THE WEINBERG GROUP when their products are at risk. Our technical, scientific and regulatory experts deliver the crucial results that get products to market and keep them there. 27