INTERMACS Collaborators: NHLBI: Sustainability – Are we there yet?

1. Sixth Annual Meeting, March 12, 2012 • INTERMACS Collaborators: • NHLBI: Sustainability – Are we there yet? • CMS: The blurred lines among DT, BTC, BTT • FDA: Benchmarks for next device approval • Industry: INTERMACS – The ultimate post market study • Hospitals: Utilizing the Quality Assurance Reports INTERMACS Annual Meeting March 2012

2. Sixth Annual Meeting, March 12, 2012 • NHLBI: Sustainability–Are we there yet? • M Miller INTERMACS Annual Meeting March 2012

3. National Heart, Lung, and Blood Institute: INTERMACS-Looking Forward to Full Sustainability Marissa A. Miller, DVM, MPH Project Officer Chief, Advanced Technologies and Surgery Branch National Heart, Lung, and Blood Institute INTERMACS Annual Meeting March 12, 2012 INTERMACS Annual Meeting March 2012

4. INTERMACS Annual Meeting March 2012

5. INTERMACS: From an Idea To….. 2005 2012 6492 patients/131 centers Sustainable Public Private Partnership Pre/post market studies 40+ publications & abstracts 700+ citations MEDAMACS, PEDIMACS, IMACS, ‘JAPANMACS’, ‘CANADAMACS’….. • 0 patients/0 centers • Complete NHLBI funding • No pre/post market studies • 0 publications • 0 citations • 0 spin-offs INTERMACS Annual Meeting March 2012

6. INTERMACS: Sustainability? • Financial • 131 hospitals engaged • Device manufacturers integrated—sound business plan • Longstanding NHLBI commitment • Scientific • Where were we before the INTERMACS patient profiles, INTERMACS survival curves, INTERMACS comparator data? • Public Health Relevance • The trend toward rigorous registries—AHRQ publication, TVR Registry • Regulatory and reimbursement decisions being based on INTERMACS data INTERMACS Annual Meeting March 2012

7. INTERMACS What’s Left To Do To Assure Sustainability? • Expand and Improve the Data • MEDAMACS! & PEDIMACS! • Augment collection of functional capacity & health status • Streamline data fields • New site monitoring paradigm • Rigorous hospital standards • Strategically align with other programs • PumpKIN • REVIVE-IT • International data collection efforts • Don’t get complacent! INTERMACS Annual Meeting March 2012

8. INTERMACS What’s Left to Do To Assure Sustainability? • Enhance as research tool and expand access • De-identified data sets • Semi-annual research fairs • Web-based data requests • Formulate New Hypotheses • Connect with transplant registry • Link to CMS/reimbursement /insurance data • Examine quality improvement/best practices • Ongoing Safety Surveillance (for the future) • Link registry data to other data sources through UDI • Implement automated safety surveillance tools to prospectively monitor for failures and complications INTERMACS Annual Meeting March 2012

9. INTERMACS Partnerships Researchers Public NHLBI FDA International Organizations The Next Frontier—Strategic Partners? Industry CMS Academia Hospitals INTERMACS Annual Meeting March 2012

10. INTERMACS Annual Meeting March 2012

11. Sixth Annual Meeting, March 12, 2012 • CMS: View of INTERMACS • Jyme Schafer, MD INTERMACS Annual Meeting March 2012

12. Medicare and INTERMACS: Past, Present and Future Jyme Schafer, MD Director, Division of Medical and Surgical Services Coverage and Analysis Group INTERMACS Annual Meeting March 2012

13. Brief History of Medicare Coverage • VAD • Postcardiotomy – 1993 • Bridge to transplant – 1996 • Destination therapy with registry requirement – 2003 • * INTERMACS was written into policy in 2007 • * Joint Commission hospital certification effective 2009 • Artificial Heart • Bridge to transplant in approved studies – 2008 • Destination therapy in approved studies - 2008 INTERMACS Annual Meeting March 2012

14. Social Security Act 1862(a)(1) Notwithstanding any other provision of this title, no payment may be made under part A or part B for any expenses incurred for items or services— (A) which, except for items and services described in a succeeding subparagraph or additional preventive services (as described in section1395x(ddd)(1)of this title), are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member *** (E) in the case of research conducted pursuant to section 1142, which is not reasonable and necessary to carry out the purposes of that section INTERMACS Annual Meeting March 2012

15. What is the definition of R&N? • Congress has not defined it in statute. • For practical uses, CMS has operationalized the following definition: Adequate evidence to conclude that the item or service improves clinically meaningful health outcomes for the Medicare population INTERMACS Annual Meeting March 2012

16. Health Outcomes of Interest More Persuasive • Longer life and improved function/participation • Longer life with arrested decline • Significant symptom improvement allowing better function/participation • Reduced need for burdensome tests and treatments Less Persuasive • Longer life with declining function/participation • Improved disease-specific survival without improved overall survival • Surrogate test result better • Image looks better • Doctor feels confident Historically, Medicare has stated publicly as a matter of policy that it does not consider cost in making national coverage determinations. INTERMACS Annual Meeting March 2012

17. What is an NCD? • National Coverage Determination (NCD) • Policy for the Medicare FFS program • Continuity in coverage across the country • May include clinical indication, patient population, centers of excellence, provider qualifications, etc. • NCD Manual Section 20.9, Artificial Hearts and Related Devices http://www.cms.gov/manuals/downloads/ncd103c1_Part1.pdf INTERMACS Annual Meeting March 2012

18. Artificial Hearts and Related Devices (20.9) • Each VAD indication has different coverage criteria • Postcardiotomy(1993): limited to FDA device label • Bridge to transplant (1996): patient approved and listed for transplant, transplant center (some exceptions) • Destination therapy (last updated 2010): detailed patient selection (NYHA, OMM, LVEF, peak VO2); facility criteria (procedure volume, third party certification, INTERMACS, focus on informed consent for procedure) INTERMACS Annual Meeting March 2012

19. MEDICARE NATIONAL COVERAGE PROCESS PreliminaryDiscussions Reconsideration Benefit Category 9 months or 12 months Final Decision Memorandum and Implementation Instructions Proposed Decision Memorandum Posted National Coverage Request StaffReview Public Comment External Technology Assessment Departmental Appeals Board Staff Review INTERMACS Annual Meeting March 2012 MEDCAC

20. Medicare and INTERMACS • Past • Supported registry innovation and data collection • Present • Continuous communication with UAB • Information sharing, status updates • Monitoring of participation • NCD requires registry participation • Consider INTERMACS an example for others • Future • INTERMACS data and policy development (e.g., terminology, patient selection, facility selection) • Policy changes??? INTERMACS Annual Meeting March 2012

21. Sixth Annual Meeting, March 12, 2012 • FDA: Benchmarks for next device approval • S Patel INTERMACS Annual Meeting March 2012

22. INTERMACS and FDA:The Clinical Goal Line Sonna Patel-Raman, Ph.D. March 12, 2012 Acting Chief Circulatory Support and Prosthetics Branch Division of Cardiovascular Devices Center for Devices and Radiological Health INTERMACS Annual Meeting March 2012

23. Financial Disclosures • None INTERMACS Annual Meeting March 2012

24. Post-Market - Where Have We Been? • Post-market is not intended to demonstrate safety and effectiveness of the device • Provides sponsors opportunity to design & conduct post-approval studies (PAS) in cost efficient way to meet FDA requirements • Track real world usage of the device • Adverse events • Labeling and/or product modifications • Satisfies CMS reporting requirement for DT INTERMACS Annual Meeting March 2012

25. Pre-Market – Where Have We Been? • BTT = Performance Goal based upon published literature • DT = Randomized Controlled Trial • FDA’s thinking is evolving as the distinction becomes extinct INTERMACS Annual Meeting March 2012

26. Clinical Trial Design – Reasons to Conduct an RCT for VADs • Not enough historical data to serve as control group • Unknown risk factors due to limited experience with device • Practice of medicine has changed • Produce study groups comparable with respect to known and unknown risk factors INTERMACS Annual Meeting March 2012

27. Clinical Trial Design –Reasons Not to Conduct an RCT for VADs • Extensive historical reporting, experience and/or literature available for a given therapy/device • Limited patient enrollment • Longer trials resulting in unreasonable burden to sponsors • Increase in technology – fewer patients to study per device INTERMACS Annual Meeting March 2012

28. Post-Market - Where Are We Now? • Adverse event reporting that may lead to minor modifications to labeling, device, or other interventions when appropriate • Publications of aggregate data allowing for interpretation of certain datasets • Balancing pre-market and post-market expectations of a registry INTERMACS Annual Meeting March 2012

29. Pre-Market – Where Are We Now? • FDA has approved: DT = RCT • FDA has approved: BTT = Concurrent/Contemporaneous Control – INTERMACS • Trial design evolving • Appropriate amount of data to provide valid scientific data to support a pre-marketing application • How much data is enough data? • How much analysis is enough analysis? INTERMACS Annual Meeting March 2012

30. Where Are We Going? • Agree that distinction is changing due to practice of medicine INTERMACS Annual Meeting March 2012

31. Where Are We Going? All-comers? INTERMACS Annual Meeting March 2012

32. Where Are We Going? • Agree that BTT/DT lines are becoming obsolete • The most robust clinical trial is still an RCT • Ongoing discussions about an “all-comers” trial to understand what is the appropriate comparator • Need robust data that are appropriately audited and adjudicated • FDA believes in maximizing its role in the review and mining of registries to analyze and interpret trial data • Trial conduct and registry conduct of critical importance INTERMACS Annual Meeting March 2012

33. Emphasis on Trial Conduct • Avoid missing data! • Prospective plan to account for it • Report amount of missing data at specific intervals • FDA encourages sponsors to closely monitor patients and collect ALL appropriate data • Data integrity and collection (audit/adjudicate) • Safety and effectiveness evaluated on TOTALITY of ALL the data INTERMACS Annual Meeting March 2012

34. Conclusions • FDA evolving with the field of MCSD • RCT = gold standard for an all-comers trial • FDA willing to accept alternative designs and controls when based on sound, scientific rationale • Emphasis on trial conduct and appropriate data collection INTERMACS Annual Meeting March 2012

35. QUESTIONS? sonna.patel@fda.hhs.gov INTERMACS Annual Meeting March 2012

36. Sixth Annual Meeting, March 12, 2012 • Industry: INTERMACS – The ultimate post market study • D Naftel INTERMACS Annual Meeting March 2012

37. Device Manufacturers • What services do the device manufacturers receive for their fee? • I. Registry Data • Data contained in the Registry that relate only to MCSD’s manufactured by the Company • Information is de-identified • Dataset includes all pre-implant medical conditions, implant details, re-hospitalizations, adverse events, quality of life information, neurocognitive assessments and transplant and survival status INTERMACS Annual Meeting March 2012

38. Device Manufacturers (Continued) • What services do the device manufacturers receive for their fee? • II. Standard Reports • Provided as an aggregate basis and are de-identified • Reports include pre-implant medical conditions, implant details, re-hospitalizations, adverse events, quality of life information, neurocognitive assessments and transplant, recovery and survival status • Allows device manufacturers to benchmark its MCSDs against the national data for comparison purposes INTERMACS Annual Meeting March 2012

39. Device Manufacturers (Continued) • What services do the device manufacturers receive for their fee? • III. Company MCSD Reports • Provided as an aggregate basis and are de-identified • Report contains summaries of outcome events including actuarial depictions and competing outcome analyses and will include all pre-implant medical conditions, implant details, adverse events, re-hospitalizations, quality of life information, neurocognitive assessments, and transplant and survival status INTERMACS Annual Meeting March 2012

40. Device Manufacturers (Continued) • What services do the device manufacturers receive for their fee? • IV. Device Malfunction Notifications: Upon Occurrence • Company will be notified within 72 hours if a device malfunction occurs with respect to a MCSD manufactured by the Company • A complete report will be sent within 45 days of the event to the Company providing full details, sufficient to enable the Company to fulfill its CFR reporting requirements to the US Food and Drug Administration. INTERMACS Annual Meeting March 2012

41. Sixth Annual Meeting, March 12, 2012 • Hospitals: Utilizing the Quality Assurance Reports • D Schmuhl INTERMACS Annual Meeting March 2012

42. DARLENE SCHMUHL, RN CLEVELAND CLINIC INTERMACS Annual Meeting March 2012

43. UTILIZING THE QUALITY ASSURANCE REPORTS INTERMACS Annual Meeting March 2012

44. Sixth Annual Meeting, March 12, 2012 4:00 Final Comments and Adjournment James Young INTERMACS Annual Meeting March 2012