1. March 17, 2004Syncardia Systems, P0300110

2. CIRCULATORY SUPPORT DEVICES PANEL Wednesday, March 17, 2004 Syncardia Systems, Inc. CardioWest Total Artificial Heart (TAH) System PMA P030011

3. March 17, 2004Syncardia Systems, P0300112 FDA Review Summary Syncardia Systems, Inc. CardioWest Total Artificial Heart (TAH) System Eric Chen M.S. FDA/CDRH/ODE/DCD

4. March 17, 2004Syncardia Systems, P0300113 Overview of Presentation History of Clinical Study Pre-clinical Evaluation Statistical Evaluation Clinical Evaluation Panel Questions

5. March 17, 2004Syncardia Systems, P0300114 FDA Review Team M. Berman E. Chen V. Covington D. Fleischer D. Gantt M. Hazes D. Kezer I. Piña J. Rinaldi W. Scott J. Swain S. Turtil L. Yue

6. March 17, 2004Syncardia Systems, P0300115

7. March 17, 2004Syncardia Systems, P0300116 Left VentricleRight Ventricle Driveline Exit Sites Drivelines

8. March 17, 2004Syncardia Systems, P0300117 Proposed Indication for Use The CardioWest TAH is intended for use as a bridge to transplantation in cardiac transplant- eligible candidates at risk of imminent death from non-reversible biventricular failure. The CardioWest TAH is intended for use inside the hospital.

9. March 17, 2004Syncardia Systems, P0300118 U.S. Clinical Study IDE G920101 –Two-arm prospective and retrospective, non- randomized, multi-center clinical trial –Initial sample size of 64 patients – 32 TAH / 32 control Based on 90% power to detect a difference in clinical outcome between patients surviving to 30 days post-transplant –Control arm Historical - 22 (gathered from centers before trial initiated) Retrospective - 10 (gathered from centers after trial completed) Concurrent - 3 (eligible but declined the device)

10. March 17, 2004Syncardia Systems, P0300119 Class III Device Provide reasonable assurance of safety and effectiveness (Federal Food, Drug, Cosmetic Act, §513(a)(1)(C)) Relevant factors (21 CFR 860.7(b)) –Patient population –Conditions of use –Probable benefit vs. probable injury –Reliability of the device

11. March 17, 2004Syncardia Systems, P03001110 Preclinical Evaluation Determined To Be Satisfactory Alarms Battery Performance Biocompatibility Electrical Safety and EMC Reliability Software

12. March 17, 2004Syncardia Systems, P03001111 Preclinical Evaluation Remaining data to be examined Sterilization, packaging, shelf life, shipping Manufacturing

13. March 17, 2004Syncardia Systems, P03001112 Engineering Conclusion Results of the pre-clinical testing in conjunction with the outcome of the reliability results from the clinical trial demonstrate reasonable assurance of device safety.

14. March 17, 2004Syncardia Systems, P03001113 Statistical Summary Syncardia Systems, Inc. CardioWest Total Artificial Heart (TAH) System Lilly Yue Ph.D. FDA/CDRH/OSB/DBS

15. March 17, 2004Syncardia Systems, P03001114 Study Design Two-arm, non-randomized, multi-center (5) 35 control patients: 32 retrospective 3 prospective 81 TAH patients for effectiveness assessment Primary effectiveness endpoint: Treatment success at 30-days post-transplant Secondary effectiveness endpoints include: Survival to transplant Survival to 30-days post transplant Safety: adverse events

16. March 17, 2004Syncardia Systems, P03001115 “Implant” Frequency

17. March 17, 2004Syncardia Systems, P03001116 Non-comparable Baseline Covariates in Control vs. TAH Factor Control TAH Favored Ischemic 74.3% 53.1% TAH Smoking History 82.9% 54.3% TAH Anticoagulated 74.3% 46.9% TAH Myocardial Infraction 71.4% 30.9% TAH Prior Cardiac Surgery 60.0% 38.3% TAH IABP 68.6% 35.8% TAH CPB 0.0% 18.5% control Cardiac Arrest 25.7% 37.0% control Ventilated 34.3% 42.0% control

18. March 17, 2004Syncardia Systems, P03001117 Two treatment groups are not comparable –Imbalance of the year of implant –Imbalance in multiple baseline covariates Any direct treatment comparisons on effectiveness endpoints are inappropriate So, all p-values from direct treatment comparisons are uninterpretable

19. March 17, 2004Syncardia Systems, P03001118 What about treatment comparisons adjusting for imbalanced covariates? –Traditional covariate analysis –Propensity score analysis Example of adjustment for one covariate, e.g., age

20. 1. Matching Age TAH vs. Control Pair 2. Sub-classification 50 Age Two Methods Adjusting for Age x1x1

21. March 17, 2004Syncardia Systems, P03001120 Adjusting for Multiple Covariates Usually there are many covariates that should be adjusted simultaneously Replace the collection of covariates with one single number: the propensity score (PS) Age, Gender, Propensity Prior cardiac surgery, … Score (PS) PS: The conditional probability of receiving the TAH, given a patient’s observed baseline covariate values, e.g., age, gender, prior cardiac surgery, …

22. March 17, 2004Syncardia Systems, P03001121 Propensity Score Analysis Propensity score methods can only adjust for observed covariates and not for unobserved ones Propensity score is seriously degraded when important variables influencing treatment selection have not been collected

23. March 17, 2004Syncardia Systems, P03001122 Propensity Score Analysis When the propensity scores are balanced across the treatment and control groups, the distribution of all the covariates are balanced in expectation across the two groups We can use the propensity scores as a diagnostic tool to measure treatment group comparability If the two treatment groups overlap well enough in terms of the propensity scores, we compare the two treatment groups adjusting for the PS

24. 1. Matching PS TAH vs. Control Pair 2. Sub-classification 0 S1 S2 S3 S4 S5 1 PS Two Methods Adjusting for PS x1x1

25. March 17, 2004Syncardia Systems, P03001124 Propensity Score Analysis Performed multiple imputations for 19% patients with missing baseline covariate values Adjusted for all imbalanced and/or clinically important baseline covariates as well as the year of “implant” The propensity score model accurately predicted the treatment group membership However, the two treatment groups did not overlap enough to allow a sensible treatment comparison

26. March 17, 2004Syncardia Systems, P03001125 Propensity Score Distribution

27. March 17, 2004Syncardia Systems, P03001126 Distribution of Patients in Propensity Score Quintiles Propensity Score Quintile 1 2 3 4 5 Control 23 11 1 0 0 (66%) (31%) (3%) (0%) (0%) TAH 0 12 23 23 23 (0%) (15%) (28%) (28%) (28%)

28. March 17, 2004Syncardia Systems, P03001127 How to Proceed? So, any treatment comparisons adjusting for imbalanced covariates are problematic How to proceed? Since the two treatment groups are not comparable, any judgment of the performance of TAH has to be based on the results from the TAH group alone

29. March 17, 2004Syncardia Systems, P03001128 S ingle Arm Study Results TAH Group (N = 81) Outcome Rate 95% C.I. Treatment Success56/81 69.1% (57.9%, 78.9%) Survival to Transplant64/81 79% (68.5%, 87.3%) Survival to 30-days Post Transplant 58/81 71.6% (60.5%, 81.1%)

30. March 17, 2004Syncardia Systems, P03001129 Single Arm Study Results TAH Group (N = 81) Outcome Rate 95% C.I. 6-m survival from implant61/81 75.3% (64.5%, 84.2%) 1-y survival from implant57/81 70.4% (59.2%, 80%) 1-y Conditional Survival from Transplant 55/64 85.9% (75%, 93.4%)

31. March 17, 2004Syncardia Systems, P03001130 Time to transplant or death before transplant: Mean: 79 days Median: 47 days Kaplan-Meier estimate of survival probability prior to transplant Event: Death; Censoring: Transplant Assumption underlying K-M: Independence of censoring and event Concern: Sicker patients received transplants sooner? Potential Problem: the K-M survival probability estimates are biased

32. March 17, 2004Syncardia Systems, P03001131 Statistical Summary Without appropriate control, it is difficult to perform statistical evaluation of the effectiveness of the device For survival prior to transplant, K-M survival estimates are potentially seriously biased

33. Clinical Review CardioWest TAH Julie Swain M.D. Cardiac Surgery Ileana Piña M.D. Cardiology

34. March 17, 2004Syncardia Systems, P03001133 FDA-APPROVED BTT LVADs No randomized, controlled studies for BTT devices No comparable control groups in previous BTT studies In general, slow enrollment, multi-year studies

35. March 17, 2004Syncardia Systems, P03001134 LVAD BTT Performance Goals (Literature Search) Criteria for Inclusion: Bridge to transplant indication, LVAD One of the 4 approved devices was used Published in 1997 or after [thus representing patients mostly studied after 1993-5] Series must have at least 20 patients, adults only Peer reviewed journals, no abstracts, must have original data English, Includes OUS data, wide geographic distribution Detailed enough data to determine results in adult patients with LVAD

36. March 17, 2004Syncardia Systems, P03001135 LVAD BTT Performance Goals Criteria for Exclusion: Duplicate papers reporting same population Registries, meta-analyses, and reviews RV support at initial implant Primarily cardiogenic shock patients

37. March 17, 2004Syncardia Systems, P03001136 LVAD BTT Performance Goal Survival to Transplant 65-70% % 74% HFSA 2002 WaiShun Wong, Mohamad El-Zaru, Joseph Lau, Douglas Gregory, Marvin A. Konstam, David DeNofrio Tufts - New England Medical Center, Boston, MA 0 20 40 60 80 100 Performance Goal Wong Meta analysis % 65-70% 74%

38. March 17, 2004Syncardia Systems, P03001137 BiVAD Survival to Transplant 1.Magliato ASAIO 2003 2. McBride ATS 1999 3. El-Banayosy TCVS 1999 4. Farrar JTCVS 1997 Success = survival 30 days post Tx, NYHA Class I or II, ambulatory, not vent, not dialysis 67 59 43 71 58 79 69 0 20 40 60 80 100 LVAD goal MagliatoMcBrideEl-BanaFarrarCW TAH CW TAH success %

39. March 17, 2004Syncardia Systems, P03001138 LVAD Implantation with RV Failure RV failure rate 10-30% Medical Rx (inotropes, volume load, NO) Short-term pumps Long-term percutaneous pumps

40. March 17, 2004Syncardia Systems, P03001139 CardioWest TAH Study approved by FDA 1993 FDA agreed that clinical equipoise did not exist FDA approved the control group

41. March 17, 2004Syncardia Systems, P03001140 U.S. Clinical Study 5 U.S. centers 10 Year clinical study 95 TAH patients –81 patients met all inclusion/exclusion criteria (Core group) –14 patients treated as “compassionate” use “off label” –Efficacy judged on 81 “core” patients, safety on all 95 patients 35 Control patients –32 historical data –3 prospective patients who refused the TAH

42. March 17, 2004Syncardia Systems, P03001141 79 75 59 69 67 0 20 40 60 80 100 CoreAll DeviceOUS"Success"Perf. Goal CardioWest TAH Survival to Transplant Success = survival 30 days post Tx, NYHA Class I or II, ambulatory, not vent, not dialysis %

43. March 17, 2004Syncardia Systems, P03001142 Adverse Events Difficult to develop a performance goal for AE’s –No definitions listed in some studies –Different definitions in other studies –Rates differ among approved devices –Rates for same device change over time Clinical judgement is required

44. March 17, 2004Syncardia Systems, P03001143 CardioWest TAH Serious Adverse Events % Infection = device related 0 20 40 60 80 100 BleedingInfectionTENeuro %

45. March 17, 2004Syncardia Systems, P03001144 Areas for Discussion 1.Distribution of implants among study centers 2.Indications for BiVAD vs LVAD

46. March 17, 2004Syncardia Systems, P03001145 Distribution of Implants UMC 71.6% Loyola 16.0% LDS 9.9% STL 1.2% UPMC 1.2%

47. March 17, 2004Syncardia Systems, P03001146 0 20 40 60 80 100 UMCOther 4 % Treatment Success UMC vs other 4 Institutions Success = survival 30 days post Tx, NYHA Class I or II, ambulatory, not vent, not dialysis 69% 69.6% CI

48. March 17, 2004Syncardia Systems, P03001147 CVP>18 63% CPS/ECMO 18%RVVF<20 14% 5% Evidence of Right Heart Failure

49. March 17, 2004Syncardia Systems, P03001148 Indications for BiVAD vs LVAD Irreversibility of procedure (no bridge-to- recovery) –our ability to predict recovery is poor RV failure may only become evident after LVAD implantation –When should this device be used? –Should this be addressed in the post-market period? –How can the label reflect this problem?

50. March 17, 2004Syncardia Systems, P03001149 Clinical Conclusions Efficacy: Survival to transplant similar to other devices reported in the literature Safety: Adverse event profile trends seem similar to other devices, but a direct comparison cannot be made due to differences in definitions