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CIRCULATORY SUPPORT DEVICES PANEL Wednesday, March 17, 2004

CIRCULATORY SUPPORT DEVICES PANEL Wednesday, March 17, 2004. Syncardia Systems, Inc. CardioWest Total Artificial Heart (TAH) System PMA P030011. FDA Review Summary. Syncardia Systems, Inc. CardioWest Total Artificial Heart (TAH) System Eric Chen M.S. FDA/CDRH/ODE/DCD.

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CIRCULATORY SUPPORT DEVICES PANEL Wednesday, March 17, 2004

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  1. Syncardia Systems, P030011

  2. CIRCULATORY SUPPORTDEVICES PANELWednesday, March 17, 2004 Syncardia Systems, Inc. CardioWest Total Artificial Heart (TAH) System PMA P030011

  3. FDA Review Summary Syncardia Systems, Inc. CardioWest Total Artificial Heart (TAH) System Eric Chen M.S. FDA/CDRH/ODE/DCD Syncardia Systems, P030011

  4. Overview of Presentation • History of Clinical Study • Pre-clinical Evaluation • Statistical Evaluation • Clinical Evaluation • Panel Questions Syncardia Systems, P030011

  5. 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 FDA Review Team Syncardia Systems, P030011

  6. Syncardia Systems, P030011

  7. Right Ventricle Left Ventricle Drivelines Driveline Exit Sites Syncardia Systems, P030011

  8. 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. Syncardia Systems, P030011

  9. 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) Syncardia Systems, P030011

  10. 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 Syncardia Systems, P030011

  11. Preclinical EvaluationDetermined To Be Satisfactory • Alarms • Battery Performance • Biocompatibility • Electrical Safety and EMC • Reliability • Software Syncardia Systems, P030011

  12. Preclinical EvaluationRemaining data to be examined • Sterilization, packaging, shelf life, shipping • Manufacturing Syncardia Systems, P030011

  13. 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. Syncardia Systems, P030011

  14. Statistical Summary Syncardia Systems, Inc. CardioWest Total Artificial Heart (TAH) System Lilly Yue Ph.D. FDA/CDRH/OSB/DBS Syncardia Systems, P030011

  15. 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 Syncardia Systems, P030011

  16. “Implant” Frequency Syncardia Systems, P030011

  17. 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 Syncardia Systems, P030011

  18. 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 Syncardia Systems, P030011

  19. What about treatment comparisons adjusting for imbalanced covariates? • Traditional covariate analysis • Propensity score analysis • Example of adjustment for one covariate, e.g., age Syncardia Systems, P030011

  20. Two Methods Adjusting for Age x1 1. Matching AgeTAH vs. Control Pair 2. Sub-classification <30 30-39 40-49 >50 Age <30 30-39 40-49 >50 Age

  21. Adjusting for Multiple Covariates • Usually there are many covariates that should be adjusted simultaneously • Replace the collectionof 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, … Syncardia Systems, P030011

  22. 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 Syncardia Systems, P030011

  23. 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 Syncardia Systems, P030011

  24. Two Methods Adjusting for PS x1 1. Matching PSTAH vs. Control Pair 2. Sub-classification 0 S1 S2 S3 S4 S5 1 PS

  25. 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 Syncardia Systems, P030011

  26. Propensity Score Distribution Syncardia Systems, P030011

  27. Distribution of Patients in Propensity Score Quintiles Propensity Score Quintile 1 2 3 4 5 Control 23 11 1 00 (66%) (31%) (3%) (0%) (0%) TAH 0 12 23 2323 (0%) (15%) (28%) (28%) (28%) Syncardia Systems, P030011

  28. 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 Syncardia Systems, P030011

  29. Single Arm Study Results TAH Group (N = 81) Outcome Rate95% C.I. Treatment Success 56/81 69.1% (57.9%, 78.9%) Survival to Transplant 64/81 79% (68.5%, 87.3%) Survival to 30-days Post Transplant 58/81 71.6% (60.5%, 81.1%) Syncardia Systems, P030011

  30. Single Arm Study Results TAH Group (N = 81) Outcome Rate95% C.I. 6-m survival from implant 61/81 75.3% (64.5%, 84.2%) 1-y survival from implant 57/81 70.4% (59.2%, 80%) 1-y Conditional Survival from Transplant 55/64 85.9% (75%, 93.4%) Syncardia Systems, P030011

  31. 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 Syncardia Systems, P030011

  32. 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 Syncardia Systems, P030011

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

  34. 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 Syncardia Systems, P030011

  35. 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 Syncardia Systems, P030011

  36. 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 Syncardia Systems, P030011

  37. 100 80 60 40 20 0 Performance Goal Wong Meta analysis LVAD BTT Performance Goal Survival to Transplant 74% 74% 65-70% 65-70% % % HFSA 2002 WaiShun Wong, Mohamad El-Zaru, Joseph Lau, Douglas Gregory, Marvin A. Konstam, David DeNofrio Tufts - New England Medical Center, Boston, MA Syncardia Systems, P030011

  38. 100 79 80 71 69 67 59 58 60 43 40 20 0 LVAD Magliato McBride El-Bana Farrar CW TAH CW TAH success goal BiVAD Survival to Transplant % • 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 Syncardia Systems, P030011

  39. LVAD Implantation with RV Failure RV failure rate 10-30% Medical Rx (inotropes, volume load, NO) Short-term pumps Long-term percutaneous pumps Syncardia Systems, P030011

  40. CardioWest TAH • Study approved by FDA 1993 • FDA agreed that clinical equipoise did not exist • FDA approved the control group Syncardia Systems, P030011

  41. 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 Syncardia Systems, P030011

  42. 100 79 75 80 69 67 59 60 40 20 0 Core All Device OUS "Success" Perf. Goal CardioWest TAHSurvival to Transplant % Success = survival 30 days post Tx, NYHA Class I or II, ambulatory, not vent, not dialysis Syncardia Systems, P030011

  43. 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 Syncardia Systems, P030011

  44. 100 80 60 40 20 0 Bleeding Infection TE Neuro CardioWest TAH Serious Adverse Events % % Infection = device related Syncardia Systems, P030011

  45. Areas for Discussion • Distribution of implants among study centers • Indications for BiVAD vs LVAD Syncardia Systems, P030011

  46. Distribution of Implants UPMC 1.2% LDS 9.9% STL 1.2% Loyola 16.0% UMC 71.6% Syncardia Systems, P030011

  47. 100 80 60 % 40 20 0 UMC Other 4 Treatment SuccessUMC vs other 4 Institutions 69.6% 69% CI CI Success = survival 30 days post Tx, NYHA Class I or II, ambulatory, not vent, not dialysis Syncardia Systems, P030011

  48. 5% CPS/ECMO RVVF<20 18% 14% CVP>18 63% Evidence of Right Heart Failure Syncardia Systems, P030011

  49. 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? Syncardia Systems, P030011

  50. 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 Syncardia Systems, P030011

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