March 17, 2004Syncardia Systems, P

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

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

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

March 17, 2004Syncardia Systems, P 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

March 17, 2004Syncardia Systems, P

March 17, 2004Syncardia Systems, P Left VentricleRight Ventricle Driveline Exit Sites Drivelines

March 17, 2004Syncardia Systems, P 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.

March 17, 2004Syncardia Systems, P U.S. Clinical Study IDE G –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)

March 17, 2004Syncardia Systems, P 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

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

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

March 17, 2004Syncardia Systems, P 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.

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

March 17, 2004Syncardia Systems, P 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

March 17, 2004Syncardia Systems, P “Implant” Frequency

March 17, 2004Syncardia Systems, P 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

March 17, 2004Syncardia Systems, P 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

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

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

March 17, 2004Syncardia Systems, P 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, …

March 17, 2004Syncardia Systems, P 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

March 17, 2004Syncardia Systems, P 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

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

March 17, 2004Syncardia Systems, P 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

March 17, 2004Syncardia Systems, P Propensity Score Distribution

March 17, 2004Syncardia Systems, P Distribution of Patients in Propensity Score Quintiles Propensity Score Quintile Control (66%) (31%) (3%) (0%) (0%) TAH (0%) (15%) (28%) (28%) (28%)

March 17, 2004Syncardia Systems, P 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

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

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

March 17, 2004Syncardia Systems, P 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

March 17, 2004Syncardia Systems, P 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

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

March 17, 2004Syncardia Systems, P 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

March 17, 2004Syncardia Systems, P 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 ] 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

March 17, 2004Syncardia Systems, P 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

March 17, 2004Syncardia Systems, P 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 Performance Goal Wong Meta analysis % 65-70% 74%

March 17, 2004Syncardia Systems, P BiVAD Survival to Transplant 1.Magliato ASAIO McBride ATS El-Banayosy TCVS Farrar JTCVS 1997 Success = survival 30 days post Tx, NYHA Class I or II, ambulatory, not vent, not dialysis LVAD goal MagliatoMcBrideEl-BanaFarrarCW TAH CW TAH success %

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

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

March 17, 2004Syncardia Systems, P 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

March 17, 2004Syncardia Systems, P 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 %

March 17, 2004Syncardia Systems, P 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

March 17, 2004Syncardia Systems, P CardioWest TAH Serious Adverse Events % Infection = device related BleedingInfectionTENeuro %

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

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

March 17, 2004Syncardia Systems, P 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

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

March 17, 2004Syncardia Systems, P 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?

March 17, 2004Syncardia Systems, P 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