CIRCULATORY SUPPORT DEVICES PANEL Wednesday, March 17, 2004

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CIRCULATORY SUPPORTDEVICES PANELWednesday,
March 17, 2004

• Syncardia Systems, Inc.
• CardioWest Total Artificial Heart (TAH)
• System
• PMA P030011

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FDA Review Summary

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

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Overview of Presentation

• History of Clinical Study
• Pre-clinical Evaluation
• Statistical Evaluation
• Clinical Evaluation
• Panel Questions

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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

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Left Ventricle
Right Ventricle
Drivelines
Driveline Exit Sites
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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.

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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)

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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

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Preclinical EvaluationDetermined To Be
Satisfactory

• Alarms
• Battery Performance
• Biocompatibility
• Electrical Safety and EMC
• Reliability
• Software

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Preclinical EvaluationRemaining data to be
examined

• Sterilization, packaging, shelf life, shipping
• Manufacturing

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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.

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Statistical Summary

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

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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

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Implant Frequency
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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

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• 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

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

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Two Methods Adjusting for Age

• 1. Matching
• Age TAH vs. Control
  Pair
• 2. Sub-classification
• lt30 30-39 40-49
  gt50 Age
• lt30 30-39 40-49
  gt50 Age

x1
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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 patients observed baseline
  covariate values, e.g., age, gender, prior
  cardiac surgery,

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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

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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

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Two Methods Adjusting for PS

• 1. Matching
• PS TAH vs. Control
  Pair
• 2. Sub-classification
• 0 S1 S2 S3 S4
  S5 1 PS

x1
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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

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Propensity Score Distribution
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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)

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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

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Single Arm Study Results

• TAH Group (N 81)
• Outcome Rate
  95 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)

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Single Arm Study Results

• TAH Group (N 81)
• Outcome Rate
  95 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)

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• 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

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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

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Clinical ReviewCardioWest TAH

• Julie Swain M.D.
• Cardiac Surgery
• Ileana Piña M.D.
• Cardiology

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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

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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

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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

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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
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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

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LVAD Implantation with RV Failure

• RV failure rate 10-30

Medical Rx (inotropes, volume load, NO)
Short-term pumps
Long-term percutaneous pumps
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CardioWest TAH

• Study approved by FDA 1993
• FDA agreed that clinical equipoise did not exist
• FDA approved the control group

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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

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CardioWest TAHSurvival to Transplant

Success survival 30 days post Tx, NYHA Class I
or II, ambulatory, not vent, not dialysis
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Adverse Events

• Difficult to develop a performance goal for AEs
• 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

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CardioWest TAH Serious Adverse Events


Infection device related
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Areas for Discussion

• Distribution of implants among study centers
• Indications for BiVAD vs LVAD

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Distribution of Implants
UPMC 1.2
LDS 9.9
STL 1.2
Loyola 16.0
UMC 71.6
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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
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Evidence of Right Heart Failure
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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?

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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