March 17, 2004 Syncardia Systems, P030011 1
CIRCULATORY SUPPORTDEVICES PANEL
Wednesday, 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 VentricleRight Ventricle
Driveline Exit Sites
Drivelines
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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” FrequencySyncardia Enrolled Patients (1991-2002)
0
2
4
6
8
10
12
14
16
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Year
Nu
mb
er
of
Pa
tie
nts
Control Core TAH
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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% TAHMyocardial Infraction 71.4% 30.9% TAHPrior Cardiac Surgery 60.0% 38.3% TAHIABP 68.6% 35.8% TAHCPB 0.0% 18.5% controlCardiac Arrest 25.7% 37.0% controlVentilated 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
1. Matching
Age TAH vs. Control Pair
2. Sub-classification
<30 30-39 40-49 >50 Age
<30 30-39 40-49 >50 Age
Two Methods Adjusting for 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 patient’s 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
1. Matching
PS TAH vs. Control Pair
2. Sub-classification
0 S1 S2 S3 S4 S5 1 PS
Two Methods Adjusting for 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
Con TAH
0.0
0.2
0.4
0.6
0.8
1.0
Pro
pe
ns
ity
Sc
ore
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Distribution of Patients in Propensity Score Quintiles
Propensity Score Quintile
1 2 3 4 5Control 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 ResultsTAH 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 to30-days Post Transplant 58/81 71.6% (60.5%, 81.1%)
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Single Arm Study ResultsTAH Group (N = 81)
Outcome Rate 95% C.I.
6-m survivalfrom 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 fromTransplant 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
Clinical ReviewClinical ReviewCardioWest TAHCardioWest 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
65-70%
%
74%
HFSA 2002 WaiShun Wong, Mohamad El-Zaru, Joseph Lau, Douglas Gregory, Marvin A. Konstam, David DeNofrioTufts - New England Medical Center, Boston, MA
0
20
40
60
80
100
Performance Goal
Wong Metaanalysis
%
65-70%74%
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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
6759
43
7158
7969
0
20
40
60
80
100
LVADgoal
Magliato McBride El-Bana Farrar CWTAH
CW TAHsuccess
%
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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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79 75
5969 67
0
20
40
60
80
100
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
%
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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
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CardioWest TAH Serious Adverse Events
%
Infection = device related
0
20
40
60
80
100
Bleeding Infection TE Neuro
%
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Areas for Discussion
1. Distribution of implants among study centers
2. Indications for BiVAD vs LVAD
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Distribution of Implants
UMC71.6%
Loyola16.0%
LDS9.9% STL
1.2%
UPMC1.2%
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0
20
40
60
80
100
UMC Other 4
%
Treatment SuccessUMC vs other 4 Institutions
Success = survival 30 days post Tx, NYHA Class I or II, ambulatory, not vent, not dialysis
69% 69.6%
CI CI
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CVP>1863%
CPS/ECMO 18%RVVF<20
14%
5%
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