march 17, 2004syncardia systems, p0300110. circulatory support devices panel wednesday, march 17,...

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


FDA Review Summary

Syncardia Systems, Inc.

CardioWest Total Artificial Heart (TAH)

System

Eric Chen M.S.

FDA/CDRH/ODE/DCD


Overview of Presentation

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


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


Left VentricleRight Ventricle

Driveline Exit Sites

Drivelines


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.


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)


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


Preclinical EvaluationDetermined To Be Satisfactory

• Alarms

• Battery Performance

• Biocompatibility

• Electrical Safety and EMC

• Reliability

• Software


Preclinical EvaluationRemaining data to be examined

• Sterilization, packaging, shelf life, shipping

• Manufacturing


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.


Statistical Summary

Syncardia Systems, Inc.

CardioWest Total Artificial Heart (TAH)

System

Lilly Yue Ph.D.

FDA/CDRH/OSB/DBS


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


“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


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


• 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


• 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


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, …


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


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


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


Propensity Score Distribution

Con TAH

0.0

0.2

0.4

0.6

0.8

1.0

Pro

pe

ns

ity

Sc

ore


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%)


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


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%)


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%)


• 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


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


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


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


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


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%


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

%


LVAD Implantation with RV Failure

RV failure rate 10-30%

Medical Rx (inotropes, volume load, NO)

Short-term pumps

Long-term percutaneous pumps


CardioWest TAH

• Study approved by FDA 1993

• FDA agreed that clinical equipoise did not exist

• FDA approved the control group


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


79 75

5969 67

0

20

40

60

80

100

Core All Device OUS "Success" Perf. Goal

CardioWest TAHSurvival to Transplant


%


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


CardioWest TAH Serious Adverse Events

%

Infection = device related

0

20

40

60

80

100

Bleeding Infection TE Neuro

%


Areas for Discussion

1. Distribution of implants among study centers

2. Indications for BiVAD vs LVAD


Distribution of Implants

UMC71.6%

Loyola16.0%

LDS9.9% STL

1.2%

UPMC1.2%


0

20

40

60

80

100

UMC Other 4

%

Treatment SuccessUMC vs other 4 Institutions


69% 69.6%

CI CI


CVP>1863%

CPS/ECMO 18%RVVF<20

14%

5%

Evidence of Right Heart Failure


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?


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

march 17, 2004syncardia systems, p0300110. circulatory support devices panel wednesday, march 17,...

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