# Presentation: 659129

## Slide 1

- Syncardia Systems, P030011

- 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

- Syncardia Systems, P030011

- March 17, 2004

## Overview of Presentation

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

- Syncardia Systems, P030011

- March 17, 2004

## 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

- Syncardia Systems, P030011

- March 17, 2004

## Slide 6

- Syncardia Systems, P030011

- March 17, 2004

## Left Ventricle

- Right Ventricle

- Driveline Exit Sites

- Drivelines

- Syncardia Systems, P030011

- March 17, 2004

## 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

- March 17, 2004

## 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

- March 17, 2004

**Notes:**
The calculations assumed a 30 day survival of 20% in the control group and 60% in the device group, with a type I error of 0.05 (two-sided)

## 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

- March 17, 2004

## Preclinical EvaluationDetermined To Be Satisfactory

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

- Syncardia Systems, P030011

- March 17, 2004

## Preclinical EvaluationRemaining data to be examined

- Sterilization, packaging, shelf life, shipping
- Manufacturing

- Syncardia Systems, P030011

- March 17, 2004

## 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

- March 17, 2004

## Statistical Summary

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

- Syncardia Systems, P030011

- March 17, 2004

## 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

- March 17, 2004

## “Implant” Frequency

- Syncardia Systems, P030011

- March 17, 2004

## 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

- March 17, 2004

## 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

**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

- March 17, 2004

## 
What about treatment comparisons adjusting for imbalanced covariates?

Traditional covariate analysis 
Propensity score analysis

Example of adjustment for one covariate, e.g., age 

- 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

- March 17, 2004

## 1. Matching
   Age            TAH      vs.     Control         Pair

2. Sub-classification

              <30      30-39      40-49         >50             Age

               <30     30-39      40-49         >50            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

***x*****1**

## 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, ...

- Syncardia Systems, P030011

- March 17, 2004

## 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

- March 17, 2004

## 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

- March 17, 2004

## 1. Matching
   PS            TAH      vs.     Control            Pair

2. Sub-classification

      0      S1          S2         S3        S4        S5       1     PS

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

- Two Methods Adjusting for PS

***x*****1**

## 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

- March 17, 2004

## Propensity Score Distribution

- Syncardia Systems, P030011

- March 17, 2004

## 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%****)**

- Syncardia Systems, P030011

- March 17, 2004

## 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

- March 17, 2004

## 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%)**_

- Syncardia Systems, P030011

- March 17, 2004

## 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%)**_

- Syncardia Systems, P030011

- March 17, 2004

## 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 

- 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

- March 17, 2004

## 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

- March 17, 2004

## Clinical ReviewCardioWest 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

- Syncardia Systems, P030011

- March 17, 2004

## 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

- March 17, 2004

**Notes:**
Agency developed with inside and outside consultants
In 2002-3, before this device submitted
It would not be correct to assume that the Agency will routinely approve single-arm BTT studies,  and certainly not destination or recovery studies

## 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

- March 17, 2004

## 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

**%**

**65-70%**

**74%**

- Syncardia Systems, P030011

- March 17, 2004

**Notes:**
Wong, Konstam 2002 HFSA abstract  74% survival 30 days p transplant

## 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

- March 17, 2004

**Notes:**
Clinical assumption BiVAD pts sicker
All studies where one could compare LVAD vs BiVAD, BiVAD did worse
LVAD surrogate for BiVAD

## 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

- March 17, 2004

**Notes:**
Konstam 24%

## CardioWest TAH

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

- Syncardia Systems, P030011

- March 17, 2004

**Notes:**
Should this be taken out since I talk about it already...does the FDA clinical equipoise put us in a bad position.

## 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

- March 17, 2004

## CardioWest TAHSurvival to Transplant

- CardioWest TAHSurvival to Transplant

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

**%**

- Syncardia Systems, P030011

- March 17, 2004

## 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

- March 17, 2004

## CardioWest TAH Serious Adverse Events

- %

**Infection = device related**

**%**

- Syncardia Systems, P030011

- March 17, 2004

**Notes:**
Konstam metaanalysis   bleeding 28%, Infection 22%, TE 8%

## Areas for Discussion

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

- Syncardia Systems, P030011

- March 17, 2004

## Distribution of Implants

**UMC**
**71.6%**

**Loyola**
**16.0%**

**LDS**
**9.9%**

**STL**
**1.2%**

**UPMC**
**1.2%**

- Syncardia Systems, P030011

- March 17, 2004

## Treatment SuccessUMC vs other 4 Institutions

- 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**

- Syncardia Systems, P030011

- March 17, 2004

## Evidence of Right Heart Failure

- Syncardia Systems, P030011

- March 17, 2004

**Notes:**
4 “other” patients:  all on IABP, max inotropes, 2 had VT, one prosthetic valve
How many LVAD pts have CVP>18

## 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

- March 17, 2004

## 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

- March 17, 2004