ppt

CIRCULATORY SUPPORT DEVICES PANEL

Monday, March 4, 2002

Thoratec HeartMate VE LVAS

P920014/S016

FDA REVIEW TEAM

• M. Berman

• V. Covington

• L. Ewing

• B. Gallauresi

• G. Gray

• W. Midgette

• W. Sapirstein

• C. Sawyer

• R. Solomon

• J. Swain

PROPOSED EXPANDED INDICATION FOR USE

The HeartMate VE LVAS is indicated for use as a bridge to transplantation in cardiac transplant candidates at risk of imminent death from nonreversible left ventricular failure. The HeartMate VE LVAS is also indicated for use in patients with end-stage left ventricular failure who are ineligible for cardiac transplantation. The HeartMate VE LVAS is intended for use both inside and outside the hospital. (Tab 3.1, page 2)

FDA MUST DETERMINE

• Reasonable assurance of safety and effectiveness (Act, §513(a)(1)(C)).

• Factors considered (21 CFR 860.7(b))– Patient population– Conditions of use– Probable benefit vs. probable injury– Reliability of the device

DEVICE DESCRIPTION

• Implanted components– Blood pump– Valved conduits– P/O perc tube

• External components– Controller– Battery packs– Accessories

PRECLINICAL EVALUATIONDetermined To Be Satisfactory

• Manufacturing• Sterilization, packaging, shelf life, shipping• Biocompatibility• Software• Electrical safety and EMC• Hydrodynamic characterization of pump• Battery performance• Alarms

PRECLINICAL EVALUATIONRemaining Concerns

• Reliability– Internal components

• Motor• Valved conduits• Percutaneous tube

• Device End of Life Indicator

RELIABILITY PROTOCOLBench Testing

• 15 units on test– All VE LVAS, none VE SNAP

• Mock circulatory loop– Implanted components in water at 37º C– External components in air @ room temp– Worst, average, and minimum operating

conditions; cycled each week• Beat rate, outlet pressure, flow

RELIABILITY RESULTSBench Testing

• 10 pumps failed– 8 main bearing– 1 diaphragm– 1 commutator

• 5 remain on test– as of 8/3/01

RELIABILITY RESULTSBench Testing

• Main bearing failures (N = 8)– Mean = 136 x 106 cycles ( 3.4 years)– STDEVP = 24 x 106 cycles ( 0.6 years)– Min = 90.3 x 106 cycles ( 2.25 years)– Max = 158.2 x 106 cycles ( 3.9 years)– Median = 142.6 x 106 cycles ( 3.6 years)

• Corrective action– CAPA #0174; open, not resolved

PREDICTED RELIABILITYBench Testing

• 86% reliability at 2 years– 60% confidence

• 76% reliability at 2 years– 90% confidence

• Mean Time To Failure, pump– 4 years @ 60% confidence– 3 years @ 90% confidence

OBSERVED END OF PUMP LIFE

Clinical TrialDays Cycles Comment

460 50 (67) Dust; bearingfailure

504 54 (72) Dust, wornbearings

651 70 (93) Pump wear

779 84 (106) Pump wear

OBSERVED DEVICE MALFUNCTIONS

Clinical Trial

• Confirmed inflow valve incompetence– 11 patients, 12 events

• 6 VE, 5 VE SNAP– Effectiveness of 90 elbow in outflow tract?

– Related to pump end of life?• Higher pump rate bearing wear

– Clinical consequences?• Surgery for replacement of inflow conduit

ENGINEERING SUMMARY

• Bench testing did not account for all observed clinical conditions– Elevated pump chamber pressure– High beat rate (inflow valve incompetence)

• Observed pump end of life events were at low end of reliability prediction

• No objective device end of life indicator– Replacement requires major surgery

Clinical SummaryClinical Summary

Thoratec HeartMate VE LVADLeft Ventricular Assist Device

Julie Swain M.D.FDA/CDRH/ODE/DCRD

Clinical Reviewers

Lesley Ewing M.D.(cardiology)

Wolf Sapirstein M.D.

Julie Swain M.D.(cardiac surgery)

Expanded Indication for Use

For use in patients with

end-stage left ventricular failure

who are ineligible for cardiac transplantation

Primary Effectiveness Endpoint

 Survival Benefit

Study Design Assumptions

Estimate

Power 92%

WorstCasePower 80%

Obs.KM

OMM 75% 60% 91%

LVAS 50% 40% 76%

Mortality at 2 years

Power calculated for 92 study deaths, 128 patients enrolled

Feb ‘02 data

Inclusion CriteriaOriginal Criteria (124/129 pts)

• Ineligible for cardiac transplantation• NYHA Class IV > 90 days (70% on

inotropes)• Intensive medical therapy• LVEF < 25%• VO2max <12 ml/kg/min

Inclusion Criteria**Later Criteria (5/129 pts)**

• Ineligible for cardiac transplantation• NYHA Class IV > 60 days • NYHA Class III or IV > 28 days and IAPB

or inotropes• Intensive medical therapy• LVEF < 25%• VO2max <14 ml/kg/min

Exclusion Criteria

Correctable cause of heart failure BSA <1.5 m2

Pulmonary hypertension Creatinine >3.5 mg/dl Active infection History of stroke <90 days, carotid

stenosis, impaired cognitive function

Baseline Characteristics (p >.05)

Age 67 (34-84) 70 (40-80)BSA (m2) 1.91 (1.53-2.4) 1.9 (1.55-2.36)

Male: female 52:15 50:11# Caucasian 63 52Able to do 6minute walk 27 22

6 minute walkdistance (m) 203 (5-421) 175 (31-355)

NYHA IV 65 60NYHA III 2 1

Table 1

LVASn = 68

OMMn = 61

Study Design

Patients Screened = 968

Patients Enrolled = 129

LVAS = 68 OMM = 61

Feb ‘02 data

716

45

0

10

20

30

40

50

60

Alive @ 2yr Alive<2yr Dead<2yr

3 5

53

0

10

20

30

40

50

60

Alive @ 2yr Alive<2yr Dead<2yr

#pts

#pts

Ratio 7.50

Survival

0

20

40

60

80

100

1 year KM 2 year KM

OMMLVAS

%Survival

Feb ‘02 data

n =16

n =33

At 27 months4/7 LVAS died3/3 OMM died

N = 3

N = 7

Serious Adverse Events

0

25

50

75

100

LVAS OMM

% pts

64/68

38/61

P <0.001

June ‘01 data

Comparison of Destination and Bridge Therapy SAE’s

• Different patient populations

• Different definition for many SAE’s

• Different time period

• Different patient care team

Serious Adverse EventsNeurological Dysfunction

27

7

0

25

50

75

100

LVAS OMM

%pts

0.12

0.03

0

0.05

0.1

0.15

0.2

LVAS OMM

Per100days

P = 0.002

P = 0.0145

June ‘01 data

Serious Adverse EventsLocal Infections

19 8

0

25

50

75

100

LVAS OMM

%pts

0.12

0.07

0

0.05

0.1

0.15

0.2

LVAS OMM

Per100days

P = 0.079

P < 0.1

Jun ‘01 data

Serious Adverse EventsSepsis

31

13

0

25

50

75

100

LVAS OMM

0.14

0.08

0

0.05

0.1

0.15

0.2

LVAS OMM

%pts

Per100days

P = 0.019

P < 0.2

Jun ‘01 data

Serious Adverse EventsPercutaneous/Pocket Infections

24

0

25

50

75

100

LVAS

%pts

0.11

0

0.05

0.1

0.15

0.2

LVAS

Per100days

Jun ‘01 data

Serious Adverse Events Pump Housing, Inflow, Outflow Infections

13

0

25

50

75

100

LVAS0.06

0

0.05

0.1

0.15

0.2

LVAS

%pts

Per100days

Jun ‘01 data

Serious Adverse EventsBleeding

25

3

0

25

50

75

100

LVAS OMM

%pts

0.16

0.02

0

0.05

0.1

0.15

0.2

LVAS OMM

Per100days

P = 0.0004

P < 0.0001

Jun ‘01 data

Serious Adverse EventsPerioperative Bleeding

34

0

25

50

75

100

LVAS

0.13

0

0.05

0.1

0.15

0.2

LVAS

%pts

Per100days

Jun ‘01 data

Serious Adverse EventsOperations (all types, after original implant)

0

5

10

15

20

1 2 3 3 4 5 6 7 8 9 10

#pts

# of Operations

Jun ‘01 data

OMM

LVAS

Device Malfunction Analysis

Implant ElementReplacement

20 Elementsin 19 pts.

External ElementReplacement

50 Elementsin 38 pts.

Device Malfunctions

156 reported malfunctions in 25 patients

8 pumps replaced4 devices removednot replaced

3 sepsis 1 pt choice

All 4 diedpostop

7/8 pts died

12 pumps removed

Jun ‘01 data

Withdrawal from Treatment

• 4 OMM patients chose to have treatment withdrawn within 1 month of randomization, 8 others chose to have treatment withdrawn later (total 12/61)

• 7 LVAS patients (or their family) chose to have device turned off or did not agree to replacement, and 6 more chose to have treatment withdrawn (total 13/68)

Jun ‘01 data

Secondary Endpoints

• NYHA class • Quality of Life Questionnaires• Functional Status

– 6-minute walk – VO2 max

• Hospitalizations, length of stay• Adverse Events• Device Malfunction

NYHA Class Results

0

50

100

Base 6 mo 12 mo

I/II

III/IV

50

100

Base 6 mo 12 mo

I/II

III/IV

LVAS

OMM

LVAS patients significantly improvedat 6 and 12 months

%pts

%pts

Jun ‘01 data

Quality of Life Results

• What is the effect on physicians and patients of not being selected for the device

• Placebo effect in unblinded study may be important

• Sample bias for missing data (e.g. may select out patients with neurological damage)

• Expect consistency between NYHA, QOL, 6-min walk, MVO2

Quality of Life(Number of Patients Tested)

22

46

3

0

20

40

60

1-yr 2-yr 1-yr 2-yr

LVAS OMM

# of patients

Jun ‘01 data

6 minute Hall Walk(number of tests performed)

3729

-5

10

25

40

55

70

never/once multiple

44

17

-5

10

25

40

55

70

never/once multiple

LVAS

OMM

Inadequate datafor comparison# pts

# pts

Jun ‘01 data

6 minute Hall Walk

0

200

400

0 3 6 9 12 15 18 21 24Months

MedianDistance ( m)

LVAS

OMM

Jun ‘01 data

Peak VO2 (ml/kg/min)

37

28

15

3 2 10

20

40

60B

ase 6 12 18 24

LVAS

OMM

months

#pts

Peak VO2 (ml/kg/min)

0

5

10

Bas

e 3 6 12 18 24

months

VO2 Maxml/kg/min

LVAS

OMM

Hospitalization

50

7164

83

0

50

100

Average Median

% of Remainderof Life Out ofHospital

Device

OMM

Jun ‘01 data

Death DuringInitial Hospitalization

n=20

n=6

0

50

100

LVAS OMM

% patients

Jun ‘01 data

Clinical Summary

• In a very advanced heart failure population LVAS use produced a survival benefit

• The mortality and morbidity associated with use of the LVAS was considerable

• Interpretation of functional testing data is limited by the small amount of data available

Statistical CommentsStatistical Comments

Thoratec HeartMate VE LVASLeft Ventricular Assist Device

Gerry Gray, Ph.D.FDA/CDRH/OSB/DBS

Study Synopsis• Patients randomized 1:1 OMM:LVAS • Primary endpoint: two-year mortality• Three interim analyses at 23 death intervals, trial

designed to stop at 92 deaths – O’Brien-Fleming; final critical p=0.044)

• Complete follow-up for survival analyses• As of 6/28/01, 128 patients enrolled (61 OMM,

67 LVAS), 40 deaths in LVAS arm, 52 deaths in OMM arm– as of 2/01/02, 129 enrolled; 50 LVAS, 56 OMM deaths

0.0

0.2

0.4

0.6

0.8

1.0

months from randomization

Su

rviv

al

0 6 12 18 24 30

LVAS, n=OMM, n=

6761

3627

1911

114

53

REMATCH, all cause mortalityJune 2001 (92 deaths)

LVASOMM

All Cause Mortality

All Cause Mortality - Update0

.00

.20

.40

.60

.81

.0

months from randomization

Su

rviv

al

0 6 12 18 24 30

LVAS, n=OMM, n=

6861

4128

3316

154

73

REMATCH, all cause mortalityFeb. 2002 update

LVASOMM

Cardiac Mortality0

.00

.20

.40

.60

.81

.0

months from randomization

Su

rviv

al

0 6 12 18 24 30

REMATCH, cardiac mortality

LVASOMM

Non-Cardiac Mortality0

.00

.20

.40

.60

.81

.0

months from randomization

Su

rviv

al

0 6 12 18 24 30

REMATCH, non-cardiac mortality

LVASOMM

• Significant increase in median survival time (OMM 150 days, LVAS 405 days)

• Significant difference between K-M survival curves (logrank test p = 0.003)

• Significant difference in mortality at one year point (19 LVAS, 11 OMM patients at risk, mortality 50.8% vs. 24.4%)

• Marginal significance in mortality at two year point (updated data; 7 LVAS, 3 OMM patients at risk, mortality 23.7% vs. 8.3%)

• Cardiac, non-cardiac mortality not independent

• Relative “drop off” in LVAS survival at ~22 months? (only 11 patients @ 22 mo.)

Mortality Results Summary

Adverse Events

• Numbers of adverse events (AE) and serious adverse events (SAE) per person both significantly greater for the LVAS arm

• Rates per 100 patient days also significantly greater

Death and Serious Adverse Events

rate per 100 patient days

DeathNeurologic DysfunctionBleedingLocalized InfectionSepsisThromboembolic EventArrhythmias:Cardiac ArrestArrhythmias:VA with cardioversionArrhythmias:SVA with cardioversionSyncopeNon-periop MIRenal FailureHepatic DysfunctionPsychiatric EpisodeLVAD Related RHFLVAD Periop BleedingDriveline or Pocket InfectionPump Inflow or Outflow InfectionDevice Thrombosis

0.2 0.1 0 0.1 0.2 0.3 0.4

LVASOMM

REMATCH, SAE and death, rates per 100 patient days

Death and Serious Adverse Events

rate per 100 patient days

DeathNeurologic DysfunctionBleedingLocalized InfectionSepsisThromboembolic EventArrhythmias:Cardiac ArrestArrhythmias:VA with cardioversionArrhythmias:SVA with cardioversionSyncopeNon-periop MIRenal FailureHepatic DysfunctionPsychiatric EpisodeLVAD Related RHFLVAD Periop BleedingDriveline or Pocket InfectionPump Inflow or Outflow InfectionDevice Thrombosis

0.6 0.2 0.2 0.6

events at 30 days or less

rate per 100 patient days

0.1 0 0.1 0.2 0.3

events after30 days

REMATCH, SAE and death, rates per 100 patient days

LVASOMM

Hospitalization Time

LVAS OMM

median total median total

Days inhospital

61 4450(24%)

16 1756(15%)

Days out ofhospital

141 13,961(76%)

105 10,085(85%)

TOTAL 18,411 11,841

• Panel will be asked to weigh survival benefit vs. adverse event rate

• Two possible ways to formally combine the death and adverse event results– Hierarchical ranking– Survival to death or some other “bad event”– (these are not the only two possibilities)

How to combine?

• Hierarchical ranking– rank patients by most important outcomes first,

then break ties by secondary outcomes– e.g. rank by death time, or if alive by # of days in

hospital

– If death time is most important then regardless of other ranking factors, improvement always significant in favor of device.

Combined death & SAE

Survival to death or first SAE0

.00

.20

.40

.60

.81

.0

months from randomization

Su

rviv

al

0 6 12 18 24

REMATCH, survival to death or first SAE

LVASOMM

First SAE or Death

LVAS OMM

Death 2 28

Other SAE 56 25

None 10 8

Updated data, n=129 patients

Subsequent SAE or death

• Clinical impression from case reports that the first “bad event” often initiates a cascade of events leading ultimately to death– is this impression borne out in formal

analysis?– Is there a difference between the two groups

in the timing of the 2nd, 3rd, 4th events?

Conditional survival to death or SAE0

.00

.20

.40

.60

.81

.0

months between events

Su

rviv

al f

rom

de

ath

or

SA

E

0 2 4 6 8 10 12 14 16 18 20 22 24

REMATCH, time to 1st, 2+ SAE or death

LVAS 1LVAS 2 +

OMM 1OMM 2 +

Similar results for unpooled 2+; distribution of death vs.. SAE similar to first event

3 Mo. 6 Mo. 12 Mo.NYHA class <0.001 <0.001 <0.001Hall Walk ns ns nsPeak VO2 ns ns ns

SF36 – physical 0.052 ns nsSF36 – mental ns ns nsBeck 0.055 0.002 0.055Minnessota LWHF ns 0.018 nsEuroQOL general 0.003 <0.001 ns

QOL

EuroQOL self assessment

0.002 <0.001 ns

Functional Status SummaryP-values, tests for difference in improvement between LVAS, OMM

Statistical Summary•Significant decrease in mortality for LVAS arm (median survival time, logrank test, or pointwise)•SAE rates much higher in LVAS arm•LVAS treatment resulted in decreased cardiac mortality rates and increased non-cardiac mortality rates•Survival past two years poor in both groups•Some indication of relative LVAS “drop off” in survival at about 22 months (but few patients)•Difference between groups almost entirely in time to first event, not time between subsequent events.

•Odds of death vs. SAE always higher for OMM•Functional status favors LVAS, but not consistently

Questions for the Panel

P920014/S16

March 4, 2002

Device Reliability1. The bench testing performed to assess

device reliability did not account for all observed clinical conditions; in particular, higher than expected pressure in the pump chamber and higher than expected beat rates. Accordingly, the observed times to device failure and device malfunction seen in the clinical study are less than those predicted by the reliability model. As well, there is no reliable end-of-pump-life indicator. Please discuss the clinical implications of the observed device reliability.

Device Reliability

2. Are the device failure and malfunction rates and their time to occurrence appropriate for a device intended for use for destination therapy?

Data Analysis

3. Given the Kaplan-Meier survival curves and the fact that 7 device patients and 3 control patients (as of 2/02) had survived to 24 months, have enough patient data been reported to demonstrate a clinically meaningful survival benefit?

Effectiveness of the System on Functional Status

4. The NYHA, QOL, and functional testing results are not consistent. From these data, can we determine that there is a clinically meaningful improvement in functional status?

Risk-Benefit of the System used for Destination Therapy

5. This device demonstrated an increase in median survival time and showed an overall difference in survival. However, this benefit diminished at two years and was associated with serious adverse events and hospitalizations throughout the course of the study. Do the benefits of this device outweigh its risks?

Labeling

6. One aspect of the pre-market evaluation of a new product is the review of its labeling. The labeling must indicate which patients are appropriate for treatment, identify potential adverse events with the use of the device, and explain how the product should be used to maximize benefits and minimize adverse effects.

The HeartMate VE LVAS is indicated for use as a bridge to transplantation in cardiac transplant candidates at risk of imminent death from nonreversible left ventricular failure. The HeartMate VE LVAS is also indicated for use in patients with end-stage left ventricular failure who are ineligible for cardiac transplantation. The HeartMate VE LVAS is intended for use both inside and outside the hospital.

A. Please discuss the appropriateness of the proposed indications for use for this device, which reads:

Labeling

b.. Does the labeling accurately inform patients of the risks of the device?

Labeling

c. Does the labeling adequately inform patients of the expected duration of use for this device

(see page 44 of the patient handbook of Tab 3.2 of the Panel Pack)?

Labeling

d. Are there any other issues of safety or effectiveness not adequately covered in the labeling?

Post-Market Evaluation

7. Based on the clinical data provided in the panel pack, do you believe that additional clinical follow-up or post market studies are necessary to evaluate the long-term effects of this device? If so, how long should patients be followed, and what endpoints and adverse events should be measured?