# Presentation: 677608

## Slide 1

## 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

## Slide 7

## PRECLINICAL EVALUATIONDetermined To Be Satisfactory

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

## PRECLINICAL EVALUATIONRemaining Concerns

- Reliability
- Internal components
- Motor
- Valved conduits
- Percutaneous tube
- Device End of Life Indicator

## RELIABILITY PROTOCOLBench 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 RESULTSBench Testing

- 10 pumps failed
- 8 main bearing
- 1 diaphragm
- 1 commutator
- 5 remain on test
- as of 8/3/01

## RELIABILITY RESULTSBench 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 RELIABILITYBench 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 Trial

## 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

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

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

## Lesley Ewing M.D.
(cardiology)

Wolf Sapirstein M.D.
Julie Swain M.D.
(cardiac surgery)

**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

- Mortality at 2 years

- Power calculated for 92 study deaths, 128 patients enrolled

**Feb ‘02 data**

**Notes:**
Discuss less than 2 yr loss of data

## Inclusion CriteriaOriginal 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

**Notes:**
Point out few III

## 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)

**LVAS**
**n = 68**

**OMM**
**n = 61**

**Notes:**
Highly selected, small
in addition to those show by sponsor

## Study Design

**Patients Screened = 968**

**Patients Enrolled = 129**

**LVAS = 68**

**OMM = 61**

**Feb ‘02 data**

**#**
**pts**

**#**
**pts**

**Ratio 7.50**

**Notes:**
1 patient consented before June, implanted after, died a couple of months later
discuss continued access, approved for 30, one done, one died POD 12

## Survival

**%**
**Survival**

**Feb ‘02 data**

- n =16

- n =33

_**At 27 months**_
- 4/7 LVAS died
- 3/3 OMM died

**N = 3**

**N = 7**

## Serious Adverse Events

**% pts**

**64/68**

**38/61**

**P <0.001**

**June ‘01 data**

**Notes:**
Submission last week

## Comparison of Destination and Bridge Therapy SAE’s

- Different patient populations
- Different definition for many SAE’s
- Different time period
- Different patient care team

**Notes:**
Expect concordance between all four

## Serious Adverse EventsNeurological Dysfunction

- %
- pts

- Per
- 100
- days

**P = 0.002**

**P = 0.0145**

**June ‘01 data**

**Notes:**
No cognitive testing
NIH stroke scale

10 strokes device, 1 stroke OMM
hard to detect a 2nd event if a big 1st, underestimate
express 2 ways, if designed now would have cognitive function in addition to NIH stroke, which is just that, not subtle

## Serious Adverse EventsLocal Infections

- %
- pts

**Per**
**100**
**days**

**P = 0.079**

**P < 0.1**

**Jun ‘01 data**

## Serious Adverse EventsSepsis

- %
- pts

**Per**
**100**
**days**

**P = 0.019**

**P < 0.2**

**Jun ‘01 data**

## Serious Adverse EventsPercutaneous/Pocket Infections

- %
- pts

**Per**
**100**
**days**

**Jun ‘01 data**

## Serious Adverse Events Pump Housing, Inflow, Outflow Infections

- %
- pts

**Per**
**100**
**days**

**Jun ‘01 data**

## Serious Adverse EventsBleeding

- %
- pts

**Per**
**100**
**days**

**P = 0.0004**

**P < 0.0001**

**Jun ‘01 data**

**Notes:**
Bleeding - causing death, hospitalization, permanent injury, or necessitates transfusion

Perioperative bleeding -  Blood loss resulting in death, reop, or tx over 6 units in 24 hrs from operation

## Serious Adverse EventsPerioperative Bleeding

- %
- pts

**Per**
**100**
**days**

**Jun ‘01 data**

**Notes:**
Bleeding - causing death, hospitalization, permanent injury, or necessitates transfusion

Perioperative bleeding -  Blood loss resulting in death, reop, or tx over 6 units in 24 hrs from operation

## Serious Adverse EventsOperations (all types, after original implant)

** ****#**
**pts**

**# of Operations**

**Jun ‘01 data**

**OMM**

**LVAS**

**Notes:**
Defined as reop in LVAS, first op in OMM  any type big or small

## Device Malfunction Analysis

**Implant Element**
**Replacement**

- 20 Elements
- in 19 pts.

**External Element**
**Replacement**

- 50 Elements
- in 38 pts.

**Device **
**Malfunctions**

- 156 reported malfunctions in 25 patients

- 8 pumps replaced

- 4 devices removed
- not replaced

- 3 sepsis

- 1 pt choice

**All 4 died**
**postop**

**7/8 pts died**

- 12 pumps removed

**Jun ‘01 data**

**Notes:**
6/7 pumps replaced died during the hospitalization

## 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**

**Notes:**
OMM not optimal in these patients

LVAS had option of replacement

## Secondary Endpoints

- NYHA class
- Quality of Life Questionnaires
- Functional Status
- 6-minute walk
- VO2 max
- Hospitalizations, length of stay
- Adverse Events
- Device Malfunction

**Notes:**
Expect concordance between all four

## NYHA  Class Results

**LVAS**

**OMM**

**LVAS patients **
**significantly improved**
**at 6 and 12 months**

**%**
**pts**

**%**
**pts**

**Jun ‘01 data**

**Notes:**
Need concordant data, if Class I or II, should be able to do 6 min and MVO2

## 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, MVO****2**

**Notes:**
Like to see concordance

high number need to be reported
placebo 30%

enroll thinking that have chance to get new therapy

## Quality of Life(Number of Patients Tested)

**LVAS**

**OMM**

**# of**
** ****patients**

**Jun ‘01 data**

**Notes:**
Need to assess is this adequate amount

## 6 minute Hall Walk(number of tests performed) 

**LVAS**

**OMM**

**Inadequate data**
**for comparison**

**# pts**

**# pts**

**Jun ‘01 data**

**Notes:**
NYHA I and II should be able to exercise

## 6 minute Hall Walk

**Months**

**Median**
**Distance**
**    ****( m)**

**LVAS**

**OMM**

**Jun ‘01 data**

## Peak VO2 (ml/kg/min)

- months

- #
- pts

## Peak VO2 (ml/kg/min)

- months

- VO2 Max
- ml/kg/min

**LVAS**

**OMM**

## Hospitalization

- % of Remainder
- of Life Out of
- Hospital

**Device**

**OMM**

**Jun ‘01 data**

**Notes:**
Time after randomization

sponsors show one way, this is another

## Death DuringInitial Hospitalization

- % 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

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

- 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

**Notes:**
Trial designed to assess two year mortality via the logrank test

## All Cause Mortality

## All Cause Mortality - Update

**Notes:**
Updated data as of 2/1/02
Basic features unchanged from June 2001 data
Slightly smaller ci bands - mostly in LVAS arm (back up to previous?)
Still have the “drop off” in LVAS arm at 20 months

## Cardiac Mortality

**Notes:**
Cardiac mortality only looks good for LVAS arm

Problem  ... cardiac, non-cardiac mortality not independent ... in statistical terms, the censoring is not independent of mortality in t his analysis

## Non-Cardiac Mortality

**Notes:**
Non-cardiac mortality poor for LVAS arm
It appears that mortality causes are not independent
It also looks like the LVAD reduces the cardiac mortality rate, but at the same time increases the non-cardiac mortality rates.
This is also evident when you look at the causes of mortality (next slide)

## 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.)

- 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

**Notes:**
So here’s a summary of the mortality results.

Mortality is not the whole story, however.  The LVAS arm also had a significant increase in the number of adverse events (and in the rates adjusting for time in the study)  ... next slide

## 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

**Notes:**
Serious adverse event and death rates per 100 patient days
First 5 bars are LVAD events - not possible for OMM patients
Overall, LVAD rates are significantly higher than OMM
Note bleeding, neurologic dysfunction for LVAS arm

## Death and Serious Adverse Events

**Notes:**
Serious A.E. and death rates per 100 days, peri-operative and after.
Rates for both groups drop off after first 30 days (note x-axis scale)
LVAD rates significantly higher for both time periods (?check >30)
Note bleeding, neurologic dysfunction still much higher in LVAS arm, even after 30 days
Mortality nearly identical for first 30 days, then LVAS much better
Note: prop hazards assumption probably not met ... first equal mortality, then LVAS much better, then at the end OMM is better.

## Hospitalization Time

## 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)

- 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.

- 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 SAE

**Notes:**
If we count all “bad events”, that is, serious adverse events or death as the same, then we can analyze the time to the first “bad event”
This graph shows K-M survival curves for the time to death or first serious A.E.
This analysis treats all first events as equal.
LVAS survival time much less than OMM (median survival 13 vs 87 days)
Rates after about 5-6 months virtually identical

## First SAE or Death

**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 SAE

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

**Notes:**
Conditional survival to first, second, 3+ events ... time to event 2 given you have already had event 1, etc.
First events are the same as the previous slide
Second, 3+ events occur rapidly ... median survival times to 1st, 2nd, 3+ events for LVAS arm are 13, 6, 4 days ... medians for OMM 87, 5, 7 days
That is, after a patient has one ‘bad event” they are very likely to have events 2, 3, etc. in a very short time.
The biggest difference between OMM and LVAS is in the time to the FIRST event.  Given that a patient has that first event, the times to subsequent events are much less and much more similar for the two arms.

## Functional Status Summary

**P-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

## Slide 70

## Questions for the PanelP920014/S16

- March 4, 2002

## Device Reliability

- 1.	**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. **

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

**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?**

## Slide 83