**SUMMARY MINUTES**

**OF THE**

**CIRCULATORY SYSTEM DEVICES**

**ADVISORY PANEL MEETING**

**OPEN SESSION**

**March 4-5, 2002**

**Gaithersburg Marriott Washingtonian Center**

**9751 Washingtonian Boulevard**

**Gaithersburg, MD**

**CIRCULATORY SYSTEM DEVICES ADVISORY PANEL MEETING**

**March 4-5, 2002**

### Attendees

## Acting Chairperson

Warren K. Laskey, M.D.

University of Maryland School of Medicine

## Executive Secretary

Lesley Ewing, M.D.

Food and Drug Administration

## Voting Members

Salim Aziz, M.D.

University of Colorado

Janet T. Wittes, Ph.D.

Statistics Collaborative, Inc.

# Consultants

James A. DeWeese, M.D.\*

University of Rochester

Jeffrey Brinker, M.D.+

The Johns Hopkins Hospital

Anthony Comerota, M.D.\*

Temple University

Tony W. Simmons, M.D. +

Wake Forest University

Michael J. Domanski, M.D.

National Institutes of Health

Mark Haigney, M.D. +

Uniformed Services University of Health Sciences

Francis Klocke, M.D.\*

Northwestern University Medical School

Mitchell Krucoff, M.D. +

Duke University Medical Center

Ileana Pina, M.D.

Case Western Reserve University

Steven Nissen, M.D.

The Cleveland Clinic

Marvin Konstam, M.D.

New England Medical Center

Pilar Ossorio, Ph.D., J.D.

University of Wisconsin

# Consumer Representative

Robert Dacey

# Patient Representative

# Joseph Knapka, Ph.D.

# 

# Industry Representative

Michael Morton

Alcon Laboratories

**Food and Drug Administration**

Bram Zuckerman, M.D.

Michael Berman, Ph.D.

Julie Swain, M.D.

Gerry Gray, Ph.D.

Doris Terry

Helen Barold, M.D.

\*attending only March 4

+attending only March 5

**OPEN SESSION---March 4, 2002**

# Call to Order

**Acting Chairperson Warren K. Laskey, M.D.,** called the meeting to
order at 10:03 a.m. and read the charge to the panel, which was to
consider a supplement to premarket approval application (PMA)
P920014/S016 for Thoratec Corporation's HeartMate VE LVAS. **Panel
Executive Secretary Lesley Ewing, M.D.,** read the conflict of interest
statement, noting that matters concerning Drs. Salim Aziz, Francis
Klocke, and Marvin Konstam had been considered but their full
participation would be allowed. Drs. James A. DeWeese and Anthony
Comerota had declared institutional interests potentially affected by
the day's deliberations interest, but their full participation would be
allowed. **Dr. Laskey** asked the panel members to introduce themselves
and state their areas of expertise**. Dr. Ewing** then read appointments
to temporary voting status for Drs. Pilar Ossorio, Michael J. Domanski,
James A. DeWeese, Francis Klocke, and Anthony Comerota, and an
appointment as acting panel chairperson for Dr. Laskey for the
meeting**. Dr. Ewing** noted that Drs. Steven Nissen, Ileana Pina, and
Marvin Konstam were voting members or consultants for advisory
committees of the Center for Drug Evaluation and Research.

# Open Public Hearing

There were no requests to address the panel.

# Sponsor Presentation---PMA 910014/S016

**Donald A. Middlebrook of Thoratec Corporation** thanked the FDA and
panel and explained that the PMA supplement sought FDA approval to
expand the current indications for use of a left ventricular assist
device (LVAD) with patients awaiting cardiac transplantation to include
patients with end-stage left ventricular failure who are ineligible for
cardiac transplantation. The PMA contained results from the Randomized
Evaluation of Mechanical Assistance in the Treatment of Congestive Heart
Failure (REMATCH), which was a landmark randomized controlled trial of
the device versus optimal medical management conducted by cooperative
agreement between the sponsor, NIH/NHLBI, and Columbia University.

**Victor Poirier of Thoratec** gave an overview of the device,
summarizing changes made to prevent kinking and suture problems. He
presented statistics on device reliability based on long-term in vitro
testing that showed a 3.1-year estimated mean time to failure and a 76%
chance that the device would be free of critical failures at two years.
He acknowledged that in vivo results were not as good but suggested that
comorbidity and patient management factors were to blame for the less
favorable clinical experience.

**Eric Rose, M.D., principal investigator for REMATCH,** sketched the
history and design of the REMATCH trial, a multicenter controlled trial
which randomized 129 patients with end-stage heart failure who were
ineligible for cardiac transplantation into a device group to receive a
left ventricular assist device (LVAD) or optimal medical management
(OMM). Patients and physicians were not blinded to treatment assignment.
An intent to treat analysis using Kaplan-Meier and Log rank methods was
used to assess the key efficacy objective of survival, with safety
measured by adverse event and device malfunction rates in the context of
a highly ill population. Secondary endpoints included quality of life,
functional status, time in/out of hospital, and cardiovascular
mortality. Dr. Rose listed techniques used to control bias and stated
that key study assumptions were that patients and clinicians would not
adopt LVAD unless all-cause mortality over two years was reduced by 1/3
or more and that quality of life with LVAD should equal or exceed that
of the OMM group. The study was powered for survival, and the stopping
point was based on number of deaths, not patients enrolled. He
emphasized that the trial was not stopped early but stopped when the
predetermined number of deaths was reached. Patients were randomized in
a one-to-one ratio by study center.

**Dr. Lynne Warner Stevenson, a study investigator and chair of the
Medical Management Committee,** presented information on the REMATCH
patient population in the context of the heart failure population. She
outlined REMATCH eligibility criteria and explained the reasons why
these patients were not transplant candidates, which was predominantly
because of age and/or diabetes. After presenting statistics on REMATCH
therapies at baseline, ACEI intolerance and renal dysfunction in various
trials, REMATCH patient baseline characteristics, other profiles of
heart failure in various trials, medical management of the OMM
population, and use of IV inotropic agents in the trial, Dr. Stevenson
concluded that REMATCH patients define a new profile of severe heart
failure. By the time of randomization REMATCH patients had already
received "optimal management" and moved beyond medical therapy. She also
raised the question of what constitutes a meaningful benefit in
end-stage heart disease in terms of percentage of one-year relative
benefit or absolute benefit.

**Dr. Rose** presented clinical results of the REMATCH trial. Baseline
characteristics of the two arms showed no real differences. Kaplan-Meier
survival analysis illustrating the probability of survival of LVAS
versus OMM patients after 92 deaths revealed a 46% reduction in
mortality at two years and a 52% reduction at one year. The predominant
cause of death for the control group was heart failure for the control
group and sepsis or device failure for the LVAS group. One-year survival
rates doubled for the device group, with an absolute reduction of
mortality rate of 27% at one year. Two-year survival rates tripled, and
median survival time was 408 days for LVAS patients versus 150 days for
the control group. Because all-cause mortality was reduced by 46% in
LVAS patients, the primary trial objective of a 33% reduction in
mortality was exceeded.

Dr. Rose reported that serious adverse events were more common in the
device group, although the rate decreased over time, with the majority
being neurologic or bleeding/sepsis events. Neurologic events were more
likely to be transient and to occur within 30 days. Experience with
bleeding was largely associated with device implant or reimplant and
infection was a specific complication of VAD use, with an initially
unappreciated association with malnutrition. Of the 156 device
malfunctions reported, most dealt with broken lead wires, incompetence
of the inflow valve, or a broken Y-connector. Dr. Rose stated that the
incidence of overall adverse events was acceptable compared to the
natural history of terminal illness, and that sponsors had identified
various opportunities for improvement.

The SF-36 Heart Survey, the Minnesota Living with Heart Failure Test,
the NYHA functional assessment, the Beck Depression Inventory, and the
EuroQOL were used to assess quality of life. Dr. Rose observed that LVAD
scores were never worse than the control group except for short-term
postoperative pain. LVAD generic quality of life scores were better than
control at 12 months in key prespecified SF-36 domains. LVAD
disease-specific quality of life scores on the Minnesota Living with
Heart Failure Test improved over control at 12 months but were not
statistically significant. NYHA functional class improved significantly
with device use over control and reduced depressive symptoms to the
normal range, unlike the control group. In context, the LVAD physical
function scores were not normal, but were analogous to patients
receiving long-term hemodialysis and ambulatory heart failure patients.
LVAD emotional--role scores were better than those reported for clinical
depression and similar to those for ambulatory heart failure patients.

Dr. Rose also answered questions previously raised by the FDA on device
reliability, suggesting modifications to the device for end of pump life
indicators. He thought the observed failure rates define what is
acceptable now in the context of the available alternative therapies and
terminal illness and that the reliability is sufficient to produce
survival benefit. Dr. Rose noted that a clinically meaningful benefit in
survival had been defined in a prestudy agreement, and that the study
results surpassed this figure. He stated that the trends in the quality
of life data are consistently favorable, although no benchmarks are
available, and that the NYHA class and prespecified physical function
domains are significant at 12 months. Dr. Rose also listed proposed
post-market surveillance activities.

**Dr. Donald A. Middlebrook** emphasized that the study presented strong
evidence of a clinically meaningful survival benefit, with the VE LVAS
providing reasonable evidence for safety in the context of terminal
illness. All quality of life instruments showed sustained improvement
trends over control and an unprecedented reduction in mortality in
end-stage heart failure patients when compared to landmark drug studies,
making it the only proven alternative therapy for nontransplantable end-
stage heart failure patients.

# FDA Presentation

**Michael Berman, Ph.D., lead reviewer,** introduced the review team and
read the proposed expanded indication for use. He described the device
components and listed satisfactory elements of the preclinical
evaluation. Remaining FDA concerns include the reliability of the
internal components and a device end-of-life indicator. Dr. Berman
explained the reliability protocol used and results obtained in bench
testing, noting a problem still to be corrected in main bearing failures
observed at three and a half years. Clinical trial observations also
revealed an elevated pump chamber pressure and high beat rate (inflow
valve incompetence), and observed pump end of life events were at the
low end of reliability predictions made in bench testing. These issues,
along with the lack of a device end-of-life indicator, raised concerns
because device replacement requires major surgery.

**Julie Swain, M.D.,** presented the clinical review. The study design
assumptions were based on mortality at two years as presented in
clinical literature, with the power calculated for 92 study deaths and
128 patients enrolled. She described inclusion and exclusion criteria
and study design. Dr. Swain presented survival statistics showing that
at 27 months, four out of seven device patients died and three out of
three control patients died. Serious adverse event data, however, showed
64 out of 68 device patients experienced a serious event, compared to 38
out of 61 control patients. Comparing destination and bridge therapy
adverse events was not helpful because of differences in patient
populations, definitions, and patient care teams. Dr. Swain presented
bar graphs on these adverse events by neurological dysfunction, local
infections, sepsis, and bleeding. Analysis of device malfunctions showed
high rates of mortality. Rates of withdrawal from treatment were roughly
similar for the two groups.

For secondary endpoints, Dr. Swain presented NYHA class results showing
that LVAS patients significantly improved at 6 and 12 months. However,
she questioned the effect on physicians and patients of not being
selected for the study and noted that the placebo effect of device use
in the unblinded study might be important. She thought there should be
consistency between NYHA, quality of life, six-minute hall walk, and
peak VO2 results. Peak VO2 results and length of hospitalization,
however, did not show significant improvement for the LVAS patients over
control. She concluded that LVAS use did produce a survival benefit in a
very advanced heart failure population, but the mortality and morbidity
associated with its use were considerable. Interpretation of the
functional testing data is limited by the small amount of data
available.

**Gerry Gray, Ph.D., statistical reviewer,** synopsized the study,
noting that the trial was designed to stop at 92 deaths and that there
was complete follow-up for survival analysis. He showed graphs
indicating a significant difference in mortality for the device arm at
the one-year point, a significant increase in median survival time for
the device group of 405 days as opposed to 150 for control, and a
significant difference between Kaplan-Meier survival curves favoring the
device. However, the serious adverse event rates were much higher in the
device arm; he noted that device treatment resulted in decreased cardiac
mortality rates and increased non-cardiac mortality rates. Survival past
two years was poor in both groups, with some indication of a relative
drop-off in LVAS survival at 22 months, although there were few
patients. The numbers of adverse and serious adverse events per person
and per 100 patient days were significantly greater for the device arm
than for control arm, however, and he asked the panel to weigh the
survival benefit versus the adverse event rate. The difference between
control and device groups was almost entirely in the time to first
event, not time between subsequent events, and the odds of death versus
serious adverse event were always higher for the control group. Analysis
of functional status favored the device group, but not consistently.

**Michael Berman** read the FDA questions for panel review.

## Open Committee Discussion

**Lead panel reviewer Marvin Konstam, M.D.,** congratulated the sponsors
and FDA review team on a landmark study but had several areas of
concern. The first involved whether the primary endpoint had been met,
given that there was not significant improvement in mortality at two
years. Sponsors replied that the study was designed, per agreement with
the FDA, to provide observation over a two-year period rather than a
single, discrete endpoint at two years. His second concern involved the
clinical relevance of the device if most patients are dead at two years
and whether unreliability of the device contributed to this mortality.
The third area of concern involved the quality of life assessment, which
he found partially reassuring and partially confusing because of the
high dropout rate and the criteria selected. Fourth, he expressed
concern about the high number of neurological events and bleeding
problems, suggesting that anticoagulation therapies needed further
attention. Finally, he asked for a clearer indication of the intended
population of use, given the limited number of those alive at two years
and the large number of adverse events.

**Lead panel reviewer Salim Aziz, M.D.,** praised the company for
involving academia as well as industry and NIH in the study. He asked
for further information on the etiology of the grand mal seizures,
expressing concern about the need for metabolic control of surgical
patients. The problem of sepsis was multi-factorial, but he suggested
attention to albumin levels and preoperative nutrition. Dr. Aziz stated
that he was not convinced that the device could be used as a destination
therapy, despite its success as a bridge therapy, and questioned its
duration to four years.

Other members of the panel raised questions involving plans for
follow-up to provide more data on device failure and ways to prevent
device-related sepsis. Several panel members panel wanted more in vivo
and in vitro data on the mean time to device failure. Concerns were
expressed about the quality of life data, including investigator bias,
the small numbers used, and the unblinded nature of the trial. It was
suggested that sponsors present data for both control and device on
rates of death and cerebrovascular accidents at one year rather than
simply mortality. Several members stated that an independent outsider
not involved in the study should have made the assessment of NYHA
classification. The high rate of infection for the device group prompted
considerable panel discussion; it was suggested that sponsors look more
closely at malnutrition and also at female versus male immune responses
or differences in racial or ethnic response to treatment. Others asked
about correlation of outcome to age and if a risk profile for sepsis or
CVA could be developed. Issues of informed consent and non-resuscitation
orders also needed attention. A training program for physicians and for
patients was recommended.

**Consumer Representative Mr. Dacey** suggested simplification of the
language used in the patient information. **Industry Representative Mr.
Morton** observed that many other heart prostheses do not have an
end-of-device-life indicator, and that this device should not be held to
an unfair standard.

# FDA Questions to the Panel

## Device Reliability

1.  The bench testing performed to assess device reliability did not
    account for all observed clinical conditions. 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.

The panel asked for more data on device reliability, in particular
distribution of time to failure (all data points), given that the
clinical reliability to date fell short of that seen in the in vitro
testing.

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

There was no panel consensus on this issue. Some panel members said the
device was not appropriate as destination therapy, given the failure
rates. Some asked for clarification on destination therapy. Others said
there was insufficient data to decide, particularly asking for mean and
median time to failure and actual distribution of those data points.

**Data Analysis**

3.  Given the Kaplan-Meier survival curves and the fact that seven
    device patients and three control patients as of 2/02 had survived
    to 24 months, have enough patient data been reported to demonstrate
    a [clinically]{.underline} meaningful survival benefit?

The panel had a range of answers. Some stated there were unknown data in
the pipeline and insufficient data reported to answer. Another viewpoint
was that the device could be approved as safe and efficacious to extend
life by one year. Other members disagreed, saying that the device might
extend life by one year but with inconsistent results for quality of
life, high rates of hospitalization, and high failure rates. There was
considerable philosophical discussion between those reluctant to deny
the possibility of increased survival to patients who were made aware of
the potential risks of adverse events and those who found the quality of
life benefits debatable and the risk of adverse events too high for a
one-year improvement in survivability. After FDA clarification of what
the agency meant by some idea of a clinically meaningful survival
benefit, Dr. Laskey pointed out that an index of survival benefit
showing how many days or months a patient can expect is possible but
said it was difficult to divorce survival from quality of life and
adverse events.

**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?

The panel consensus was that while they would like to read into these
results an improvement in functional status, it was difficult to
conclude definitively that there had been such an improvement, given
problems with lack of blinding, investigator bias, and possible placebo
effect. The panel recommended that NYHA classification assessment always
be done by a third party not involved with the study.

**Risk-Benefit of the System used for Destination Therapy**

5.  This device demonstrated an increase in medial 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?

There was no panel consensus on this issue. All agreed that the risks
are real and evident, but the ratio of risk to benefit is unclear, given
that there are concerns about both numerator and denominator.

**Labeling**

6.  Please discuss the appropriateness of the proposed indications for
    use for this device.

> The panel recommended that there should be more detailed information
> in the indications: all complications should be enumerated and all
> risks discussed as well as careful delineation of those for whom the
> device is and is not indicated. It should be stressed that the device
> is only indicated for the severely ill with a limited life expectancy
>
> b\. Does the labeling accurately inform patients of the risks of the
> device?
>
> The panel recommended conspicuous warnings on the risks of mechanical
> failure as well as infection and ways to minimize or manage risk of
> infection. Members urged the FDA and sponsors to work together both on
> wording and on patient training.
>
> c\. Does the labeling adequately inform patients of the expected
> duration of use for this device?
>
> The panel recommended more patient information on the uncertainty
> about device reliability and duration. Labeling should state that
> there is no indication of end of device life and that reimplantation
> is risky and limited.
>
> d\. Are there any other issues of safety or effectiveness not
> adequately covered in the labeling?

The panel urged that the labeling be blunt in stating that life
expectancy is not known.

> **Post-Market Evaluation**

7.  Do you believe that additional clinical follow-up or post-market
    studies are necessary to evaluate the long-term effects of this
    device?

The panel recommended additional post-market studies on which patients
will benefit and which will not, on internal device malfunction, on lack
of predictability, on the time course of different types of
complications, on anticoagulation regimens, and on additional
ascertainments of endpoints.

**Open Public Hearing**

There were no requests to speak.

## Closing Sponsor Comments

The sponsors thanked the panel, FDA, and presenters for their remarks.

##  Recommendations and Vote

## Dr. Ewing read the panel the regulatory definitions and voting instructions. A motion was made by Dr. Konstam and seconded by Dr. Comerota to recommend the PMA as approvable with the following conditions:

## 1a) Additional analysis of existing data from the current data set should be performed pertaining to device reliability at two years. This condition passed.

1b) Analysis of time to death or stroke should be made performed on the
existing data set to see if it is consistent with the current survival
analysis. This condition passed.

2\) The patient population indicated for the device should be more
clearly delineated. This condition passed.

3\) Rigorous criteria for implantation for both surgeon and facility
regarding patient selection, surgeon expertise, and follow-up should be
established. The FDA should ensure that the training is rigorous and
that procedures are performed in centers and by individuals highly
trained with patients in end-stage heart failure. This condition passed.

4\) A registry should be established for postmarket surveillance, with
an independent evaluator to assess rates of survival; life expectancy;
post-implantation reliability including device failure, durability and
longevity; and adverse events, including thrombo-embolytic events. This
condition passed.

5\) There should be a detailed set of patient information delineating
the trade-off between survivability and adverse events and major
complications, with an indication of patient functioning. The patient
information package should clarify risks and outcomes and rates of
adverse events and explantation. This condition passed.

The motion to recommend the PMA as approvable subject to the above
conditions carried by a vote of eight to two. Those who opposed the
motion stated that they did so because they thought the device promising
but not yet ready for approval given its internal failure rate.

## Open Public Hearing

##  There were no requests to speak.

## Adjournment

## After thanking the presenters and FDA review team, Dr. Laskey adjourned the Open Session for the day at 5:50 p.m. 

## OPEN SESSION---MARCH 5, 2002

# Call to Order

**Acting Chairperson Warren K. Laskey, M.D.,** called the meeting to
order at 8:05 a.m. and read the charge to the panel, which was to
consider a premarket approval application (PMA) P010031 for the
Medtronic InSync Implantable Cardioverter Defibrillator Model 7272
System. **Panel Executive Secretary Lesley Ewing, M.D.,** read the
conflict of interest statement, noting that a limited waiver had been
granted for Dr. Tony Simmons for his interest in firms that could
potentially be affected by the panel's recommendations. The waiver
allowed Dr. Simmons to participate only in the panel discussion. Other
matters regarding Drs. Simmons, Salim Aziz, Mitchell Krucoff, Jeffrey
Brinker, Mark Haigney, and Marvin Konstam were considered but deemed
unrelated and their full participation was allowed. **Dr. Laskey** asked
the rest of the panel to introduce themselves and state their areas of
expertise. **Dr. Ewing** then read appointments to temporary voting
status for Drs. Pilar Ossorio, Michael J. Domanski, Steven Nissen,
Ileana Pina, Marvin Konstam, Mitchell Krucoff, Mark Haigney, and Jeffrey
Brinker and an appointment as acting panel chairperson for Warren K.
Laskey, M.D., for the duration of the meeting. **Dr. Ewing** noted that
Drs. Steven Nissen, Ileana Pina, and Marvin Konstam were voting members
or consultants for advisory committees of the Center for Drug Evaluation
and Research.

## Open Public Hearing

There were no requests to address the panel.

## Sponsor Presentation

**Dr. William T. Abraham, study investigator,** provided background on
ventricular dysynchrony and cardiac resynchronization (CRT) and
explained the design of the original InSync trial, which was a
prospective, randomized, double-blind trial comparing candidates for
cardiac resynchronization with no indication for an ICD in a device
group with activated CRT to an implanted group without activated CRT at
the one, three, and six month follow-up points, with later crossover to
CRT for the control. Primary endpoints, which included improvement in
quality of life, NYHA class, and six-minute walk, were all met.
Secondary endpoints, which were peak VO2, exercise time, and composite
response, also markedly improved. Primary safety results, which included
implant success; low complication rates for device, leads, and pacing
system; and attainment of prespecified pacing thresholds, were all met.
Dr. Abraham then explained the background of the InSync ICD device
trial, which sought to ensure that patients with an ICD indication
responded favorably to resynchronization and that the coexistence of
resynchronization did not adversely affect ICD function. Patients were
randomized into a control group with the pacing mode off or a device
group with the pacing mode on.

**Dr. James Young, study investigator,** explained the study design,
methodology, and patient population of the InSync ICD trial, comparing
entry criteria, study design, and timing of baseline tests to the
original InSync trial and explaining the blinding procedures. The three
primary effectiveness endpoints were the change from baseline to six
months in quality of life score (Minnesota questionnaire), NYHA
classification, and six-minute hall walk distance for device as compared
to control group (implanted with device with CRT off and ICD active),
using the Hochberg adjustment for multiplicity. Secondary effectiveness
endpoints included exercise performance, clinical composite response,
health care utilization, echocardiographic variables, QRS duration, and
neurohormonal variables. The primary study cohort consisted of 421 NYHA
Class III and IV patients (176 control and 186 device), although class
II patients were also admitted and studied separately. Results were
presented based on an intention to treat analysis for patients with
paired data at baseline and six months, including crossovers, with a
last observation carried forward analysis. Patient baseline demographics
for control and device groups were roughly similar.

**Dr. Angel Leon, study investigator,** presented the safety results.
Primary objectives were survival with freedom from device-, lead-, and
system-complications. Secondary safety objectives were characterization
of patient survival, complications, and observations. Lead effectiveness
objectives were implant success, evaluation of the electrical
performance of the leads, spontaneous VT/VF therapy effectiveness,
comparison of VT/VF event rates in the two arms, and biventricular ATP
therapy effectiveness. All primary safety objectives were satisfied, and
secondary safety objectives were within prescribed bounds. Lead
effectiveness results were within the statistically defined parameters.

**Dr. Young** presented effectiveness results. The change in quality of
life score showed a highly significant improvement from baseline to six
months for the device group as compared to control. Change in NYHA
functional class also favored the device group, although not at as high
a level of statistical significance. Differences in six-minute hall walk
distance did not achieve statistical significance. Clinical endpoints
such as exercise performance, clinical composite response, and
healthcare utilization showed favorable trends but did not achieve
statistical significance.

**Dr. Abraham** compared the InSync and InSync ICD trials, which were
designed to be nearly identical, with the exception of performing the
cardiopulmonary exercise tests post-implant in the InSync ICD trial. The
populations of the two trials were very similar with the exception of a
higher percentage of those with heart failure of ischemic origin in the
ICD study. Changes in quality of life score for the two trials showed a
similar pattern of improvement for the device group and a similar
magnitude of change, as did the change in NYHA class. The change in
six-minute hall walk, which showed a highly significant improvement in
the InSync trial for device over control, showed far less improvement
for the InSync ICD trial results. A comparison of the primary endpoints
and secondary clinical endpoints for the InSync and InSync ICD studies
showed strikingly similar results between the two studies, with similar
improvement. Comparison of the risk of death or worsening heart failure
favored device over control for the InSync ICD, with a favorable but
less significant results for the InSync trial in a posthoc analysis. Dr.
Abraham concluded that the benefits of resynchronization in patients
with an ICD indication are similar in both direction and magnitude to
the effects seen in patients without an ICD indication.

## FDA Presentation

**Doris Terry** acknowledged the FDA review team and outlined the
regulatory history of the modular PMA. She described the InSync ICD
model 7272 system components, the preclinical testing performed on the
model, software validation, and preclinical testing on the leads. All
these results met the acceptance criteria.

##  Dr. Helen Barold presented the FDA clinical summary. She read the proposed indication for use and explained randomization and timing of testing. Patients and CHF physicians or staff were blinded; EP physicians were unblinded. Dr. Barold listed the three co-primary effectiveness endpoints and the three primary safety objectives, as well as all secondary objectives. She read the inclusion and exclusion criteria and delineated the patient accountability for the 362 NYHA III/IV patients randomized, noting that 71 (20%) were "administratively censored." There were a number of protocol deviations from blinding and 25 patients who crossed over from CR off to on. Baseline characteristics of the control and device group were roughly similar, with the majority being NYHA Class III older male patients. 

Dr. Barold presented the safety results on an intent to treat basis,
noting that the quality of life results showed a large improvement in
both device and control group but with a larger improvement in the
device group. Change in NYHA classification also was more prevalent in
the device group, although not at the same level of statistical
significance. Six-minute hall walk results, however, showed little
difference. Thus, the device met the third criterion of the Hochberg
adjustment for multiplicity. On the primary endpoint of LV lead
effectiveness, Dr. Barold noted a 10% implant failure rate and noted
that FDA has not yet reviewed materials requested on a breakdown of
Class II and IV patients.

Secondary objectives such as CHF composite showed an improvement of
treatment group over control group, but no difference in patient global
assessment score. There were no differences in hospitalization.
Echocardiographic results and neurohormones showed no difference between
the groups, although the neuroepinephrine level showed an unfavorable
trend in the device group. Mortality rates for the two groups were very
similar. Observed adverse event rates for both groups produced
unremarkable results, although there was a higher rate for the
unexplained "other" grouping for device.

Dr. Barold noted that FDA has requested information on VF detection time
to ensure that the addition of biventricular pacing does not interfere
with the ability to sense VF and to ensure that the left ventricular
lead and/or biventricular pacing is not responsible for inappropriate
shocks. FDA has also requested information to see if ICD programming
interferes with continuous biventricular capture. She listed a number of
programming issues involving device-device interaction and limitations
for consideration.

**Doris Terry** read the FDA questions for panel review.

**Open Committee Discussion**

**Lead panel reviewer Dr. Ileana Pina** had several questions for the
sponsors, including the incidence of sudden death and whether these
deaths were linked to ineffective shocks. She also asked about the
quality of life information and the relationship to rate of
hospitalization. Dr. Pina asked whether it was possible to predict lead
dislodgment or lead implant failure by correlation with lead diameter or
NYHA class function and if subgroup analysis would be useful. Dr. Pina
also asked for clarification about blinding procedures during the
cardiopulmonary tests and about medication therapy involving initiation
of beta blocker use during the trial.

**Lead panel reviewer Dr. Mark Haigney** congratulated the sponsors on
their study but raised concerns about the small magnitude of effects
seen and raised issues about blinding procedures and possible placebo
effects on the quality of life data. He asked whether subgroup analysis
had identified which patients benefited the most and if they could now
be identified in advance before therapy. Dr. Haigney urged in particular
that subgroup analysis be done on correlation of QRS with magnitude of
effect on quality of life. He asked about placing of the lead in the
lateral wall position and correlation of lead position with outcome or
treatment effect. He also favored a postmarketing study on how long the
lead could function. Dr. Haigney concluded that the device appeared to
be effective at converting VT and VF but could lead to inappropriate
shocks and was less effective in cardioversion of fast VT from the
coronary sinus and right ventricle.

Statistical concerns raised by the panel involved how to deal with the
co-endpoints and the administrative censoring, as well as whether the
protocol of stopping at 224 patients was prespecified with the FDA.
Members of the panel differed in the level of their concerns about
blinding procedures in the trial. Several asked for greater subgroup
analysis. Inappropriate shocking was a concern as a part of the
risk/benefit ratio. It was suggested that the trial population should
have included more women and people of color. One panel member asked for
more information on the electrical safety of the device and on how the
device was programmed. Issues of investigator bias because of the high
number of crossovers from control to device group were a concern, as
were training issues and the learning curve involved with device
implantation.

**FDA Questions to the Panel**

**Study Design and Analysis Method**

1\) Please address the following issues:

a.  *Are there any concerns related to the \"administrative censoring\"
    of 20 % of the enrolled patients who had not passed the six-month
    point at the time of the submission?*

The panel expressed repeated concerns about the missing data on the 20%
of the enrolled patients. The panel agreed that the decision to stop the
study at the predetermined point was a major concern for them.

# *Please discuss the benefits and limitations associated with the six-month follow-up duration for the primary endpoints.*

The duration of the follow-up was not an issue for the panel so much as
the robustness of the data collected, about which there was divided
sentiment.

# *Please discuss any concerns about the propensity for crossovers and any additional issues that may be related to blinding.*

The panel expressed uneasiness with the propensity for crossovers and
for what lay behind that propensity, whether it was investigator bias or
lack of blinding.

# *The intent-to-treat analysis on NYHA class, quality of life, and 6-minute hall walk produced nominal p-values of .027, .009, and .407, respectively. Thus, the study results meet the prespecified Hochberg criteria for statistical significance in that one of the endpoints (quality of life) produced a p-value less than .0167. In light of this, please comment on the possible interpretation of the results for each of the co-primary endpoints individually.*

There was a long discussion about the individual p-values and the
Hochberg criteria, with the panel aware of the strengths and benefits of
a combined endpoint analysis, but the panel sought to move beyond that
issue to discuss what the data signified statistically and how to
correlate that significance to clinically meaningful results.

In answer to a follow-on question from the FDA about upcoming new
trials, the panel emphasized that they prefer complete data sets but can
cope with incomplete data sets if they are given better endpoints and
tools for analysis as they grapple with devices in new areas.

## Effectiveness of the System in Treating CHF

# *The primary endpoints of the study were improvement in NYHA class, quality of life, and six-minute hall walk. Please discuss the clinical relevance of these endpoints for evaluating a therapy for congestive heart failure (CHF).*

The panel thought there was a discordance within the scientific
community over the three measures, but that they would have to live with
that unhappiness until there are more precise tools. It was noted that
the tremendous scatter of results and noise would diminish as a study
gets larger.

2.  Please discuss the clinical relevance of the sponsor's choice of
    secondary endpoints for evaluating a therapy for CHF. Are there
    specific secondary endpoints, such as peak VO2, that should be more
    heavily weighted in the assessment of the device?

The panel did not find any of these endpoints conclusive and noted that
many others were discussed in the last panel meeting on the InSync
device, such as echocardiographic assessment or change in mitrocardial
regurgitation. Some panel members emphasized that the dialogue over
endpoints and denominators should occur early, in the pre-IDE stage,
because a prospective clinical trial has to be evaluated by its design.
In answer to an FDA request for clarification, the panel added that
there is no non-mortality endpoint that is consistently compelling
across trials and that multivariate endpoints are acceptable.

3.  Please comment on whether the results of the clinical study support
    the effectiveness of the device for the treatment of patients with
    medically stable Class III/IV CHF.

Concerns remained that the data set was incomplete and failed to answer
all issues, but a slim majority thought the results within the
constraints of the prespecified and multiple endpoints supported
efficacy of the device.

**Safety of the System in Treating CHF**

4.  When evaluating the safety of the device, one concern is whether the
    treatment contributes to the worsening of CHF. Please comment on
    whether the results support the safety of the system for treating
    CHF in the population studied.

The consensus of the panel was that there was no evidence that the
treatment worsens CHF within the six-month timeframe. Beyond six months,
there were no data.

**Effectiveness of the System as an ICD**

5.  Please comment on whether the sponsor has provided adequate
    information to assure that there is no interference of proper ICD
    functionality with the addition of biventricular pacing, and that
    both biventricular pacing and ICD therapy can be delivered
    simultaneously.

The panel stated that they had insufficient data in this area to answer
the question, including rates of inappropriate shocking.

6.  Please discuss whether you have any comments or recommendations
    regarding programming considerations for the device.

Various ideas were suggested such as a relative contraindication for
device use with very slow ventricular tachycardia, but ultimately the
panel agreed that they had insufficient data to answer this question and
recommended more data collection.

**Safety of the System**

7.  Please comment on whether the results provide a reasonable assurance
    of the safety of the Model 7272 ICD pulse generator.

The panel had no concerns about the safety of the pulse generator.

8.  Please comment on whether the results provide a reasonable assurance
    of the safety of the Model 4189 lead.

The panel recommended that more information be gathered on lead-related
complications.

**Safety of the System**

9.  The sponsor has provided analyses of the system-related
    complications at six months and the adverse events (complications
    and observations) reported in the clinical study. Please comment on
    whether the results provide a reasonable assurance of the safety of
    the InSync ICD System.

The panel recommended a plainer explanation of the data and said that
they were unsure what the risk of reoperation was and what patient
expectations should be with the average practitioner. The data should be
structured with recognition that the indicated population warrants ICD
placement and with attention to what else is needed to structure
biventricular pacing.

**Risk-Benefit of the System for Treatment of CHF**

10. Please discuss the overall risk-benefit of the system.

The panel remained concerned with the numerator, saying that its
magnitude was still unclear.

**Labeling**

11. If you recommend approval of the device, please address the
    following questions,

```{=html}
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a.  Do the Indications for Use adequately define the patient population
    studied?

> In addition to the proposed indications, the panel recommended two
> additional bullets stating that

-   This device is intended for people requiring an ICD

-   This device in the setting of heart failure improves quality of life
    and may improve NYHA classification.

b.  Based on the clinical experience, should there be additional
    contraindications, warnings and precautions for the use of the
    InSync Model 7272 ICD System?

> The panel recommended that the warnings should include the additional
> risk compared to an ICD in terms of the lead. It should also be stated
> that the benefits of this device are known to extend to six months.

c.  Please comment on the operator instructions as to whether they
    adequately describe how the device should be used to maximize the
    benefits and minimize adverse events.

> The panel recommended operator training similar to that required for
> the InSync device, to include a didactic program, use with animal
> models, and a center for training.
>
> **Labeling**

d.  Please provide any other recommendations or comments regarding the
    labeling.

> The panel had no additional remarks.

**Post-Market Study**

13\. With approval of the Medtronic In Sync biventricular pacing system
FDA and the sponsor agreed on the following post-approval conditions: a)
obtaining 12-month mortality data on the IDE cohort, and b) performing a
three-year evaluation of mortality and chronic lead performance,
including electrical performance and adverse events, on 1,000 patients.
If you recommend approval, please comment on whether additional clinical
follow-up or post-market studies are necessary for this device.

# This question was deferred until the vote.

# Closing Sponsor Remarks

Sponsor representatives thanked the panel and added that further
documentation requested would be provided on the interaction between
biventricular pacing and the ICD. They added that there is a meaningful
clinical effect with device use, not just a statistically significant
effect, for these two overlapping populations.

## Closing Comments from the Consumer and Industry Representatives

## Consumer Representative Robert Dacey noted that more work is being done to define quality of life, which is a core issue for this population. He urged the sponsors to simplify the patient manual.

## Open Public Hearing

There were no requests to speak.

## Panel Recommendations and Vote

**Dr. Ewing** read the panel the regulatory definitions and voting
instructions. A motion was made by **Dr. Pina** and seconded by **Dr.
Konstam** to recommend the PMA as not approvable because the data set
did not provide a concordance of data showing benefits for patients who
need an ICD. She also stated concerns over the amount of patients who
had crossover and that fact that the improvement in quality of life may
reflect a small number of patients who received real benefit from the
therapy. This motion initially resulted in a tie, which **Acting Panel
Chairperson Dr. Laskey** resolved by voting against the motion, which
then failed.

A motion was then made by **Dr. Nissen** and seconded by **Dr.
Domanski** to recommend the PMA as approvable subject to the following
conditions:

1)  A postmarketing study as defined in FDA question 13 with 12-month
    mortality data would be performed. This condition carried
    unanimously.

2)  A data set on the interaction of the ICD function and the
    synchronization pacing function would be completed and brought to
    the FDA for review. This condition carried unanimously.

3)  The complete data set regarding the safety of the lead and a clearly
    aggregated combined risk of lead placement failure and in toto
    device risk should be reported to the FDA. This condition carried
    unanimously.

4)  The sponsor should provide to the FDA in writing documentation of
    the agreement on the stopping point of the study. This condition
    carried unanimously.

> The motion to recommend the PMA as approvable subject to the four
> conditions above resulted in a tie vote, which **Acting Panel
> Chairperson Dr. Laskey** resolved in favor of the motion. The motion
> thus passed by a vote of six to five.

**Dr. Laskey** thanked those present and adjourned the Open Session at
3:30 p.m.

I certify that I attended the Open Session of the Circulatory Systems
Devices Panel Meeting on March 4-5, 2002, and that this summary
accurately reflects what transpired.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Lesley Ewing, M.D.

Executive Secretary

I approve the minutes of this meeting as recorded in this summary.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Warren K. Laskey, M.D.

Acting Panel Chairperson

Aileen M. Moodie

9821 Hollow Glen Pl.

Silver Spring, MD 20910

301-587-9722