**SUMMARY MINUTES**

**OF THE**

**CIRCULATORY SYSTEM DEVICES**

**ADVISORY PANEL MEETING**

**OPEN SESSION**

**JUNE 19-20, 2000**

**Gaithersburg Hilton**

**620 Perry Parkway**

**Gaithersburg, MD**

**CIRCULATORY SYSTEM DEVICES ADVISORY PANEL MEETING**

**June 19, 2000**

**PANEL PARTICIPANTS**

**CHAIRPERSON**

Anne B. Curtis, M.D.

University of Florida

**EXECUTIVE SECRETARY**

Megan Moynahan, M.S.

Food and Drug Administration

**VOTING MEMBERS**

Michael D. Crittenden, M.D.

Harvard University

Renee S. Hartz, M.D.

Tulane Medical Center

Tony W. Simmons, M.D.

Wake Forest University

**CONSULTANTS (Temporary Voting Status)**

Kent R. Bailey, Ph.D.

Mayo Clinic

Michael J. Domanski, M.D.

National Institutes of Health

Cynthia M. Tracy, M.D.

Georgetown University Hospital

Melvin L. Griem, M.D.

University of Chicago

Minesh P. Mehta, M.D.

University of Wisconsin---Madison

Alfred F. Parisi, M.D.

Miriam Hospital and Brown University

Kenneth E. Najarian, M.D.

University of Vermont College of Medicine

J. Frank Wilson, M.D.

Medical College of Wisconsin

## Industry Representative

## Gary Jarvis

St. Jude Medical

# Consumer Representative

Robert A. Dacey

Longmont, California

# Guest 

# Robert L. Ayres

U.S. Nuclear Regulatory Commission

**FOOD AND DRUG ADMINISTRATION**

James E. Dillard III

Director, Division of Cardiovascular, Respiratory, and Neurological
Devices

Brian E. Harvey, M.D.

Chris M. Sloan

John E. Stuhlmuller, M.D.

Kimberly B. Peters

Henry T. Heaton II

Gary L. Kamer

Marian S. Linde, R.N.

**OPEN SESSION---JUNE 19, 2000**

**Anne B. Curtis, M.D., Chairperson**, called the meeting to order at
10:05 a.m. **Executive Secretary Megan Moynahan** read the conflict of
interest statement, noting that waivers allowing full participation had
been granted to Drs. Hartz and Parisi for their interests in firms
potentially affected by the day's deliberations. Other matters
concerning Drs. Curtis, Mehta, and Najarian were also considered but
deemed unrelated and their full participation would be allowed. Ms.
Moynahan read the appointment to temporary voting status for Drs.
Bailey, Domanski, Tracy, Griem, Mehta, Parisi, Najarian, and Wilson.
Panel Chairperson Dr Curtis asked members of the panel to introduce
themselves.

OPEN PUBLIC HEARING

There were no requests to address the panel.

OPEN COMMITTEE DISCUSSION---PMA P990036 FOR CORDIS CORPORATION'S
CHECKMATE SYSTEM

Sponsor Presentation

Dr. Dennis Donohoe, vice president for clinical research at Cordis, gave
the presentation overview. He discussed the problem of in-stent
restenosis, noting that there are no effective therapies available, that
the patient population is growing and experiences recurrent admissions,
and that the pathology is well understood. Dr. Donohoe noted that
radiation therapy has been used for about 100 years in treatment of
malignancies and that there is a sizeable body of knowledge about
handling of radioactive sources and clinical response to benign
hyperproliferative lesions. He discussed the selection of gamma
radiation and the radiation procedure and described the source ribbons,
catheter, and delivery device used. Dr. Donohoe stressed the team of
experts used to ensure medical, radiation, and oncology expertise, and
he also outlined the regulatory history of the device. He stated that
the three randomized, double-blinded placebo controlled trials had shown
overwhelming efficacy and durability of treatment in a difficult patient
population with no alternative therapies and that risk was manageable by
avoiding placement of new stents during the procedure and providing
extended antiplatelet therapy.

Dr. David R. Holmes, Jr., of the Mayo Clinic gave the sponsor's clinical
review. He discussed the mechanism and frequency of in-stent restenosis
and gave specific case histories, as well as summarizing factors
associated with in-stent restenosis and current treatment options.
Clinical data were provided by three randomized, placebo-controlled,
double-blind trials conducted with the Ir-192 radiation system, which
were overseen by an independent safety board and angiographic core lab.

Dr. Holmes explained the evolution, design, and clinical demographic
variables of the three trials, known as SCRIPPS I, WRIST, and GAMMA I.
He also gave in-stent and in-lesion restenosis rates at six months and
major adverse coronary events (MACE) for the SCRIPPS I and WRIST I
trials, as well as similar data for the GAMMA I trial. In addition he
described the influence of lesion length and diabetes on in-lesion
restenosis for the GAMMA I trial, and freedom from MACE at two years for
the WRIST and GAMMA I trials. He concluded that the device showed
concordant angiographic and clinical efficacy in all three studies, as
well as durability and efficacy across a wide range of patient
populations. On safety, Dr. Holmes reviewed a summary of all deaths in
the three trials based on an intention to treat analysis and reviewed
all individual deaths in the GAMMA I trial. In particular he analyzed
myocardial infarctions (MIs) associated with late thrombosis in the
GAMMA I trial. He noted that one death in the radiation group was
possibly associated with late thrombosis and that there is an overall
higher rate of MI in the radiation group because of the occurrence of
late thrombosis. Dr. Holmes stated that long-term (three-year)
angiographic follow-up in the SCRIPPS I trial showed no aneurysms or
perforations. On radiation safety, he noted there had been no device
failures, no Nuclear Regulatory Commission (NRC) reportable events, and
no aborted procedures in the 1,000 patients treated to date.

Dr. Richard Kuntz of Brighams and Women's Hospital discussed specific
clinical issues. He analyzed the issue of defining late total occlusions
and late thrombosis, noting that late thrombosis is the most specific
endpoint. He examined the GAMMA I trial results on late total occlusions
and showed that a multivariate analysis of determinants for late
thrombosis and late occlusions showed no significant predictors. Dr.
Kuntz also examined the pooled data from all three trials, after
justifying such pooling, which identified factors associated with late
thrombosis and allowed the hypothesis that it could be prevented by
avoidance of new stent placement in conjunction with radiation. Dr.
Kuntz also discussed the role of antiplatelet therapy in the prevention
of late thrombosis by using prospective data from the SCRIPPS III
registry and the WRIST Plus registry. He concluded that the rate of late
thrombosis for radiation without new stent placement is comparable to
placebo, that late thrombosis is largely confined to patients who
received a new stent at time of radiation therapy, and that extended
antiplatelet therapy helps prevent late thrombosis.

Dr. Holmes concluded that there is a major clinical need for the device
and no alternative therapies. The device showed marked and concordant
efficacy in all three trials in high-risk patients and showed durability
over a two- to three-year follow-up. Safety was shown in over 1,000
procedures without a bailout or reportable event and through three-year
angiographic follow-up that showed no radiation injury to vessels. Late
thrombosis, which was an unanticipated event for the GAMMA I trial, is
preventable by avoidance of new stent use and extended antiplatelet
therapy. He concluded that risk could be managed through a warning in
the labeling, a physician training program, and provision of updated
information through postmarket surveillance.

FDA Presentation

John E. Stuhlmuller, M.D., introduced the multidisciplinary FDA review
team. He listed the four categories of the nonclinical evaluation: in
vitro testing, biocompatibility testing, animal testing, and source
dosimetry, noting that most issues had been satisfactorily addressed.
Sponsors have agreed in principle to revisions the FDA has requested on
source dosimetry in the labeling.

The FDA clinical evaluation focused primarily on the SCRIPPS I
feasibility trial and the GAMMA I pivotal efficacy trial, but included
data from the WRIST, SCRIPPS-III, WRIST Plus, and pooled analysis. Dr.
Stuhlmuller described the SCRIPPS I study, noting that 60 patients were
enrolled and stratified into eight subgroups for analysis and followed
at four to six months. He noted two cases of stent thrombosis and the
resulting proposed lengthening of post-procedure anticoagulation from 14
days to eight weeks. Outstanding issues from the SCRIPPS report included
the poolability of data across the subgroups and the interpretation of
the pooled analysis of the six-month and three-year angiograms.

Dr. Stuhlmuller also described the GAMMA I study on 252 patients with
angiographic and clinical follow-up at six and nine months. He described
the study endpoints and noted that issues with the GAMMA I report
included modification of definitions of myocardial infarction (MI) and
target lesion revascularization (TLR) and duration of clinical
follow-up.

On evaluation of safety and effectiveness, Dr. Stuhlmuller asked the
panel to discuss how to evaluate study endpoints such as late total
occlusion and late stent thrombosis and the edge effect, given the
multiple definitions used during the studies. He summarized data from
the GAMMA I study on effectiveness, edge effect, safety, and clinical
benefit versus risk and read the panel questions for discussion.

Panel Clinical Review---Dr. Michael Domanski

Dr. Domanski noted that the problem of in-stent restenosis is acute and
there is no effective treatment. He raised a number of issues, including
whether the device is safe and whether it prevents or reduces target
lesion revascularization (TLR). For him, the central issue was that the
device appears to reduce TLR, but more patients in the device group die
or have a myocardial infarction. Dr. Domanski expressed other concerns
over the poolability of data over the subgroups of patients and over the
duration of time proposed. He was unsure that death and myocardial
infarction statistics should be pooled and concerned about the low
numbers and low power of the study, which prevent an analysis of death
versus myocardial infarction incidence. He concluded that it was
important for the panel to be convinced of device safety regarding death
and myocardial infarction because the study numbers are so small.

Other panel questions concerned the distribution of types of TLR, the
total duration of the procedure, the change in definitions and study
design during the protocol, the proposed postmarket surveillance
program, and the lack of animal studies. Some concerns were expressed
over the efficacy data and the need for further studies. Issues
involving labeling, dosage range, and the physicians' training program
were noted, as was the need for maximizing information presented to
consumers as well as physicians.

OPEN PUBLIC HEARING

There were no requests to speak.

OPEN COMMITTEE DISCUSSION (resumed)

FDA Questions to the Panel

The panel agreed that the definitions for myocardial infarction and
target lesion revascularization used in the trial were adequate to
assess the clinical performance of the device. In answer to the second
question, panel members noted that the company now states it is
providing angiographic and clinical follow-up at and beyond nine months.
The panel had some debate over the meaningfulness of the definitions of
late thrombosis and late total occlusion but agreed that there is no
better way known to tease out any difference between the phenomenon
without immediate clinical observation. They therefore thought the
definitions as adequate as possible to differentiate late stent
thrombosis from late total occlusion.

The panel thought the definition used to quantify edge effect was not
adequate as given, but actual measurement of the edge effect is possible
if required.

The panel agreed that the warning should be revised to include
information as it becomes available on late thrombosis. The warning
should note that the optimal length of antiplatelet therapy is unknown
but an important factor in treatment.

The consensus of the panel was that the probable clinical benefit of the
radiation treatment outweighs the probable risks posed by the device in
the intended patient population.

On the proposed labeling, the panel suggested that one warning be
revised to read: "Do not use in patients who underwent previous
intravascular brachytherapy of the same vessel segment or previous
radiation treatment in the immediate vicinity of the targeted vessel."
In addition, they suggested a modification to another warning to read:
"Do not use in patients with known genetic radiation sensitivity
disorders (e.g., ataxia-telangiectasia, etc)."

The panel agreed that a physicians' training program is critically
important and that the device must be used by a multidisciplinary team.
Cooperation between the FDA and the NRC on the specifics of regulations
that authorize the handling of radiation sources and cooperation through
a multidisciplinary approach are likely to continue, as the NRC
regulations on prescription of dose calculation and verification are
still unfolding. There is an ACGME training program for cardiologists
and physicians in handling radioisotopes, which is linked to training
and licensing in the ACGME-approved training program in radiation
oncology.

The panel agreed that postmarket evaluation should include angiograms
and specific evaluation of the irradiated area as well as clinical
follow-up of chronic effects of intravascular radiation on the 650
patients of the GAMMA I trial. One long-term routine angiogram three to
five years for all 650 patients to look for potential aneurysm formation
was suggested. Some members suggested that information on function tests
could be provided if available, although there was less panel agreement
on this. It was not thought necessary to follow up the placebo patients,
although follow-up on patients to look for repeated incidents as
specified in the protocol should be performed.

**SPONSOR CLOSING COMMENTS**

There were no requests to address the panel.

## FDA CLOSING COMMENTS

There were no requests to address the panel.

## PANEL VOTING INSTRUCTIONS AND OPTIONS

**Panel Executive Secretary Megan Moynahan** read the voting options and
instructions.

A motion was made and seconded to recommend the PMA as approvable with
conditions. The conditions were as follows:

1)  Labeling should be amended as discussed above.

2)  A multidisciplinary team approach should be required to include
    physicians and radiation specialists such as an interventional
    cardiologist, physicist, and oncologist. The sponsor would provide
    training in a regulated fashion to the team in the hospital setting.
    This would not just be to meet the criteria for handling of the
    isotope but also for training in the procedure.

3)  Postmarketing surveillance would be mandatory, with the FDA
    standardizing details of the surveillance with the sponsors, but
    including at a minimum postmarket study of antiplatelet treatment
    and postapproval data on the premarket cohort for at least five
    years. Various specific additional suggestions were made but not
    necessarily agreed to, including clinical follow-up of the original
    cohort of GAMMA I patients for long-term adverse events, postmarket
    surveillance of control patients surveyed in cohort 1 in subsequent
    trials, and follow-up of both arms of all trials, especially
    GAMMA I. There was no clear panel agreement on a registry.

The motion to recommend the PMA as approvable subject to the above
conditions passed, with a strong recommendation for the FDA to look at
experimental models of radiographic long-term patient handling.

FDA representatives thanked the panel members and the audience
presenters.

Panel Chairperson Dr. Curtis adjourned the panel for the day at 5:10
p.m.

**CIRCULATORY SYSTEM DEVICES ADVISORY PANEL MEETING**

**June 20, 2000**

**PANEL PARTICIPANTS**

**CHAIRPERSON**

Anne B. Curtis, M.D.

University of Florida

**EXECUTIVE SECRETARY**

Megan Moynahan

Food and Drug Administration

**VOTING MEMBERS**

Michael D. Crittenden, M.D.

Harvard University

Renee S. Hartz, M.D.

Tulane Medical Center

Tony W. Simmons, M.D.

Wake Forest University

**CONSULTANTS (Temporary Voting Status)**

Kent R. Bailey, Ph.D.

Mayo Clinic

Michael J. Domanski, M.D.

National Institutes of Health

Cynthia M. Tracy, M.D.

Georgetown University Hospital

George W. Vetrovec, M.D.

Medical College of Virginia

## Industry Representative

## Gary Jarvis

St. Jude Medical

# Consumer Representative

Robert A. Dacey

Longmont, California

**FOOD AND DRUG ADMINISTRATION**

James E. Dillard III

Director, Division of Cardiovascular, Respiratory, and Neurological
Devices

Michael G. Bazaral, M.D.

Brian E. Harvey, M.D.

Chris M. Sloan

John E. Stuhlmuller, M.D.

Kimberly B. Peters

Henry T. Heaton II

Gary L. Kamer

**OPEN SESSION---JUNE 20, 2000**

**Panel Chairperson Dr. Anne Curtis** called the Open Session to order
at 10:15 a.m.

**Mr. James Dillard, director of the Division of Cardiovascular and
Respiratory Devices,** showed an organization chart of the division,
noting that it has been reorganized and new personnel added. He noted
that three issues were discussed at the last panel meeting, which sought
panel input on clinical trial design on rate responsive pacemakers,
spinal cord stimulators for treatment of angina, and treatment of atrial
fibrillation. He stated that the outcome of that meeting had been
helpful both to the FDA and to industry, and he hoped to see more of
such meetings in the future. Mr. Dillard presented letters of
appreciation and certificates to outgoing panel member Dr. Tony Simmons
and outgoing panel chairperson Dr. Anne Curtis.

**Panel Executive Secretary Megan Moynahan** read the conflict of
interest statement, noting that waivers had been granted to Drs. Curtis,
Hartz, and Vetrovec, and that matters concerning Drs. Curtis, Vetrovec,
Tracy, and Laskey had been considered but deemed unrelated and their
full participation would be allowed. Dr. Curtis asked the panel members
to introduce themselves.

## OPEN COMMITTEE DISCUSSION---MODIFICATION TO DRAFT GUIDANCE FOR IMPLANTABLE CARDIOVERTER DEFIBRILLATORS

**Mr. Mike Bazaral** **of the FDA's Division of Cardiovascular and
Respiratory Devices** read the indications for implantable cardioverter
defibrillators (ICDs) and the study entry criteria. He noted an
exception for one company, Guidant, which has an additional patient
population. Mr. Bazaral also read the proposed functional indication for
use that does not attempt to specify which patients are at risk of
life-threatening ventricular arrhythmias and proposed modifying the
guidance document to include that functional indication. Mr. Bazaral
reviewed four implicit assumptions and read similar functional intended
use statements for artificial heart valves and coronary balloon
angioplasty devices. He noted that the functional intended use statement
for ICDs would be incorporated in the ICD guidance, adding that the
proposed indication would replace the current indications in the
guidance document and could, at the manufacturer\'s request, replace the
indications for use on currently marketed devices.

## OPEN PUBLIC HEARING

**Hugh Calkins, M.D. of Johns Hopkins University and representing the
North American Society for Pacing and Electrophysiology (NASPE),**
discussed the proposed indications for implantable cardioverter
defibrillators (ICDs). After a brief review of the function of NASPE,
Dr. Calkins stated that NASPE supports the FDA proposed revision to the
indications for ICD use. He stated that NASPE agrees with the FDA
rationale for the proposed change, which is that current indications for
ICD use are out of date vis a vis current clinical practice. He
discussed several studies that pertain to the proposed change, such as
the AVID trial, AVID registry, and other smaller studies. The rationale
for NASPE's support of the proposal, he said, was that NASPE recognizes
that the decision to implant an ICD is a medical decision made by
patients and their physicians made on the most current clinical
evidence. Professional organizations such as NASPE publish guidelines on
the indications for ICD implantation that are updated on a regular
basis, and these guidelines also prevent overuse by the medical
community.

**Dr. John Fisher of Montefiore and representing Medtronic** discussed
the current FDA labeling indications and the proposed changes, as well
as the FDA rationale. He listed the potential advantages from a
clinician's perspective, which included broader ability to decide on
appropriate treatment in an individual case. As a potential clinical
disadvantage, he noted the potential for "overuse" of ICDs but said that
the medical community has safeguards against such overuse, including
professional guidelines. Dr. Fisher stated that as a clinician he
supported the proposed change.

**Dr. Marshall Stanton of Medtronic** said that he agrees that the
proposed labeling should be adopted. He listed the potential advantages
from the industry perspective, which included consistency of indications
and promotion of industry cooperation. One potential disadvantage he
cited could be discouragement of clinical research on specific high-risk
patient populations, but he noted that manufacturers and physicians are
committed to supporting clinical research. He concluded that Medtronic
strongly supports the proposed change as consistent with current
clinical practice, as enhancing timely dissemination of clinical trial
data, and as decreasing the regulatory burden.

**Dale DeVries of Guidant**, a company involved in pioneering the
technology, stated that Guidant supports the proposed FDA change. He
noted that patients have the most to gain by the change in that
physicians would then have the flexibility to treat patients at high
risk. He agreed with representatives from Medtronic that the proposed
change may actually facilitate trials.

## OPEN COMMITTEE DISCUSSION

Panel members asked why the matter was brought to panel, given that the
FDA and major manufacturers all agree on the proposed change.

**Mr. Dillard** stated that he heard the very strong consensus of the
panel in support of the FDA's making the proposed change. He clarified
that while there will no longer be a need for a PMA supplement for a
population substudy, there would be a need for some interaction with a
sponsor prior to a new indication, and there might still be a need for
PMA supplements in the future.

**Dr. Stanton of Medtronic** asked Mr. Dillard to clarify whether a PMA
supplement would be needed as long as the promotional data were not
related to a specific claim. Mr. Dillard replied that it would still be
necessary to check with the FDA; the change means that a supplement is
no longer mandatory but still must be discussed with the FDA.

**Dr. Hartz** suggested adding the word "documented" to the last line of
the proposed intended use statement to read "treatment of a documented
life-threatening ventricular arrhythmia," but the rest of the panel
disagreed because of the difficulty involved in such documentation.

**Mr. DeVries of Guidant** clarified that a manufacturer can still
submit a specific feature for an indication or for a specific patient
population, and Mr. Dillard agreed that manufacturers can do so, but it
is no longer a necessity.

After reiterating the panel's support for the proposed change, Panel
Chairperson Dr. Curtis adjourned the session at 11:15 a.m.

> I certify that I attended the Open Session of the Circulatory Systems
> Devices Panel Meeting on June 19-20, 2000, and that this summary
> accurately reflects what transpired.
>
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Megan Moynahan.

Executive Secretary

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

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

Anne B. Curtis, M.D.

Chairperson

­­­­­

Executive Summary prepared by

Aileen M. Moodie

9821 Hollow Glen Pl.

Silver Spring, MD 20910

301-587-9722