UNITED STATES OF AMERICA

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FOOD AND DRUG ADMINISTRATION

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CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

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MEDICAL DEVICES ADVISORY COMMITTEE

CIRCULATORY SYSTEM DEVICES PANEL

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OPEN SESSION

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Thursday

March 6, 2003

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The meeting came to order in Salons A, B, and C of the Gaithersburg
Marriott, 9751 Washingtonian Boulevard., Gaithersburg, Maryland, at
10:30 a.m. Warren K. Laskey, M.D., Temporary Chair, presiding.

PRESENT:

WARREN K. LASKEY, M..D. Temporary Chair

SALIM AZIZ, M.D. Voting Member

CYNTHIA TRACY, M.D. Voting Member

MARK C. HAIGNEY, M.D. Voting Member

CHRISTOPHER J. WHITE, M.D. Voting Member

GEORGE W. VETROVEC, M.D. Voting Member

RICHARD LEIGHTON PAGE, M.D. Voting Member

ALBERT WALDO, M.D. Voting Member

FRANCIS R. GILLIAM, III, M.D. Voting Member

MITCHELL W. KRUCOFF Voting Member

MERCEDES DULLUM, M.D. Voting Member

KENT R. BAILEY, Ph.D. Voting Member

GERETTA WOOD Executive Secretary

MICHAEL MORTON Industry Representative

ALLEN A. HUGHES, Ph.D. Consumer Representative

BRIAN ZUCKERMAN Director, Division of Cardiovascular Devices

FDA PARTICIPANTS:

JAMES CHENG Lead Reviewer

LESLIE EWING, M.D. Clinical and Animal Review

LILLY YUE, Ph.D. Statistical Review

CINDY DEMIAN Biocompatability Review

ELAINE MAYHALL Sterilization Review

KEVIN HOPSON Bioresearch Monitoring Review

SPONSORS:

JEAN-PIERRE DESMARAIS, M.D. Vice President, Scientific Affairs, CryoCath
Technologies, Inc.

JEREMY RUSKIN, M.D. Massachusetts General Hospital

MARC DUBUC, M.D. Montreal Heart Institute

PETER FRIEDMAN, M.D., Ph.D. Harvard Medical School

MARWAN ABBOUD Director of Engineering, CCT

PATRICK CHAUVET Pre-clinical Scientist, CCT

SUSAN BONDY Consultant, Cato Research

ANDREW SKRYLOV Consultant, Cato Research

RICHARD HOLCOMB, Ph.D. Consulting Statistician

JOHN LEHMANN, M.D. Consultant, CCT Medical Director

JOSE NAZARI, M.D. Illinois Masonic Hospital, Chicago

MARK NIEBAUER, M.D. University of Nebraska, Omaha

DAVID KEANE, M.D. MGH, Boston

[C O N T E N T S]{.underline}

Call to Order 6

Warren K. Laskey, M.C.

Introduction of Members 9

Open Public Session 12

Sponsor Presentation: 13

CryoCath Technologies, Inc.,

P020045, 7F Freezer Cardiac

Cryoablation Catheter

Jean-Pierre Desmarais, M.D. 13, 24, 55

Jeremy Ruskin, M.D. 17

Marc Dubuc, M.D. 27

Peter Friedman, M.D. 31

FDA Presentation: 57

James Cheng 57

Leslie Ewing, M.D. 63

Lilly Yue, Ph.D. 70

Question-and-Answer Period 84

Open Committee Discussion 129

[C O N T E N T S]{.underline}

Open Committee Discussion 188

Sponsor Comments 259

Industry and Consumer Representatives\' 259

Comments

Open Public Session 262

Recommendations and Vote 262

[P R O C E E D I N G S]{.underline}

10:41 a.m.

CHAIRMAN LASKEY: Good morning. I would like to call us to order.

The topic before us is a PMA for the CryoCath Technologies\' 7 French
Freezor Cardiac Cryoablation Catheter, P020045.

I would like to ask Ms. Wood to read the paragraph regarding the Chair,
Committee, and conflict-of-interest statement. Ms. Wood, please.

MS. WOOD: Just a couple of reminders: If you haven\'t signed in at the
table outside, please do so. Also, please turn your cell phones to
silent or off during the meeting. Thank you for your cooperation.

Dr. Cynthia Tracy has been excluded from chairing recent meetings as a
result of the regulation governing covered appearance relationships.
Since it is expected that for most future Panel meetings Dr. Tracy\'s
covered relationship will continue to preclude her from functioning
fully as the Panel Chair, she has graciously stepped down as
Chairperson, but will continue as a voting member of the Panel until the
expiration of her term. Dr. Warren Laskey will be the Temporary Voting
Chair for this meeting.

The following announcement addresses conflict-of-interest issues
associated with this meeting and is made part of the record to preclude
even the appearance of an impropriety. To determine if any conflict
existed, the agency reviewed the submitted agenda for this meeting and
all financial interests reported by the Committee participants.

The conflict-of-interest statutes prohibit special government employees
from participating in matters that could affect their or their
employer\'s financial interest. The agency has determined, however, that
the participation of certain members and consultants, the need for whose
services outweighs the potential conflict-of-interest involved, is in
the best interest of the government. Therefore, waivers have been
granted for Drs. George Vetrovec, Kent Bailey, Mercedes Dullum, and
Albert Waldo for their interest in firms that could be affected by the
Panel\'s recommendations.

Dr. Vetrovec\'s waiver involves stock in the parent of a competitor. The
stock is valued from \$50,001 to \$100,000.

Dr. Bailey\'s waiver involves a grant to his institution for the
sponsor\'s product study in which he had no involvement and for which
funding was between \$100,001 and \$300,000 per year.

Dr. Dullum\'s waiver involves stock in a competitor. The stock is valued
from \$25,001 to \$50.000.

Dr. Waldo\'s waiver involves consulting for a competitor\'s unrelated
product, for which he receives an annual fee of less than \$10,001.

Copies of these waivers may be obtained from the agency\'s Freedom of
Information Office, Room 12A‑15 of the Parklawn Building.

We would like to note for the record that the agency took into
consideration other matters involving Drs. Vetrovec, Dullum, Mark
Haigney, Mitchell Krucoff, and F. Roosevelt Gilliam. Each of these
panelists reported interests in firms at issue, but in matters that are
not related to today\'s agenda.

The agency has determined, therefore, that they may participate fully in
all discussions. In the event that the discussions involve any other
products or firms not already on the agenda for which an FDA participant
has a financial interest, the participant should excuse him or herself
from such involvement, and the exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of
fairness that all persons making statements or presentations disclose
any current or previous financial involvement with any firm whose
products they may wish to comment upon.

CHAIRMAN LASKEY: Thanks, Geretta.

At this point I would like to have the Panel members introduce
themselves, starting to my left, please.

DR. ZUCKERMAN: Brian Zuckerman, FDA, Division Director, Cardiovascular
Devices.

DR. GILLIAM: Roosevelt Gilliam with the Virginia Cardiovascular
Specialists in private practice of electrophysiology, Richmond,
Virginia.

DR. PAGE: Rick Page, Cardiac Electrophysiologist, now at the University
of Washington in Seattle.

DR. WALDO: I\'m Al Waldo, Cardiac Electrophysiologist, Case Western
Reserve University in Cleveland.

DR. BAILEY: Kent Bailey, Biostatistician at Mayo Clinic.

MS. WOOD: Geretta Wood, Exec. Sec. of the Circulatory System Devices
Panel.

CHAIRMAN LASKEY: Warren Laskey. I\'m an Interventional Cardiologist at
the National Naval Medical Center.

DR. WHITE: Chris White. I\'m an Interventional Cardiologist in the
Ochsner Clinic Foundation in New Orleans, Louisiana.

DR. VETROVEC: George Vetrovec, Chairman, Division of Cardiology,
Virginia Commonwealth University.

DR. DULLUM: Mercedes Dullum, Cardiac Surgeon, cryo practice, Washington
Hospital Center.

DR. TRACY: I\'m Cindy Tracy. I\'m at Georgetown University Hospital, and
I not so graciously did try to get my brother fired, but it didn\'t
work.

(Laughter.)

DR. HAIGNEY: I\'m Mark Haigney. I\'m a Cardiac Electrophysiologist at
the National Naval Medical Center and Director of Cardiology at
Uniformed Services University.

DR. HUGHES: Alan Hughes, Assistant Professor of Decision Sciences and
MIS at George Mason University, and I\'m the consumer representative.

MR. MORTON: I\'m Michael Morton. I\'m an employee of Sorin-COBE
Cardiovascular, and I\'m the industry representative to the Panel.

CHAIRMAN LASKEY: Thank you, colleagues.

Geretta, if you could read the voting status statement, please?

MS. WOOD: \"Pursuant to the authority granted under the Medical Devices
Advisory Committee charter, dated October the 27th, 1990, and as amended
August the 19th, 1999, I appoint the following individuals as voting
members of the Circulatory System Devices Panel for this meeting on
March the 6th, 2003:

\"Mark C. Haigney, M.D.; Christopher J. White, M.D.; George W. Vetrovec,
M.D.; Kent R. Bailey, Ph.D.; Mitchell W. Krucoff, M.D.; Richard L. Page,
M.D.; Albert L. Waldo, M.D.; Francis R. Gilliam, M.D., and Mercedes K.
Dullum, M.D.

\"For the record, these individuals are special government employees and
are consultants to this Panel under the Medical Devices Advisory
Committee. They have undergone the customary conflict-of-interest review
and have reviewed the material to be considered at this meeting.

\"In addition, I appoint Warren K. Laskey, M.D., to act as Temporary
Chairperson for the duration of this meeting.\"

And it is signed by David W. Feigal, Jr., M.D., MPH, Director, Center
for Devices and Radiological Health, on February 26th, 2003.

CHAIRMAN LASKEY: I would like to open the public hearing portion of this
morning\'s program. Is there anyone in the audience who wishes to
address the Panel on today\'s topic or any reasonably-germane topic?

(No response.)

If not, then I will close the open public hearing session.

I would like to begin with the sponsor\'s presentation.

MS. WOOD: I would also like to remind the speakers to introduce
themselves and to state your conflict of interest before speaking.

DR. DESMARAIS: Good morning, ladies and gentleman, Mr. Chairman, and
Panel members.

My name is Jean-Pierre Desmarais. I am CryoCath Vice President of
Scientific Affairs. It is my pleasure to present our technology to this
Panel. As well, we will present the results of our pivotal study. Here
is the agenda of the meeting:

I\'m introducing the group. Then we will present the evolution of
technology, the details of the freezor device, a brief synopsis of the
pre-clinical testing, the pivotal clinical study, and a few concluding
remarks.

The presenters will be myself, Dr. Jeremy Ruskin, Director, Cardiac
Arrhythmia Service, Massachusetts General Hospital.

Dr. Marc Dubuc, Co-Principal Investigator, Chief of Electrophysiology
Service, Montreal Heart Institute.

Dr. Peter Friedman, Co-Principal Investigator, also Professor of
Medicine, Harvard Medical School, Brigham and Women\'s Hospital.

Also available for questions will be from CryoCath: Marwan Abboud,
Director of Engineering; Patrick Chauvet, Pre-Clinical Scientist.
Consultants: Susan Bondy, VCRA, Cato Research; Andrew Skrylov, Study
Statistician, Cato; Richard Holcomb, Consulting Statistician; John
Lehmann, Consultant, CryoCath Medical Director.

Investigators present with us as well are: Dr. Jose Nazari from Illinois
Masonic Hospital in Chicago; Dr. Mark Neibauer, University of Nebraska,
Omaha, and Dr. David Keane from Massachusetts General Hospital in
Boston.

CryoCath is a public-traded company that was founded in 1995 and which
counts over 150 employees now. CryoCath designs, develops, manufactures,
and distributes products from its location in Montreal, Canada, as well
as the freezor catheter which is the subject of this PMA.

CryoCath offers products to interventionalists and cardiac surgeons for
the treatment of arrhythmia.

Our catheter and probe-based products include Freezor and Freezor Xtra
for the treatment of cardiac arrhythmia, Arctic Circler for the
treatment of AF originating from pulmonary veins, and SurgiFrost, a
cryosurgical probe for the surgical treatment of cardiac arrhythmia.

Our products have been on the market since 2001 in Europe, Canada,
Australia, and other countries. Several clinical trials are being
conducted in Europe and elsewhere with the Freezor Catheter, and
CryoCath has put in place an international patient registry to collect
data from the use of its various products, including Freezor.

In the USA, a feasibility trial is underway with the Freezor Catheter to
assess the feasibility of treating posterseptal pathways through the
coronary sinus.

Today we will present the results of the FROSTY trial, as well as other
pre-clinical and clinical information related to this PMA.

CryoCath has proposed the following indications for use: The CryoCath
Freezor is indicated for the cryoablation of the conducting tissues of
the heart in the treatment of patients with atrioventricular node
reentrant tachycardia, AVNRT, and for identification of aberrant tissue
responsible for supraventricular tachycardia, using reversible
electrophysiological cryomapping near the AV node to minimize AV block.

We will now show you the evidence that we believe supports the following
conclusion: Cryoablation with Freezor has an excellent safety profile.
No permanent AV block is clinically effective in AVNRT patients, has
excellent long-term success, and has reversible cryomapping.

I would like to introduce Jeremy Ruskin, who will present the evolution
of cryoablation.

DR. RUSKIN: Thank you, and good morning. Mr. Chairman, Panel members,
ladies and gentlemen, I am Jeremy Ruskin. I am a paid consultant to and
own a small equity position in CryoCath, and my travel expenses are paid
by CryoCath.

The purpose of my talk is to address very briefly with you some of the
history and specific technologic aspects of cryoablation therapy. This
form of ablation is not new. In fact, it dates back over a century and
currently is widely used in a number of areas of clinical therapeutics,
including gynecology, urology, tumor surgery, and dermatology.

There\'s also extensive experience with cardiac surgery using
cryoablation for the treatment of cardiac arrhythmias, and this goes
back more than 30 years.

While they are working on the slides, in the interest of time, I will
try to do the best I can from memory. There are several areas of cardiac
surgery in which cryoablation therapy has been applied. The first was
intentional creation of AV block in patients with disabling or
life-threatening drug-resistant supraventricular tachycardias. It became
obvious, when the technique was applied in this setting, that it was
both safe and highly effective in producing cold injury that would
result in the induction of AV block.

It subsequently was applied to treatment of both AV nodal reentrant
tachycardias and Wolf Parkinson-like syndrome and, in fact, was the
mainstay, the only nonpharmacological option available for the curative
treatment of AV node reentry and accessory AV connections until catheter
ablation emerged, particularly that using radiofrequency current in the
late 1980s.

Cryoablation has also been used in the treatment of ventricular
tachycardia, primarily as an adjunct to endocardial resection, but also
as a primary therapy in some situations.

That\'s it. Thank you. And I will note in this particular indication, it
became evident that, because of the ability of cryoablation to preserve
the underlying tissue architecture while destroying myocytes, one was
left with intact tissue with good tensile strength, and surgeons became
comfortable applying this therapy to the papillary muscles in the
intraventricular septum, sites at which incisional therapy and
heat-based therapies could not be used because of concerns about
perforation.

More recently, cryotherapy has been applied for the treatment of atrial
fibrillation by surgeons using both open and minimally-invasive
techniques.

Next, please. What I would like to do in the next few minutes is speak
briefly about the mechanisms of tissue destruction, make a few comments
about the histologic characteristics of cryolesions, and then comment
briefly on two unique properties of cryoablation, that of adhesion and
reversibility.

Next, please. When applied to the myocardium, cold energy produces a
very well-demarcated area of freezing that results in a zone of
irreversible cell injury. This, then, progresses to replacement
fibrosis. Interestingly, as mentioned previously, despite the
destruction of myocytes, the integrity of fibrous stroma is preserved,
so that the underlying tissue architecture and the tensile strength of
the tissue is maintained, even during the acute application of
cryoablation.

Next, please. This is an artist\'s rendition of application of a
cryocatheter to the endocardium of the heart, resulting in a zone of
freezing that produces irreversible cell injury and results in the
long-term formation of a dense, fibrous scar. There is an outer halo
which is cooled to lower temperatures and at which the effects of the
cryoapplication are reversible.

Next slide, please. This is a typical histologic section. This is taken
from a canine heart one week after application of cryo energy. The key
features are illustrated here.

First, there is an extremely homogeneous dense fibrous scar with very
well-demarcated margins, and there is preservation of the endocardial
surface. These features are relatively unique to cryotherapy.

Next slide, please. This is just a photograph from our institution in
the late 1970s illustrating the use of a surgical cryoprobe in a patient
with ventricular tachycardia, and you can see the frost forming on the
probe at this point. As mentioned, the surgeons were particularly
comfortable using this form of energy because of their ability to treat
tachycardias over the papillary muscles and also the septum without
major concerns about the risk of perforation.

Next slide, please. Cryo has a number of unique properties, two of the
most important of which are illustrated in the next two slides.

The first is that, when a cryoablation device is applied to the
myocardium, it adheres firmly to that tissue during the freeze period.
Loss of adhesion occurs immediately upon rewarming. This is a unique
attribute of cryoablation, and it allows application of cold energy in
close proximity to critical structures like the AV node without concern
about catheter migration or slippage. This property is distinctly
different from what is seen with heat-based energy sources.

Next, please. This slide is a movie of a cryocatheter, outlined in blue,
introduced through the neck and into an anterioseptal position on the
tricuspid annulus.

I hope that this continues to play. If we can run that one more time,
what you will see during this is remarkable stability of this catheter
on the tricuspid annulus in an anterioseptal position. You see
termination of the tachycardia, restoration of sinus rhythm with
literally no movement of the catheter except in conjunction with the
cardiac cycle. In that position, which is a very delicate position, that
kind of stability is almost impossible to achieve with radiofrequency
devices. That is a result of adherence during the freeze.

Next, please. The other unique property is that reversibility, which is
defined as using warmer temperatures or shorter durations of application
to cause reversible alterations in cardiac conduction. This is currently
referred to as cryomapping and historically was known as ice mapping,
something that was used extensively by the surgeons, and in some cases
still is.

It is used most commonly when working in close proximity to the AV
conduction system, and is a unique attribute which allows reversible
interruption of cardiac conduction without creating permanent
electrophysiologic effects.

Next, please. This is another artist\'s rendition, just to emphasize the
fact that cryomapping and cryoablation are part of a spectrum and that
cryomapping, which is defined as a reversible change in the
electrophysiology of the tissue, occurs at warmer temperatures and with
shorter durations of exposure, whereas true ablation occurs at colder
temperatures and with longer durations of exposure.

Next, please. In conclusion, then, cryoablation is a unique technology
that has been used safely and effectively in the surgical treatment of
cardiac arrhythmias for more than 30 years. So this is not a new form of
ablation. What is unique about today\'s presentation is the availability
of this energy source in a catheter-based platform.

Cryoablation has different properties from heat-based energy and results
in the following unique attributes: One, it produces well-demarcated,
homogeneous, dense fibrous lesions with minimal to no disruption of the
endocardium and a low propensity to thrombus formation.

Cryoablation devices adhere to cardiac tissue, providing an inherent
stability to catheters during the ablation itself, and cryoablation
provides the ability to cause reversible alterations in cardiac
conduction, which provide operators with the potential for targeting
desirable sites for ablation while avoiding undesirable sites, such as
the AV conduction system.

Thank you for your attention, and I would like to turn the podium back
to Jean-Pierre Desmarais.

DR. DESMARAIS: Thank you, Dr. Ruskin.

I would like to present a technical aspect of this device. First, I will
begin with some definitions of cryoablation terms. Cryocatheter, an
ablation catheter which causes necrosis by application of low
temperature. Cryoapplication, cooling a specific portion of the heart
with either diagnostic mapping or therapeutic ablative intent.
Cryoablation, cryoapplication at the coldest attainable temperature for
a period sufficient to cause tissue necrosis. In the FROSTY study,
cryoablation consisted of one four-minute cryoapplication at a set
temperature of minus 68 degrees Centigrade or colder.

Cryoadhesion, the adherence of the tip of a cryocatheter to tissue
during a cryoapplication. Cryolesions, lesions created by cryoablation.
And, finally, cryomapping, a limited cryoapplication intended to cause
reversible alteration in cardiac conduction, achieved by using shorter
times or warmer temperatures.

This table shows the differences between cryoablation and RF ablation
catheters, and I would like to point to the main difference. The energy
source is nitrous oxide for cryocatheters, which is widely used as
anesthesiology gas. The mode of action and ablation mechanism
cryofreezes tissue, leading to ice formation and disruption of cellular
membranes while RF heats tissues and denatures protein. Finally, cryo
energy has the ability to provide reversible mapping, a unique feature,
unlike RF current energy.

The system is comprised of a console which contains a refrigerate, the
user interface, and the safety-monitoring system, a 7 French catheter
with a 4-millimeter deflectable tip, electrical and mechanical umbilical
to transport the refrigerant and electrical signals between the console
and the catheter.

The major safety features include a vacuum system that maintains the
catheter shaft under negative pressure to prevent any potential release
of refrigerant gas into the bloodstream, flow detection monitoring and
vacuum sensors to monitor key operating parameters to prevent catheter
pressurization.

A leak detection system which disables refrigerant injection, in the
unlikely event of a catheter breach; a blood detector in the handle to
prevent the aspiration of blood through the catheter. We believe these
were well-designed and tested features and will offer unparalleled
safety for this device.

This slide presents the extensive design verification testing done on
the safety system and the device attribute. All the testing conformed to
FDA guidance and industry standards.

I would like now to introduce Dr. Marc Dubuc from the Montreal Heart
Institute, who will summarize the pre-clinical experimentation.

DR. DUBUC: Thank you. Ladies and gentlemen, Mr. Chairman, and Panel
members, my name is Marc Dubuc. I am Co-Principal Investigator of the
FROSTY trial and I am also a paid consultant to CryoCath. I do not have
an equity position in CryoCath. My travel expenses for this meeting have
been paid by the company.

I would like to present a pre-clinical testing. Extensive animal testing
in over 250 animals confirmed cryocatheters\' handling characteristics,
safety features, and ability to make cryolesions.

In addition, we demonstrated the ability to cryomap, and we compared
cryolesions to RF lesions, demonstrating reduced thrombogenicity
compared to RF lesions.

We also have demonstrated the ability to ablate safely adjacent to
coronary vessels. These studies provided sufficient evidence of
feasibility and safety to proceed to IDE clinical study.

On the left is a typical cryolesion, homogeneous, sharply-demarcated,
and dense. This lesion was made with the four-minute cryoapplications at
minus 70 degrees Centigrade. Note the intact endocardium.

On the right is representative RF lesions for comparison made with
temperature-controlled RF at 70 degrees Centigrade for 60 seconds. Note
the adherent thrombus.

Next slide. A study randomizing RF and cryolesions in the canine heart
demonstrated that the median depth for cryoablation of 5 millimeters and
RF lesions 5.3 millimeters, shown in the first column, were the same.
However, lesion volumes for RF ablation, 95 cubic millimeters, were
roughly twice as large as cryoablation lesions at 49 cubic millimeters.
This resulted directly from the larger surface area of RF lesions in
comparison to cryolesions.

Note that the interquartile range for cryolesions are much smaller than
those for RF ablation. Cryolesions are more focused at equal lesion
depths with less tissue destruction and have much less dimensional
variability than RF ablation lesions.

Next. In this same study, lesion-associated thrombus was compared using
computerized morphometry. Only 13 percent of cryolesions had
lesion-associated thrombus compared with 76 percent of the RF lesions.
This difference was highly significant.

In addition, the median thrombus volume was zero for cryolesions and 2.8
cubic millimeters for RF ablation lesions. This difference was also
highly significant.

This slide shows the lesion-associated thrombus in this study. On the
left you see cryoablation lesions of 23 lesions with no detected
thrombus and three lesions with thrombus volumes of 0.4, 0.6, and 5.5
cubic millimeters.

On the right you see that the RF lesions at over 75 percent of the
lesions with associated thrombus ranging in size to several thrombi
lighter than 20 cubic millimeters. The association of RF lesions with
increased frequency and size of thrombus remain even after all other
variables were controlled for.

Next. The use of the freezor catheter to ablate accessory pathways via
the coronary sinus system was also studied in a canine model. Ablation
was performed within 2 millimeters of the adjacent coronary artery,
using RF at 30 to 50 watts for 60 seconds. Cryoablation was administered
at minus 75 degrees Centigrade for either one or two four-minute cycles.
Sacrifice was performed at one week for RF and one week and three months
for cryo. Assessments were made for transmurality of the coronary sinus
lesions and for stenosis by IVUS and geography and histology.

These slides depict the placement of the ablation catheters in the
coronary venous system . On the top, three angiograms of RF animals, we
see the development of a significant stenosis in the left coronary
artery one week after RF ablation in the CS adjacent to the artery.
Compare this to the lower panel in which no stenosis developed in
cryolesion animals one week and three months after cryoablation.

This study showed that both RF and cryoablation led to transmural
coronary sinus lesions. At all subsequent time points, measures of
stenosis were much worse in the RF-ablated hearts as compared to
cryoablated hearts with no cryoablated lesions showing atrial stenosis.
Histology at three months showed healed and endothelialized with no
stenosis, only minor intimal proliferation, two to three cell layers.

In summary, our animal experimentation with the CryoCath cryoablation
catheter demonstrated that cryolesions are dense, homogeneous, and
well-demarcated. Cryolesions are focused as deep as RF lesions with a
smaller volume of tissue destruction. Cryolesions are associated with
significantly less frequent and significantly smaller thrombi, even when
lesion dimensions are controlled for.

Cryoablation in proximity to coronaries is significantly less likely to
produce coronary artery stenosis. These studies provided sufficient
evidence of feasibility and safety to proceed to IDE clinical study.

Now I would like to introduce Dr. Peter Friedman.

DR. FRIEDMAN: Thank you, Marc. Ladies and gentlemen, Mr. Chairman, and
Panel members, my name is Peter Friedman. I am Co-Principal Investigator
for the FROSTY trial. I\'m also a paid consultant to CryoCath. I do not
have an equity position in CryoCath. My travel expenses for this meeting
have been paid by the company.

I would like to present the FROSTY study. Next, please. The FROSTY study
was a non-randomized, single-arm, multicenter study. It utilized FDA\'s
previously-determined objective performance criteria, or OPCs, that were
developed during RF catheter testing.

The primary safety endpoint was acute major complications, or AMCs, and
the primary effectiveness endpoint, acute procedural success, or APS.
The safety secondary endpoint was the occurrence of long-term major
complications and the effectiveness secondary endpoint, freedom from
recurrence of the targeted arrhythmia. Furthermore, this study was
designed to investigate the cryomapping effect and the reversibility of
cryomapping.

Next, please. The inclusion criteria for FROSTY were a documented
history of supraventricular tachycardia, either AV nodal reentrant SVT,
AV reentrant tachycardia utilizing a bypass track, or atrial
fibrillation requiring AV node ablation for rate control.

Patients had been referred for radiofrequency ablation. The ejection
fraction had to be greater than or equal to 35 percent, age greater than
or equal to 18 years.

Finally, the diagnostic electrophysiologic study had to document
inducible sustained AVNRT or AVRT in the baseline state or the presence
of a rapid ventricular response in the setting of AF, requiring AV nodal
ablation.

Next slide, please. These are the exclusion criteria in the trial,
typical for what one would expect. Note that atrial tachycardia was an
exclusion criterion, and the others are ones that you would predict.

Next, please. These are the FROSTY study hypotheses for safety: the 95
percent, double-sided upper confidence bound of the proportion of safety
subjects with AMCs was greater than 7 percent for the null hypothesis
and less than or equal to 7 percent for the alternative hypothesis.

For effectiveness, acutely, the 95 percent double-sided lower confidence
bound of acute procedural success, or APS, for intent-to-treat subjects
was less than 85 percent for the null hypothesis and greater than or
equal to 85 percent for the alternative hypothesis. Long-term clinical
success, freedom from recurrence at six months would be greater than or
equal to 85 percent.

We estimated that a sample size of 165 evaluable safety subjects was
required to establish a 95 percent upper confidence bound of less than
or equal to 7 percent, when the acute major complication did not exceed
a target value of 3 percent.

We also estimated that a sample size of 150 subjects intent to treat was
required to establish a 95 percent lower confidence bound of greater
than or equal to 85 percent, when the acute procedural success exceeded
a target value of 91 percent.

Next, please. One hundred and sixty-six subjects were enrolled at 14
sites. Eleven of these were in the United States; three were Canadian.

The first subject enrolled on March 23rd of 2001. The last six-month
followup was on October 23rd of 2002. Protocol compliance supported the
scientific validity of the study conclusions.

Next, please. Overall, 166 patients were enrolled with a mean age of 48
years. Patients with AVNRT and patients with AVRT tended to be older
than the atrial fibrillation patients.

As one can see, the mean of body surface indices were typical for what
one would expect in North America, and there was a female preponderance
in each of the three groups in a ratio of approximately two to one.

Next, please. One hundred and sixty-six subjects were enrolled. All of
these are considered safety subjects, and they were comprised of 103
patients with AVNRT, 51 patients with AVRT, and 12 with atrial
fibrillation. This distribution of diagnoses closely matches that seen
in routine clinical practice.

Two patients with AVRT were not treated because of equipment failures,
which left a total of 164 intention-to-treat patients. One of the
subjects initially diagnosed as AVNRT turned out to have atrial
tachycardia, which was an excluded arrhythmia in this trial, and,
therefore, cryo treatment was abandoned in that individual. Six other
subjects did not have a protocol-specified, qualifying cryoablation;
namely, one lasting for four minutes at less than or equal to minus 68
degrees. Excluding these seven patients yields 157 per-protocol patients
who were correctly diagnosed and had at least one qualifying
cryoablation.

Next slide, please. Basic study procedures were nearly identical to
standard diagnostic and therapeutic RF ablation procedures with the
addition of protocol-mandated assessments. All of the preparation of
these patients and the diagnostic portion of the EP study were
identical.

When the cryocatheter had been introduced into the body and correctly
positioned, the console was activated, either for cooling to achieve
ablation or for mapping at the ablation catheter tip. A physician
monitored the response at the tip, noting particularly temperature and
time of application. When the cryoapplication was complete, the console
stopped the flow of refrigerant gas, the catheter was allowed to thaw,
and the catheter was then moved, if desired.

Next, please. This slide shows a typical panel from the cryo console
during the cryoablation. On the righthand side are the controls to set
the pre-determined tip temperature and the time of application. In the
mid-panel note the orange tracing which depicts the pre-determined tip
temperature that was set. The white tracing represents the actual tip
temperature in the catheter, recorded by a thermocouple. We can see how
closely it mirrors the pre-determined desired temperature during the
cryoapplication.

At the end of 240 seconds, the injection is halted and very quickly one
sees a return of the tip temperature to body temperature; namely, 37
degrees. The total application here was 240 seconds.

Next, please. This slide illustrates the procedural details for all the
patients. One hundred and sixty-four patients underwent cryoablation.
There were 1,230 cryoapplications for ablation with a mean of 7.5,
ranging between 1 and 36. One hundred and thirty-five subjects had
cryomapping with a total of 820 cryomapping attempts, a mean of 6.1 per
patient, ranging from 1 to 37. Mean fluoroscopy time was 25 minutes,
mean procedural duration 265 minutes. The mean cryoablation temperature,
minus 71.2 degrees Centigrade, and mean cryomapping temperature, minus
26.6 degrees Centigrade.

Next, please. I would like to now present the safety results. I will
discuss major safety outcomes; namely, acute major complications, or
AMCs, deaths and serious adverse events, SAEs, and other device-related
adverse events. I would then like to present the safety results for the
AV nodal reentry tachycardia subjects specifically.

I would like to add that all adverse events were reviewed by the
investigators, study monitors, and the medical monitor, and were then
reviewed and adjudicated for final characterization by an independent
adverse event adjudication committee which convened on three separate
occasions.

Next, please. Seven subjects experienced a total of eight acute major
complications, for an AMC rate of 4.2 percent with a 95 percent
confidence interval ranging from 1.7 to 8.5 percent.

No AMC was device-related, as adjudicated by the independent committee.
All subjects recovered completely. However, the primary safety
hypotheses based on OPC with a 95 percent upper confidence bound of less
than or equal to 7 percent was, therefore, not met.

Next, please. This slide illustrates the AMC in each subject. One
subject had a minor pulmonary embolism requiring brief hospitalization.
One subject developed prostatitis after traumatic placement of a Foley
catheter.

One subject, after a lengthy procedure utilizing cryoablation which
failed and then RF ablation, was found the day after the procedure by
echocardiography to have adherent thrombus in the inferior vena cava.
This patient\'s procedure began at 9:00 in the morning, and heparin was
not administered until three or four o\'clock in the afternoon. The
patient was treated with anticoagulation, and a follow-up echocardiogram
revealed resolution of the thrombus.

One subject with a left lateral accessory pathway failed cryoablation
and then was treated with radiofrequency catheter ablation. Several
hours after the procedure he developed evidence of acute myocardial
infarction. Emergency angiography revealed occlusion of the right
coronary artery, a site distant from the site of ablation. This was
treated by angioplasty and stenting, with complete resolution of the
symptoms and of the evidence of infarction. He was discharged some days
later with a normal ejection fraction.

One subject was noted to have a partially-sheared introducer sheath
during removal of a diagnostic catheter. One subject had perforation of
the right ventricle during manipulation of the RV apex diagnostic
catheter. This patient required pericardial centesis. The same subject
was also noted to have deep venous thrombophlebitis on day two after the
procedure

Finally, one subject with failed cryoablation ‑‑ this was the subject
with the atrial tachycardia ‑‑ had the cryoablation catheter removed
from the body, and preparations were then initiated for a transseptal
catheterization because the focus was located in the left atrium. An
intracardiac echo was performed that revealed thrombus that was adherent
to a diagnostic catheter extending down the IVC. That catheter and the
thrombus were removed. A small, residual thrombus remained on the right
atrial wall. The patient was anticoagulated and had no permanent
sequelae.

Next, please. This slide shows deaths and serious adverse events. One
unrelated death occurred in an 89-year-old subject who was hospitalized
for cholecystectomy and who had a stroke. This was four months after
successful cryoablation.

Twenty subjects, or 12 percent of the total, had a total of 26 serious
adverse events. None of these was device-related, as adjudicated by the
independent committee. Seventeen of 20 subjects recovered completely and
three did not: the subject who died, another with unrelated compression
fractures, and a third unrelated depression.

Next, please. All device-related adverse events were various kinds of AV
conduction disturbances. The duration of these was a median of 45
seconds, ranging between 10 seconds and 24 hours. All of the
longer-duration AV conduction disturbances were examples of incomplete
or complete right bundle branch block. No patient developed permanent AV
block.

The etiology of these conduction disturbances was felt to be related to
cryoablation in seven, related to cryomapping in one, due to mechanical
trauma in one patient during pacing and was noted post procedure in one
patient.

Next, please. This table shows you all 14 instances of AV conduction
disturbance in the 11 patients. You see that the longest duration
abnormalities were those of incomplete or complete right bundle branch
block. AV block, ranging from first degree to complete AV block,
generally was very, very short-lasting, often resolving within a matter
of seconds. I would like to emphasize how dramatically different this is
compared to radiofrequency catheter ablation.

During RF ablation, an accelerated junctional rhythm is induced which
impairs the operator\'s ability to assess anterograde AV conduction.
When transient AV block occurs during RF ablation, 30 to 50 percent of
those patients go on to have permanent conduction abnormalities that
require a permanent pacemaker. The chance of that developing ranges from
1 to 4 percent, depending on the site of ablation.

Cryoablation is very, very different. There is no junctional rhythm. One
can assess anterograde conduction during the ablation, and if AV block
develops, it resolves very quickly. Indeed, the investigators in this
trial quickly obtained a high degree of confidence with this technology
in using it very close to the AV node.

Next, please. This slide shows the procedure-related acute major
complications in the AV nodal reentry track of cardio subjects.
Specifically, three of the 103 patients, or 2.9 percent, had
procedure-related acute major complications. One was the subject with
the pulmonary embolism; another with prostatitis due to a traumatic
Foley placement, and the third, the patient we have mentioned already,
with atrial tachycardia who developed thrombus on a diagnostic catheter.

There were, of course, again no permanent AV blocks in this group. This
is a clinically-excellent safety profile in this patient group. You can
see that the 95 percent confidence interval for the AMC rate was .6 to
8.3 percent, and with the Bonferroni correction for multiple
comparisons, it ranged from .4 to 9.6 percent.

Next, please. To summarize the safety results in FROSTY, it is true that
the overall statistical endpoint was not met. However, as an experienced
electrophysiologist, I can assure the Panel that this outcome represents
an excellent safety profile overall, particularly for the AVNRT
patients.

I should emphasize again there were no device-related AMCs. There were
no device-related SAEs, and there were no instances of permanent AV
block in 151 patients at risk.

Next, please. Now I would like to present the effectiveness data. I\'ll
present the acute procedural success for all intent-to-treat subjects
and for the AVNRT subjects specifically. Then I will discuss those
subjects who were acute cryoablation failures who were treated with
radiofrequency ablation. Finally, I will discuss long-term clinical
success.

With regard to acute procedural success in the intent-to-treat subjects,
there were 164 such subjects with AVNRT, including the one misdiagnosed
who had atrial tachycardia, AVRT, or AF. One hundred and thirty-six
subjects had acute procedural success, yielding a point estimate of 83
percent with 95 percent confidence intervals ranging from 76 to 88
percent. The primary effectiveness endpoint, a 95 percent lower
confidence greater than or equal to 85 percent, was, therefore, not met.

Acute procedural success, however, was significantly different among the
three diagnostic groups. This slide shows overall procedural success of
83 percent in the 164 patients overall. Note that the acute procedural
success in the patients with AVNRT was 91 percent compared with 69
percent in the AVRT patients and 67 percent in the AF subjects.

Next, please. A number of subjects were also treated with RF ablation
when cryoablation had not been successful. Twenty-five of 28 subjects
with acute procedural failure during cryoablation went on to have RF
ablation; two subjects did not. Sorry, three subjects did not.
Twenty-three of these 25 of the RF-treated subjects had acute clinical
success.

Considering both cryoablation and RF ablation, acute clinical success
was achieved in 161 of 166 patients. This was a point estimate of 97
percent with confidence intervals ranging from 93 to 99 percent. Adverse
event measures in the cryoablation plus RF ablation patients did not
differ from those in the cryoablation-alone subjects.

Next, please. I would like now to discuss long-term clinical success.
There are two ways of assessing long-term outcome. One is by life table
analysis, another by Kaplan-Meier survival analysis.

This slide shows the life table analysis for all 136 patients who had
acute procedural success. We see that the long-term clinical success
rate in this group was 91 percent with 95 percent confidence intervals
ranging from 86 to 96 percent.

This outcome is clinically excellent, exceeds the protocol-specified
rate of 85 percent and exceeds the subsequently-published FDA RF
ablation guidance of a conditional long-term clinical success rate of 90
percent with a 95 percent lower confidence bound of 80 percent.

This slide shows the Kaplan-Meier analysis with the same 136 patients,
all of whom had acute procedural success. Using this method of analysis,
we get essentially the same long-term, chronic success rate of 91
percent with 95 percent confidence intervals ranging from 86 to 96
percent.

Note that there was no recurrence of the targeted arrhythmia after the
third month of followup. This durable response is exactly what we are
accustomed to seeing with radiofrequency ablation.

This is the life table analysis for the AVNRT subjects and demonstrates
that the long-term clinical success rate was 94 percent with a corrected
98.3 percent confidence interval ranging between 87 to 100 percent.
Again, this outcome exceeds the FDA generic RF ablation guidance of a
conditional long-term success rate of 90 percent with 95 percent lower
confidence bound of 80 percent.

Here is the Kaplan-Meier survival analysis for the AVNRT patients. This
results in a very similar outcome as the life table analysis with a
long-term clinical success rate of 94 percent, corrected 98.3 percent,
with a confidence interval ranging from 87 to 100 percent.

Next slide. Thank you. To summarize the FROSTY effectiveness outcomes,
for all 164 intent-to-treat subjects, the primary endpoint was not met
with an overall acute procedural success rate of 83 percent. The
secondary effectiveness endpoint, however, was met with a long-term
clinical success rate of 91 percent at six months of followup. For the
103 AVNRT subjects, acute procedural success was 91 percent with a
long-term clinical success rate of 94 percent at six months of followup.

Post-hoc analyses need to be carefully assessed. The analysis of the
AVNRT group has substantial clinical and statistical validity for a
number of reasons.

To begin with, this is a clinically-relevant group. Furthermore, the
group was defined a priori in the protocol. There was a highly
significant correlation between diagnosis and acute procedural success.

The univariate relationship between diagnosis and acute procedural
success was for AVNRT 91 percent; AVRT, 69 percent, and AF, 67 percent.
By chi square, this was highly significant with a p-value of .002.

The multivariate relationship demonstrated that diagnosis was a
highly-significant factor in predicting acute procedural success. With a
stepwise logistic regression, the p was .022.

Finally, there is a significant amount of additional clinical
information, much of it filed with the PMA, that supports the FROSTY
AVNRT safety and effectiveness results, as we have reported here. For
these reasons, we believe that this analysis of the AVNRT subjects is
valid and is clinically useful.

Next, please. I would like now to discuss cryomapping, which I believe
is one of the most unique and potentially most important features of
this new technology. Cryomapping is defined as a limited cryoapplication
intended to cause a reversible alteration in cardiac conduction.

In the FROSTY study, cryomapping was done at minus 30 degrees Centigrade
for up to 80 seconds. This allowed for a reversible assessment of the
potential effects of cryoablation at a chosen target site.

Next, please. I would like to show you just one example, and for the
non-electrophysiologists on the Panel whose eyes may glaze over, please
bear with me. We see two panels here during cryomapping. In the top
panel and in each panel you see surface electrocardiographic leads one,
two, three, V1 and V6, and then high-right atrial electrograms here from
the high-right atrium, from the ablation catheter, and from the his
bundle electrogram.

In the baseline state, this patient had sustained AV nodal reentrant
supraventricular tachycardia of the typical variety. These atrial
electrograms represent retrograde conduction to the atrium over the fast
AV nodal pathway. The impulse then turns anterograde and conducts
through the AV node over the slow AV nodal pathway to complete the
reentrant circuit. The cycle length here is 390 milliseconds.

During cryomapping one sees progressive slowing of the tachycardia cycle
length here and here, and then, finally, termination of the tachycardia.
Note that the termination occurs in the anterograde limb, the slow
pathway, which is exactly where the catheter had been placed. When the
catheter was then rewarmed, this patient again had inducible, sustained
AVNRT.

Next, please. One hundred and thirty-five intent-to-treat subjects had a
total of 820 cryomap attempts. The remaining 29 intent-to-treat subjects
had no attempted cryomaps.

On a per-subject basis, 87 of the 135 subjects, or 64 percent, with an
attempted cryomap, had one or more effective cryomaps. On a per-cryomap
basis, 164 of 820 attempts, or 20 percent of the attempts, resulted in
effective cryomaps. So a majority of study subjects and about two-thirds
of those in whom it was attempted had one or more effective cryomaps.
Any given cryomap attempt had a 20 percent chance of being positive.

With regard to cryomapping reversibility, of the 164 effective cryomaps,
102 were converted immediately into cryoablation without warming to
assess reversibility; 62 of the effective cryomaps were warmed after
mapping. Forty-nine of these reversed immediately and completely; nine
reversed in one to six minutes after rewarming, and four went on to
cryoablation from four to twenty-one minutes after cryomapping but
before complete reversal had been observed. Ninety-four percent, 58 out
of 62, of the effective cryomaps definitely and rapidly reversed.

A subject with one or more effective cryomaps was significantly more
likely to have acute procedural success than patients with only
ineffective cryomaps or patients in whom cryomapping was not attempted
at all. Looking at the total group, for patients with effective
cryomaps, the acute procedural success rate was 94 percent as compared
to only 67 percent in patients with ineffective maps or 76 percent in
patients with no cryomapping attempted.

Thus, considered as a diagnostic tool for catheter location, having one
or more effective cryomaps predicts a group significantly more likely to
have acute procedural success. This significant difference is present in
the AVR patients, but the trend in the AVNRT patients and the AF
patients was not significant.

I suspect that the effect in the AVRT patients represents the much
greater localization challenge inherent in treating accessory pathways
and the corresponding benefit that cryomapping offers in that group.

To summarize cryomapping, the FROSTY study demonstrates that cryomapping
can reversibly alter cardiac conduction in the majority of subjects in
whom it is attempted. Effective cryomaps are associated with a higher
procedural success rate, but this trend did not reach statistical
significance in the AVNRT diagnostic group.

Cryomapping utility has many interesting possibilities. Clinical
applications at the moment include the ability to map in order to
confirm a desirable site for ablation, but also to identify sites that
are undesirable where ablation would likely result in an unintended
outcome.

To summarize the FROSTY study with regard to safety and effectiveness,
cryoablation with the Freezor catheter is a safe modality in patients
with supraventricular tachycardia. There were no instances of permanent
AV block in 151 ablated AVNRT and AVRT subjects, despite frequent
ablations near the AV node. AV block can be monitored and is quickly
reversible. There were no device-related AMCs or serious adverse events.

Cryoablation with Freezor is a clinically-effective treatment for AVNRT
subjects, resulting in an acute procedural success rate of 91 percent
and a long-term clinical success rate of 94 percent.

Cryomapping with Freezor was observed in 64 percent of subjects
attempted. Cryomapping was quickly reversible in almost every case, and
subjects with effective cryomaps had a significantly higher acute
procedural success rate compared to subjects without an effective
cryomap, 94 percent versus 67 percent.

From FROSTY, I think we can conclude that Freezor is safe for the
treatment of patients with supraventricular tachycardia. Freezor is a
clinically-effective treatment for patients with AVNRT, and cryomapping
with Freezor may offer advantages for safely confirming desirable
ablation sites and also avoiding undesirable ablation sites.

Thank you for your attention. I will now turn the podium over to Mr.
Desmarais.

DR. DESMARAIS: Thank you, Dr. Friedman.

Here are my concluding remarks: Cryoablation for arrhythmia has a long
history of safety. Cryoablation has been shown to be safe and effective
for the treatment of cardiac arrhythmias in surgery over 30 years.

Freezor has many proven safety systems included in the catheter and
console to ensure patient safety. In over two years of worldwide
commercial distribution and over a thousand procedures, there is no
reported instance of permanent AV block. In studies of almost 600
cryoablated SVTs there have been no instances of permanent AV block as
well.

Freezor cryoablation, as demonstrated, an excellent safety profile with
no permanent AV block. It is clinically effective in AVNRT patients, has
excellent long-term success and reversible cryomapping.

Ladies and gentlemen, Mr. Chairman, Panel members, thank you for your
attention.

CHAIRMAN LASKEY: Thank you very much, and congratulations on adhering to
schedule. It was much appreciated up here.

Barring any burning questions from the Panel, which I would like to hold
until after lunch, I would like to proceed with the FDA\'s presentation.
Does anybody have a question for the sponsor? If not, we will just hold
until after lunch.

MR. CHENG: Good morning. I\'m James Cheng, and I am the Lead FDA
Reviewer for the CryoCath Cryoablation System submitted under PMA
P020045.

The FDA review team was comprised of myself, our Medical Officer, Dr.
Leslie Ewing, who will present the FDA clinical review summary; our
Statistician, Dr. Lilly Yue, who will present the FDA\'s statistical
review summary; Cindy Demian, who performed the biocapability review;
Elaine Mayhall, who performed the sterilization review, and Kevin
Hopson, who performed the bioresearch monitoring review.

The sponsor-proposed indications for use as seen earlier, the basic
components of cryoablation system, the Freezor catheter, the
cryoconsole, and the umbilicals and accessories:

The Freezor catheter is a 7 French single-use catheter with a
4-millimeter gold-plated metal tip, 3 EGE ring electrodes, a
thermocouple sensor, and a flexible, maneuverable shaft. The catheter
lumen contains a refrigerant injection tube, ECG wires, a leak detection
wire, and a thermocouple wire. The catheter handle contains a deflection
mechanism.

The cryoconsole provides refrigerant delivery and recovery. It maintains
a vacuum condition inside the catheter lumen. It controls the
refrigerant pressure and flow rate to achieve the target temperature
range. It contains a device safety system. It monitors the integrity of
umbilical connections, and injection control is implemented in dedicated
hardware and has a manual override function for shutting down injection.

The umbilicals and accessories consist of the coaxial umbilical which
delivers liquid nitrous oxide under pressure to the catheter and
evacuates the nitrous oxide gas; the electrical umbilical, which carries
the catheter electrical signals to the auto connection box; the auto
connection box, which connects the electrical umbilical and ECG cable to
the console, and the ECG, which carries the catheter ECG signals to an
external monitor.

The basic principles of operation of the system, cryogenic temperatures
are generated only at the catheter tip. Pre-cooled liquid nitrous oxide
is injected under pressure to the tip, where the liquid nitrous oxide
expands to a gas. The face change that the nitrous oxide undergoes is an
endothermic reaction which generates the cryogenic temperatures at the
catheter tip.

Cryoablation involves achieving a catheter tip target temperature of
between minus 68 to minus 75 degrees Centigrade and maintaining that
temperature for up to 240 seconds.

Cryomapping involves achieving a catheter tip target temperature of
between minus 25 to minus 30 degrees Centigrade and maintaining the
temperature for 60 seconds.

The FDA pre-clinical review goals were to ensure the safety and
reliability of the device. For safety, we want to ensure that the device
has been appropriately designed and tested, that potential device
hazards have been analyzed and mitigated, and that the device safety
features have been qualified for use. For reliability, we want to ensure
that the design and manufacture of the device provide us with assurance
of consistency with performance specifications.

Testing of the catheter included biocompatibility testing of the
catheter materials, reliability testing of the catheter design,
mechanical and electrical testing of catheter performance, and
qualification of a sterilization process.

Qualification of the console included software and hardware
qualification. For software, we assess the sponsor\'s design and
development methodology, the device software hazards analysis, and the
software verification and validation process. For hardware, we assess
the design of the nitrous oxide injection and recovery systems, the
temperature controller performance, the device risk analysis, and the
design and performance of all device safety features.

The major hazard posed in the device design is the potential for causing
a gas embolism. The manufacturer addressed this hazard with several
mitigation features. One mitigation features involves the design and
qualification of the catheter, which included burst and leak testing.
Another mitigation is that the catheter lumen is kept under continuous
vacuum during the procedure, which prevents the release of the
refrigerant gas into the patient\'s bloodstream if there is a catheter
breach. There is also a catheter safety interlock which prevents device
operation until all the catheter connections have been properly
configured.

Additional mitigation features include redundant blood and fluid
detector systems that would detect the presence of blood or fluid in
various parts of the catheter as a result of a catheter breach.

The flow profile of recovered injectant gas is also monitored to detect
any unusual catheter performance. The pressure relief valve helps ensure
that the catheter doesn\'t become pressurized, and any loss of vacuum
will immediately disable the injection. To minimize the risk of
exsanguination, again, you have the blood and fluid leak detectors and
the catheter design and qualification.

Another hazard that was addressed by the sponsor was the risk of
experiencing freezing temperatures along the catheter shaft, instead of
only at the tip. Catheter qualification testing demonstrated that a
break in the injection tube inside the catheter did not allow external
shaft temperatures to approach freezing, and the injection flow profile
monitoring also helps monitor for catheter failure conditions.

One last device hazard is the risk of software controller failure. This
hazard was addressed by the use of a dedicated, hardware-based injection
controller with a manual override for stopping injection delivery and by
the use of hardware-based watchdog circuitry to monitor the software for
failure.

In conclusion, based on the documentation provided to the FDA by the
sponsor, the pre-clinical testing performed by the sponsor is
appropriate and acceptable. Specific hazards posed by the device have
been appropriately analyzed and addressed by the sponsor\'s device
design and qualification testing. Overall testing shows that the device
is reliable for human use.

Now to present the FDA clinical review summary, it is Dr. Leslie Ewing.

DR. EWING: Good morning. I am Leslie Ewing, and I have no conflicts to
report. I will be presenting the results of the study, and following me
will be Dr. Lilly Yue, who will talk about the statistical analysis of
those results.

The initial purpose of the study, as you have heard, was to study the
safety and effectiveness of this cryoablation system to treat the two
types of SVT AV node reentry SVT and SVT due to an accessory pathway,
and to treat patients with atrial fibrillation who have rapid
ventricular response.

The study was a single-arm, randomized, multicenter study using OPCs, as
previously described. These OPCs were based on the medical literature on
RF ablation and designed to be used for the entire pooled study
population. These OPCs have been used in previous ablation clinical
trials reviewed by the FDA.

As also was mentioned, since the beginning of this clinical trial, the
FDA has put out a guidance document which was issued on July 1st, 2002
entitled, \"Cardia Ablation Catheters Generic Arrhythmia Indications for
Use, Guidance for Industry.\" It can be found at the web address as
listed. These recommendations were put out and intended for
radiofrequency ablation catheters and were based on medical literature
for RF catheters.

This is a table from that guidance document, and I will point out, as
has been previously mentioned, the chronic success or freedom from
recurrence was 80 percent, as is listed here.

In this study there were three patient populations included: AV node
reentry, AVRT, patients with accessory pathway, SVT, and patients with
atrial fibrillation.

The inclusion criteria is as stated here and has been previously
discussed, and the exclusion criteria have been previously discussed.

The primary effectiveness endpoint for the study was acute procedural
success. For the patients with the AV node reentry and accessory pathway
SVT it was absence of spontaneous or inducible sustained SVT at the end
of the procedure, and for the patients with atrial fibrillation it was
absence of AV node conduction.

The lower-bound OPC for the acute procedural success, as you can see
here, is 85 percent. For a secondary effectiveness endpoint or long-term
success for the patients with SVT, there was to be no recurrence of
sustained SVT by the time of their three-month followup, and for the
patients with atrial fibrillation, there was to be no evidence of AV
node conduction at the three-month followup.

For the study, the chronic success lower bound was to be 85 percent with
the asterisk pointed out to the recently-published FDA guidance, which
would be 80 percent.

The safety endpoint for the study is that the number of major
complications following the use of the device should have 95 percent
upper bound of less than 7 percent.

The definition of major complications used for the study is the standard
for FDA, the definition of major complications, and it is any adverse
event which occurs within the first week following the use of the
investigational device and is life-threatening or results in permanent
impairment of a body function or permanent damage to a body structure,
or necessitates significant intervention such as major surgery to
prevent permanent impairment of a body function or permanent damage to
the body structure or requires hospitalization or an extended hospital
stay, results in moderate transient impairment of a body function or
transient damage to a body structure, or requires intervention such as
medication or cardioversion to prevent permanent impairment of a body
function or damage to the body structure. In previous ablation studies
the definition has been consistently applied by the FDA in a fairly
strict fashion.

As has been described, the patients all had screening and enrollment
into the study and all had diagnostic electrophysiology studies. Some
patients had cryomapping, and the determination of which patients were
to have cryomapping was at the investigators\' discretion.

Cryoablation occurred in all patients that passed the diagnostic
electrophysiology study, and the followup occurred at seven days, one,
three, and six months. The followup at seven days was by telephone and
also at six months was by telephone.

A hundred and sixty-six patients were enrolled and 164 patients received
cryoablation lesions. This was at 14 study sites, 11 in the U.S. and
three in Canada. The diagnosis after the EP study showed that 61 percent
of the patients had AV nodal reentry; 31, accessory pathway; 7 percent,
atrial fibrillation, and as was discussed, one patient was diagnosed
after a short cryoablation lesion to have ‑‑ or cryoablation application
to have atrial tachycardia.

Of the 166 patients enrolled, as I said, 164 had cryoablation. There
were 157 that had per-protocol lesions, per-protocol cryoablation
application, and that is a full duration, 240-second ablation
application. Six had less than full duration lesions and were,
therefore, qualified as acute failure of the device. All those patients
went on to have radiofrequency ablation.

There were, of the total of the patients who received cryoablation, 28
failures, procedural failures, and there were 136 acute successes. There
were 122 of that patient group that had chronic success, and one of
those patients, as has been described, is the one patient who had at
four months post ablation.

So, to reiterate what has been described by the sponsor, there were 91
percent of the AV node reentry patients that had acute success, 69
percent of the accessory pathway tachycardia patients, 67 percent of the
atrial fibrillation, and as the total there were 83 percent. As has been
described, this did not achieve ‑‑ so they did not achieve their acute
procedural success or their primary effectiveness endpoint.

The chronic results are the patients who had no recurrence of
tachycardia or AV node function at three months. Also previously
discussed, of the total groups, 90 percent and 91 percent for AV node,
for the accessory pathway patients 88 percent, and 75 percent of the
atrial fibrillation ‑‑ so of the patients who had acute procedural
success, the ones that remained long-term success.

There were seven patients with acute major complications within seven
days of the procedure, which also has been stated by the company exceeds
the safety endpoint of the study. Three of these patients had the AV
node reentry ablation procedure and four with an accessory pathway
procedure. The company has very clearly identified and discussed these
patients, so I will not go into detail with these patients.

Cryomapping was performed on a subset of the entire patient population.
As you have heard, this mapping was performed by using a reversible cryo
effect on the conduction system. The use of cryomapping was decided on a
per-case basis by the investigator, and the decisionmaking process was
not collected as part of the study.

The criteria for effective cryomaps were pre-determined per tachycardia.
Cryomapping was not part of the pre-determined endpoints of the trial in
terms of effectiveness and safety.

A hundred and thirty-five patients out of 164 had cryomapping attempts.
Of those patients, 65 percent had effective cryomaps and 35 percent had
only ineffective cryomaps. The total number of cryomaps attempts was 812
with 20 percent of those being effective cryomaps, but also negative
cryomaps may have helped the investigator determine unsuccessful
cryoablation with patients.

In the data-collection form process for this study, the investigator
could mark \"reversible,\" \"not reversible,\" and that they had gone
immediately to cryoablation attempt without attempting rewarming. There
were seven AV node patients who had \"not reversible\" marked on their
data-collection form. All of these seven patients had successful
cryoablation procedures with no adverse events reported and, as has been
previously stated, no patients had unintentional AV block.

Dr. Yue will present the statistical analysis.

DR. YUE: Good morning. My name is Lilly Yue, Statistician at FDA.
Following Dr. Ewing, I will speak on the study results and give clinical
and statistical conclusions.

As specified in the protocol, the primary effectiveness endpoint: acute
procedure success. The primary safety endpoint: major complication
occurrence. The secondary effectiveness endpoint: long-term clinical
success at the three-month followup conditional on acute procedural
success, evaluated for the entire SVT patient population.

Protocol indicated that the study\'s, like I said, criterion for the
acute procedure success was that the lower 95 percent two-sided
confidence bound of the acute success rate for all intent-to-treat
patients should be larger than 85 percent.

Please note that the two-sided confidence interval here is necessary
when the acute success rate could be larger or smaller than 85 percent,
as it was agreed upon by the sponsor and the agency at the design stage.
We will see this, indeed, necessary in a few minutes.

The intent-to-treat patients are those who have a prior ablation
catheter activated. For the major complication occurrence, the study
success criterion was the upper 95 percent two-sided confidence bound of
the major complication incidence rate for all safety patients should be
less than 7 percent.

Here the 15 patients are those who have a cryoablation catheter
inserted.

For the conditional long-term success there were statistical hypotheses
specified in the protocol. The alternative hypothesis said the
conditional long-term success rate should be larger than or equal to 85
percent. It is the basic statistical concept that the success rate
indicated in the statistical hypotheses are in the population parameter,
not an observed point estimate. So the study success criterion for this
endpoint is the lower 95 percent two-sided confidence bound should be
larger than 85 percent for all intent-to-treat patients.

Let\'s look at the study results. As we can see, the point estimate of
the acute success rate is 83 percent, less than the OPC 85 percent. So
the two-sided confidence interval is, indeed, necessary, and there is no
way for the lower confidence bound to be larger than 85 percent.

The lower confidence bound is 76 percent. Therefore, the study has
failed to meet the OPC 85 percent for the acute success for planned
patient population.

Also, the upper confidence bound of major complication incidence rate,
8.5 percent, exceeded the OPC 7 percent. Therefore, the study has failed
to meet the primary safety OPC for planned patient population.

For the conditional long-term success, using the protocol specified
exact confidence interval approach, if we consider the crude probability
of success, that is, classified the two lost-to-followup patients as
failures, the lower confidence bound is 83 percent, less than the OPC 85
percent.

If we use a more liberal method and exclude the two lost-to-followup
patients from the dataset, the lower confidence bound is 85 percent,
just on the border line.

The agency also suggested survival analysis, either Kaplan-Meier or life
table cohort analysis, which should give a lower confidence bound
between 83 percent and 85 percent, and closer to 85 percent in this
case.

Then after looking at the data, the sponsor performed two types of
post-hoc subgroup analysis for endpoint statistical hypotheses. The
first one is a retrospective subgroup analysis on the ablation safety
and effectiveness endpoints for the three individual subpopulations,
using the OPCs originally developed for the entire patient population.

The second one is the retrospective subgroup analysis on the impact of
effective cryomapping on ablation acute success. However, in the
protocol, there were no statistical hypotheses and no study success
criteria and claims generated for all cryomapping at all.

According to the post-hoc subgroup analysis results, the sponsor made
two new claims to support the new indications for use. No. 1, the AVNRT
subgroup met the FDA OPCs for the safety, acute procedure success, and
the long-term success. No. 2, there was a significant association
between effective cryomapping and ablation acute success to support
these two new indications for use.

Question: Can the post-hoc subgroup analysis results be used as valid
evidence for the new claims? First of all, when should we perform
subgroup analysis?

Generally speaking, subgroup analysis is to determine if there is a
reportable subset for which the treatment effect is either significantly
more effective or harmful. So, when the study has succeeded in
pre-specified overall analysis, subgroup analysis may be useful in
suggesting hypotheses to be tested in future studies or help refine
labeling. If the data shows a significant overall treatment effect, but
non-significant treatment effect in subgroups, then the device still
could be approved for general use.

However, subgroup analysis is not intended to be used to rescue a study
with non-significant overall treatment effect. So, when the study has
failed in pre-specified overall analysis, generally, we do not perform
subgroup analysis because the risk of false positive results from
subgroup analysis increases.

Particularly, here are some criteria to check if a subgroup analysis is
appropriate:

No. 1, is the hypothesis for subgroup analysis pre-specified?
Pre-specified is more believable than post-hoc-specified.

No. 2, is the subgroup classification clinically relevant?

No. 3, is there significant treatment effect in overall analysis? If
yes, may do subgroup analysis; otherwise, generally, we do not do.

No. 4, is there significant interaction of treatment with subgroup
variable? This question generally refers to a two-arm trial, but here we
just have one arm.

Let\'s check if the subgroup analysis of ablation safety and
effectiveness for the three individual patient subpopulations is
appropriate:

No. 1, in the protocol, no statistical hypothesis was generated for the
three individual subpopulations; no study success criteria and claims
were developed for the subpopulations. And the sample size estimation
was not based on the three individual subpopulations.

No. 2, yes, the three subpopulations are generally referred to SVT
patients.

No. 3, no, there is no significant treatment effect in pre-planned
overall analysis.

No. 4, not applicable, but, indeed, there is a big difference in the
performance of the device between the three patient subpopulations. That
is why the OPCs developed for the entire patient population cannot be
directly used for subpopulations. It is just our second concern on the
next slide.

OPCS developed for the entire patient population may be wrong for all
subpopulations. So it cannot be directly used in a subpopulation. In
fact, from medical literature, the acute success rate for AVNRT patients
is significantly higher than those for AVRT and AF patients. Therefore,
the acute success OPC for AVNRT should be higher than 85 percent.

Our other concern is, if the subgroup analysis and the data analysis had
been planned in the protocol, a multiplicity adjustment for a
significance level, such as Bonferroni adjustment, should have been
performed. Otherwise, the overall Type I error rate of the study, that
is, the probability of incorrectly approving the device, would be
inflated and could be close to 15 percent.

Let\'s back up one step and let\'s suppose the original OPCs were
appropriate for the subgroups. The point estimate of acute success rate
is 91, 69 and 67 percent for the three subpopulations, respectively; 91
percent for AVNRT is significantly better than 69 percent and 67
percent. You can see a huge difference here.

Here the 95 percent confidence interval is the analysis result without
multiplicity adjustment. We also suggested Bonferroni-adjusted
confidence intervals. The highlighted numbers here are the lower
confidence bounds, but none of them match the OPC 85 percent in a group.

Similarly, for the major complication incidence rate, none of these
upper confidence bounds reached the OPC 7 percent, no matter the
confidence intervals are multiplicity-adjusted or not adjusted.

For the conditional long-term success, the second column in the table
gives the results of crude probability of success for AVNRT subgroup.
None of these lower confidence bounds reached the OPC 85 percent. The
last column gives the result of excluding the two lost-to-followup
patients from the data analysis. The lower bounds, 86 percent and 85
percent, they are omitted for the AVNRT subgroup.

So suppose the OPCs were appropriate for the subgroups. For any patient
subgroup, with or without multiplicity adjustment, the study has failed
to meet the primary safety and effectiveness OPCs.

In conclusion, none of the three subgroups met the OPCs for either
primary safety or primary effectiveness.

Let\'s look at a second subgroup analysis on the association of
effective cryomapping and ablation acute success. Of 164 patients with
cryoablations, 135 had cryomap attempts and 29 didn\'t. Of the 135
patients with cryomapping attempts, 87 had effective cryomaps and 48 had
ineffective cryomaps. So the point estimate of the effective cryomapping
rate is 64 percent. Of 87 patients with effective cryomapping, 80 had
reversibility so the rate is 92 percent.

Now we have three patient subgroups according to cryomapping: effective,
ineffective, and no attempts. The ablation acute success rate is 94
percent for effective, 65 percent for ineffective, and 79 percent for no
attempts.

The sponsor groups \"ineffective\" with \"no attempts\" and called it
\"without effective,\" then compared \"effective\" with \"without
effective\" in terms of ablation acute success, and claimed that
\"effective\" was significantly better than \"without effective\" in
ablation acute success.

These claim was supported by a p‑value less than .05 from exact test for
the overall intent-to-treat patient population. However, the significant
result was driven by 49 AVRT patients. You can see the p‑values in the
last column. However, the AVRT subgroup is not the one the sponsor is
currently claiming for.

Instead, the AVNRT is the only group indicated in the new indication for
use. However, there is no significant difference detected in the
ablation acute success between \"effective\" and \"without effective\"
patients for this subgroup, with a p‑value of 0.45 from exact test.

For this post-hoc comparison, we have the following concerns:

No. 1, what is the meaning of this comparison?

No. 2, why grouping \"ineffective\" with \"no attempts\"?

No. 3, is the subgroup classification \"effective\" versus \"without
effective\" clinically-relevant?

It seems that if we try to attach the impact of the effective
cryomapping on ablation acute success, we could compare the
\"effective\" group with the \"ineffective\" group and use \"no
attempts\" as a control.

The ablation acute success rate, 94 percent for the \"effective\" group,
is significantly better than 65 percent for the \"ineffective\" group,
but a patient had only 64 percent of a chance to have a successful
cryomapping when he had cryo attempts.

On the other hand, if we try to test the impact of attempted cryomapping
on ablation acute success, we could compare \"attempt\" with \"no
attempts.\" Here \"attempt\" includes \"effective\" and \"ineffective.\"

We performed the comparison and found that there was no significant
difference detected in the ablation acute success between \"attempt\"
and \"no attempt\" groups, with a p‑value of .59 from the exact test.
The point is made that the ablation acute success rate is 84 percent and
79 percent for the two subgroups, respectively.

From these post-hoc subgroup analyses, we can see that there are many
ways to generate a subgroup hypothesis after fact. Different post-hoc
hypotheses and data analyses could lead to different results, either
significant or non-significant.

This is the situation we always try to avoid, in which subgroups are
defined by the data and the unplanned statistical hypotheses are
generated by study results. Often, a treatment effect is so suggested
and then confirmed with statistical significance on that same dataset.

Clearly, the subgroup hypotheses and the data analysis on the
association of effective cryomapping and ablation acute success were not
pre-defined. We are not sure if the subgroup classification
\"effective\" versus \"without effective\" is clinically-relevant. Also,
we do not have information on why those 29 patients did not have
cryomapping attempts, purely by chance or due to some patient
characteristics.

No. 3, there is no significant treatment effect in overall analysis of
ablation acute success. So, the sponsor\'s significant subgroup analysis
result used as evidence of device performance is questionable.

Clinical and statistical conclusions: The device did not meet the
primary effectiveness of 50 OPCs for either the overall study population
or any patient subgroup. No patient had unintentional, permanent AV node
block at the end of the procedure or during followup. There were a low
number of recurrences after successful cryoablation. Cryoablation
adherence appears to have a durable effect.

The post-hoc assessment of cryomapping effectiveness is questionable.
There was no significant association detected between effective
cryomapping and ablation acute success for the AVNRT subgroup. There was
no adverse event reported due to cryomapping.

Thank you.

CHAIRMAN LASKEY: Thank you, Lilly.

At this point, for the record, we will read the questions. We are still,
fortunately, a tad early here for the one o\'clock break. So are the
questions from the Panel to the sponsor or to the FDA, for that matter,
the FDA presenters?

I had one question for the sponsor. I was very interested in some of the
acute and subacute and chronic changes in the subjacent coronary artery
in your pre-clinical studies. Do you have any further information on the
pathology or histopathology of these lesions? What is it that is acutely
constrictive there? Is it dynamic? Is it fixed? Is it something that we
need to worry about, if the latter?

DR. DESMARAIS: Mr. Chairman, I will ask Patrick Chauvet, our
pre-clinical scientist, to answer your question.

MR. CHAUVET: Thank you. My name is Patrick Chauvet. I am a pre-clinical
scientist for CryoCath, a full-time employee, and I own equity. My trip
was also paid for by CryoCath.

The question was dealing with the cryoablation lesions in the coronary
sinus and the effect on the adjacent left circumflex coronary artery:
What were the histological changes acutely, subacutely, and chronically?

In the early trials that we performed we had noticed histological
changes both with RF and cryo that were significantly different. In the
RF lesions, the coronary artery acute constructs, and the hypothesis
there is because of heating of the collagen fibers in the medial area of
the coronary artery, this effect is quite dramatic, and acute
constriction is evident; whereas, with cryoablation there is no heating
of the collagen fibers, and our hypothesis is that prevents acute
constriction.

In the subacute and chronic cases, we have noticed in both cases medial
necrosis of the coronary artery in similar amounts. However, due to the
differences in human processes, the cryoablated coronary sinus and
adjacent coronary artery healed very well, and there was no subsequent
stenosis up to three months in the cryoablation regions.

CHAIRMAN LASKEY: So is the acute stenosis reversible with nitroglycerin,
for example? You alluded to spasm. It is spasm? Did you give nitro and
make it go away or some other anti-spasm?

MR. CHAUVET: Nitroglycerin was given during the study. As you saw in the
presentation, stenosis was still present one week after the procedures.
So it is not just an acute phenomena.

CHAIRMAN LASKEY: One question from Dr. Waldo and then Dr. Dullum.

DR. WALDO: Actually, I have a few, but I will just take one then. I have
a question about the definition of efficacy of the cryomap. I\'m not
sure I understand the definition because to me, if you apply adequate
cooling, almost anything is effective, the way I look at it. If you
don\'t get an effect, I think that was implicit in some of the things
that presented, if you don\'t get an effect, then are you sure you know
you\'re in an area that is not useful to ablate?

Do you also know that it is safe to ablate if you want to ablate with
something else? In your instance, your presentation, it wouldn\'t be
like atrial flutter where you might want to ablate and you would want to
make sure you\'re not close to any structure.

I don\'t see why all the cryoablation shouldn\'t be considered effective
if adequate cooling is applied, because it is telling you something each
time. I am not sure why you have to have reversibility as part of it.

DR. DESMARAIS: We will ask Dr. Lehmann, our medical monitor, to answer
the question with regards to the definition.

In terms of the cryomapping clinical applicability, I would like to ask
Dr. Friedman to answer that question.

DR. LEHMANN: My name is John Lehmann. I am a paid consultant to
CryoCath. I do not own equity, and my expenses were paid by the company
to come.

Dr. Waldo, your question bedeviled us as well. There is a kind of
cryomapping where you are looking for an effect, in which case we
ultimately simply defined that as, when you cool to a non-destructive
level, did you see a physiologic change or not? And there is a kind of
cryomapping where you wouldn\'t like to see an effect, or what is
loosely called \"negative cryomapping,\" where you are working with it
at the node and you cool and you don\'t see it. Exactly how to determine
those in study was less clear to us a couple of years ago.

But at the moment we use the terminology \"cryomapping effect\" in a
positive sense, in a place we would like to see the change, and we do or
don\'t with a non-destructive cryomapping application, and cryomapping
reversibility just for those situations when we do see change in
physiology and with warming that change goes away.

DR. WALDO: So then, with Dr. Yue presenting the statistical analysis, if
I understand it, when you were ineffective, it was because you didn\'t
see anything. There was nothing reversed. But I would suggest to you,
why is that ineffective? It doesn\'t strike me that that is ineffective.
It might be very effective. You know you\'re not in a place you don\'t
want to be, for instance. That is the most obvious example. I don\'t
know why that is ineffective. If you look at just the statistics, that
would clearly affect this.

DR. FRIEDMAN: Peter Friedman.

I think that is a very good point, Dr. Waldo. As John Lehmann alluded to
just a moment ago, we struggled with how to gauge and how to measure
mapping, because it is not something that has been available with any
other technology and had never been done before.

You\'re right in the sense that, if you do cryomapping in a site and you
don\'t see the intended effect, that\'s a negative cryomap, but, on the
other hand, it tells you that you are in a place where it is actually
probably safe to ablate.

DR. WALDO: Or not the place you want to ablate.

DR. FRIEDMAN: Or not the place that you want to be. So it is another way
of analyzing the data. Of course, we could include those all as
effective, and then the numbers would be very different.

DR. WALDO: It would certainly affect the statistical analysis we just
heard, which was suggesting that it was useless, and I think that
statistical analysis doesn\'t make any sense to me in terms of how we
understand it.

DR. FRIEDMAN: Yes, I think as the study went on, we learned more about
what the true utility of this technology is. It is true that, if during
cryomapping one sees block in an accessory pathway or block in the slow
pathway, that indicates that it is a good place to do ablation.

But we learned about what we called \"negative cryomaps\" or \"safety
cryomaps,\" also, that if you\'re applying cryo energy to an area and
you see an unintended effect, that is an area not to ablate and it is
another utility for mapping that was not addressed when the protocol was
written.

DR. WALDO: Am I wrong in that, do you think? If you apply it to an area
where nothing happens, why would you continue? Did you find that, if you
don\'t see any effect, you\'re sure that that is an area that is not
desirable to ablate? For instance, if you don\'t see any effect on a
slow pathway, which would be critical for your presentation, did it
prove in your data that this was an area clearly that you should not
ablate, that you were wasting your time to ablate that?

DR. FRIEDMAN: No, and it is difficult to analyze those data from the way
they were collected. But, for example, there were investigators who did
cryomapping specifically to localize the slow pathway and were unable to
show a reversible block in the slow pathway.

Now one could conclude from that either you\'re too far away or that the
temperature you achieved during the mapping procedure was not adequate
to reach the slow pathway which may have been further below the
endocardial surface. So there were actually instances in the study where
people, after mapping and being unable to find an effective, quote,
\"cryomap area,\" actually went back and ablated at those areas, and
some of those turned out to be successful.

CHAIRMAN LASKEY: We do that in interventional cardiology as well. So it
is not an uncommon precedent.

Dr. Dullum, you had one question?

DR. DULLUM: I just wanted to ask a followup to your question about the
coronary occlusion. I noticed the intravascular ozone catheter was in
the heart in one of your pictures with the RF ablation but not on the
cryo. Did you have it in during the ablation procedures for both of them
or did that just happen to be that one picture that we saw?

MR. CHAUVET: Patrick Chauvet.

No, the AFIS catheter was positioned in every single animal whether it
was for RF or cryoablation.

DR. DULLUM: So during the ablation procedure the AFIS was in there, in
the animals?

MR. CHAUVET: That\'s correct, yes.

CHAIRMAN LASKEY: Dr. Krucoff?

DR. KRUCOFF: You mentioned that you have an experience in Europe. Is the
catheter in clinical use outside of the United States? Are there any
data available that would support any of these discussions from your
U.S. activity?

DR. DESMARAIS: Jean-Pierre Desmarais, CryoCath.

F7, the presentation, the catheter is in commercial use in Europe, in
various countries in Europe, and in Australia and other countries in the
world.

We found with the PMA there\'s two separate studies which are not
sponsored by us which are an individual initiative from the German Heart
in Munich and from the Rotterdam in The Netherlands which compared the
NRT to RF, and we do have data on that. We have submitted those data to
FDA during the PMA.

We are trying just to plug the computer and present the data to you in a
minute.

DR. ZUCKERMAN: Okay, I think I have to take issue as to whether the
agency has seen these data. I don\'t believe so. And the Panel needs to
recognize that any data not contained in the PMA Panel pack have not
been thoroughly reviewed by the agency and need to apply the appropriate
caveats to such data.

DR. DESMARAIS: Thank you, Dr. Zuckerman.

CHAIRMAN LASKEY: I am sorry, are we looking for summary of the European
data here?

DR. DESMARAIS: In about 30 seconds.

CHAIRMAN LASKEY: Sure, and then at that point I would move to adjourn
for lunch. So we will end on that response.

Oh, I\'m sorry. I\'m sorry, Dr. Waldo.

DR. WALDO: Just a very quick followup to what I was asking before: Have
you any instances where you looked for parahisian pathways? I mean, this
is one of the areas where ‑‑

DR. DESMARAIS: I would like to have Dr. Nazari to answer that question.
Excuse me, I will let Dr. Chauvet to answer that question.

DR. DUBUC: Mark Dubuc.

As you know, the product is commercially available in Canada, and we
have used that to do about 17 cases with parahisian.

DR. WALDO: Seventy or 17?

DR. DUBUC: Seventeen, 1-7. Actually, we were successful in 15 of these
cases, and we were able to make what we call a negative cryomap or
safety cryomap, and we had clearly a his electrogram on the ablation
catheter when we did that.

I can say that maybe in two cases we had transient AV block and we had
to cancel the procedure. This is why we have the 15 out of 17 were
successful.

DR. WALDO: So you also used the mapping, the cryomapping technique?

DR. DUBUC: Yes. Well, mainly, the negative cryomapping. I want to be
sure not to ablate at the same time that I\'m doing ‑‑

DR. WALDO: Precisely.

DR. DUBUC: So another thing interesting with cryo is that during the
application what you cannot do with RF, you can do program stimulation;
you can pace the atrium, pace the ventricle, to see if the AV conduction
is still there during the application. The catheter is very, very
stable.

CHAIRMAN LASKEY: Dr. Bailey had a question.

DR. BAILEY: Yes, I was wondering if you have compiled data on all
initially-enrolled patients as far as their rhythm status at the end of
the ‑‑ I know there was combining the ones who were successful after
radiofrequency ablation.

DR. DESMARAIS: Dr. Lehmann will answer that question.

DR. LEHMANN: Could I clarify that you want the overall clinical success
at the end of the procedure?

DR. BAILEY: With the strategy of cryoablation, followed perhaps by
radiofrequency.

DR. LEHMANN: Right. That was in the presentation. There was a slide that
shows that, of 166 enrolled subjects, 161 had the endpoint success at
the end of the procedure.

DR. BAILEY: And then what about at three months or six months? Did you
follow the radiofrequency cases for their status at three months?

DR. LEHMANN: We don\'t have that data here today.

CHAIRMAN LASKEY: Do you have the non-U.S. ‑‑

DR. DESMARAIS: This is partly the non-U.S. As explained earlier, that
was part of the PMA that FDA maybe did not have the chance to review.

There is a study by Dr. Zrenner at the German Heart. At the time of
filing of the PMA, that was the data we had available showing comparable
success rate fluoroscopy induration in terms of AV study.

And there is a second study by the group of Dr. Jordaens in Rotterdam,
The Netherlands. In this case, he was doing it at the NRT and right
septal pathways. Again, the success rate is comparable at this point in
time, and that was what we had at the time of filing. Obviously, these
studies are continuing, but we don\'t have formal updated data at this
point.

Does that answer your question?

DR. KRUCOFF: Yes. I guess you had references to thousands of uses.
Obviously, these are smaller trials then.

DR. DESMARAIS: Correct.

DR. KRUCOFF: You were talking about your commercial use?

DR. DESMARAIS: Correct. We do have registry data.

DR. LEHMANN: We have four IDE-like studies to either Canada or the U.S.,
which comprise roughly 300 subjects with AVNRT and AVRT. Those had no
permanent block. There\'s a total of 600 patients in the registry
collection, and then there\'s between 1,000 and 2,000 commercial uses
for which there are no event-reporting systems of any permanent AV
block.

DR. KRUCOFF: Can you just flip back to the first data slide?

DR. LEHMANN: Yes.

DR. KRUCOFF: So on the cryo side, does that four third-degree heart
blocks only transient? So \"no block,\" you mean permanent ‑‑

DR. LEHMANN: No permanent AV block.

DR. KRUCOFF: Correct.

CHAIRMAN LASKEY: Okay, thank you. On that note, we\'re at the magic
hour, and I think we\'ll have plenty of opportunity for each panel
member to ask additional material after lunch. Let\'s break for lunch
and let\'s meet again at 1:55 sharp. Thank you.

(Whereupon, the foregoing matter went off the record for lunch at 12:56
p.m. and went back on the record at 2:05 p.m.)

A F T E R N O O N S E S S I O N

2:05 p.m.

CHAIRMAN LASKEY: I would like to begin this afternoon\'s portion of the
proceedings by having our Lead Reviewer, Dr. Cynthia Tracy, present her
review and ask questions.

I also want to make a bold, and perhaps indefensible request, for Panel
members to limit their exegesis to no more than 10 to 15 minutes, so we
can get through the afternoon, if that is possible.

I\'m assuming we actually got through all the panelists\' questions
before the lunch break. Is that a fair assumption? That is not? Can you
hold them until it is on your round? Would that be okay?

Great. So, Dr. Tracy, the floor is yours.

DR. TRACY: I think it is appropriate that this is room is very frosty
for this discussion.

(Laughter.)

With that in mind, I would like to congratulate you on your
presentation. You covered a lot of data and did it very well. One thing
that I thought was remarkably well done was the pre-clinical testing. I
think this device has a lot of potential safety issues that have all
been addressed very carefully with excellent safety features built into
the device.

It strikes me that both the strength and the weakness of this device is
the small, uniform lesion that is created. I think that is why effective
in many instances, but ineffective ‑‑ it is effective and safe in many
instances, but ineffective in places where you might want to create a
larger lesion.

Just a brief question relative to that: Is there any way that a lesion
or any development that might be done could increase the size of the
lesion to make the device more applicable for a greater number of
arrhythmia substrates? Is that something that is potentially planned?
Would a larger catheter tip be useful or some other modification?

DR. DESMARAIS: At the current time, we believe that the catheter that we
have is adequate for the treatment of AVNRT, but in our design
strategies, you know, to pursue other indications, we have a lot of
design strategies and looking and addressing other arrhythmia. We will
surely approach FDA in due course on how best to bring those products to
market.

DR. TRACY: Okay. I think the cryolesion has the nice feature of not
being very thrombogenic, and that might have potential implication for
left-sided structures in the future. So it was just a passing thought.
But I think at this point you are correct that AVNRT is probably your
most approachable lesion with the current device setup.

In terms of the device itself, you mentioned that there were equipment
failures in two cases. In looking through the packet, I think one was a
console failure, and it looked like on the second one multiple catheters
were connected to the console and it was failure to deliver the nitrous
oxide, I think.

Can you explain, if I am doing math right, about a 1.2 percent device
failure? Are you happy with that? What exactly were the problems?

DR. DESMARAIS: I believe that the catheter consumption throughout the
study was about 1.14 catheter on average, I believe. The console failure
was a technical failure where a valve did not open and did not let
refrigerant into the catheter. So that case never took place with trial
as such.

In the other failure there was a catheter that kinked on two occasions,
and one the injection tube was blocked, so we could not inject.
Unfortunately, the site ran out of catheter, so we could not complete
the case with trial.

DR. TRACY: Okay.

DR. DESMARAIS: And just to answer your last question, in general, we are
very happy with the catheter as it is, and in terms of its reliability
and the way it is used.

DR. TRACY: Okay. I\'m only going to touch on this because I assume Dr.
Bailey will be asking much more detailed questions regarding the whole
statistical analysis issue, but if you had designed this study for AVNRT
alone, what endpoints would you have had to achieve in order to prove
statistically that the device was safe and effective? Have you put
thought into that?

DR. DESMARAIS: I will ask Dr. Lehmann to answer that.

DR. LEHMANN: The short answer is that we have not at this point
attempted to design just a trial for AVNRT. In this trial we used the
OPCs, which, as Dr. Yue stated, were for a cooled population, and those
were the numbers that we used.

DR. TRACY: Okay. I suspect this issue will get much more discussion as
we go around the room, but I will leave it at that for the moment.

A couple of procedural questions: The procedure time average was 265
minutes. Does that include from the moment the patient is put on the
table until the moment they are pulled off the table?

DR. DESMARAIS: Yes, it is skin to skin.

DR. TRACY: Skin to skin? Okay. So that is probably a bit long, I think.
Is that related to device issues, people having to set things up? Is it
hard to set up to deliver refrigerant?

DR. FRIEDMAN: I think there are a number of factors that go into that
procedure time. I think it is true that any investigational study by its
very nature, because of the data collection that occurs, takes longer
than a routine clinical case.

Some of the time was certainly getting familiar with hook-up procedures,
the umbilicals. Mapping I think took some time. There was a new
technology, and people were interested in exploring how it could be
used. That added to the procedure time. I think all those things
together would explain that.

I think in routine clinical practice, not in the context of a clinical
trial, procedure times would not be dramatically different than RF. In
fact, in the data that you saw just before the lunch break, where
patients had been randomized RF versus cryo in Europe, there was really
no significant difference in overall procedure duration.

Maybe Dr. Dubuc from Montreal would care to comment on that because he
probably has the largest experience and has been using it a lot since it
is commercially available in Canada.

DR. DUBUC: Well, I had a chance to use this product because it is
commercially available. I did in my institution more than 150 cases with
this technology. Actually, even our group decided to do all AV nodal
reentries with this technology since last August.

The time is comparable, and I mean the time of the procedure is
comparable, and also the fluoroscopy time. Even the fluoroscopy time has
a tendency to be a little bit lower because you don\'t have to watch or
monitor the position of the catheter during cryoapplication because of
the adherence of the catheter.

DR. TRACY: You are comfortable enough that that thing is really going to
stick on there, that you don\'t wash ‑‑

DR. DUBUC: Oh, sure, no doubt about it.

DR. TRACY: Okay.

DR. DUBUC: No doubt.

DR. TRACY: Okay. A procedural question that relates to one of the major
adverse events: I\'m assuming that that right corner infarct either was
a catheter inadvertently positioned down the right coronary artery
during a retrograde approach or was a completely unrelated event. Do you
have a comment on that particular complication?

DR. DESMARAIS: Dr. Friedman will answer that.

DR. FRIEDMAN: It\'s difficult to know precisely. That, I think, was a
case from Canada. My understanding of that procedure was that
cryoablation for the left lateral accessory pathway was done via a
retrogradic aortic approach, and there were no technical difficulties
encountered crossing the aortic valve. That was not difficult. So I
think it is unlikely, based on what was reported, that that catheter
went down a coronary.

The RF catheter ablation procedure was actually done by a transeptal
approach. That also turned out to be unsuccessful. So this was a very
lengthy procedure in a patient with pre-existing coronary disease, and
the occluded vessel, as you alluded to, was actually the opposite side
of the heart.

DR. TRACY: Okay, thanks.

I wanted to ask a few questions about the cryomapping. The whole concept
of it is a new concept that we have to try to figure out exactly what it
means.

I think that part of the idea of doing cryomapping is that it is a way
of testing where you are without creating permanent damage, and yet I
note that there\'s a little bit of contradictory information that is
being given. In one part of the packet it mentions that 100 percent of
cryomapping was reversible. Yet, we talked this morning about seven not
reversible cryomaps. Are those cryomaps, were they actually
cryoablations, or what\'s the difference there?

DR. DESMARAIS: I think what I would like to do is to answer that
question twofold: first, with Dr. Friedman, to really explain
cryomapping and make an attempt in re-explaining that, and, secondly,
for Dr. Lehmann to discuss exactly the reversibility in terms of the
data collection.

Dr. Friedman?

DR. FRIEDMAN: I can answer that question with some assurance because two
of those seven patients were patients that were done at our institution,
and I remember the details. Those were patient who actually had
cryomapping, not cryoablation, of the slow pathway during AVNRT.

In the baseline state, both patients had inducible, sustained SVT, and
during cryomapping we showed that the slow pathway was completely
blocked and SVT was no longer inducible. With cryomapping turned off,
the slow pathway recovered function and there were single, occasionally
two, echoes, but not sustained SVT. We waited a while, and still there
was no sustained SVT, although the slow pathway had recovered.

We marked that as non-reversible because it did not return to baseline,
although I think it was a function of time. Had we waited 20 or 30
minutes, in all likelihood it would have.

DR. DESMARAIS: Dr. Lehmann?

DR. LEHMANN: Part of your question related to data that doesn\'t seem to
match, and that is really the record of our good collaboration with the
FDA, to clarify what we felt the true situation was. So the report in
the FDA presentation was that 80 out of 87 cryomap subjects with an
effective cryomap had \"reversible\" marked on their form and seven had
the \"not reversible.\"

We went back and looked at that. Part of the issue was, what was
\"reversible,\" quote/unquote? Is it seconds? Is it minutes? So we did
the additional analysis of actually looking at the cryoapplication data
to see how long it was before the next application occurred either with
normal conduction restored or not. That is the data that we showed.
Either way, you get a better than 90 percent reversibility assessment in
short notice and no adverse events related to cryomapping.

DR. TRACY: Okay. In terms of the clinical utility of cryomapping, how
useful is this? There was, I think it was, 84 percent attempted and
successful, 79 percent not attempted, and yet the ablation was
successful. So it is 79 percent versus 84 percent. Is that hugely
different?

DR. DESMARAIS: Dr. Friedman will answer.

DR. FRIEDMAN: Well, I\'m a believer in cryomapping. I think that it is
useful. Having used this technology, in my mind, it is very useful.

I think there are differences among the different patient groups, and
that is partly why we presented the data that we did. For AVRT, if you
think about patients with an accessory pathway, these tend to be very
discrete structures and they are not the sorts of things that one can
localize simply by looking at catheter position fluoroscopically. It
requires very careful mapping technique. It needs to be very precise.

In my mind, the clearly-demonstrated effect of this, of cryomapping, in
that group relates to the fact that, with cryomapping, you\'re affecting
a relatively small area with the tip of that catheter. You need to be
very close to the accessory pathway in order to interrupt conduction in
that pathway temporarily. If you see that effect, then that predicts
effective cryoablation because you\'re right on the spot.

With AV nodal reentry, it may be different because in many cases
patients are undergoing AV node r-entry ablation based on anatomy
fluoroscopically. You can position the catheter in what you think is the
slow pathway position without regard to mapping ‑‑ this is typical of
radiofrequency ablation ‑‑ and often get a successful ablation.

So the area of ablation for the AVNRT may be larger and mapping
precisely may be less critical, but, conversely, the negative cryomap in
that group I think is a very important and useful thing clinically,
because to map during the slow pathway ablation a spot and find
transient AV block identifies a place that you do not want to do
ablation. So it is useful in a different kind of way.

DR. DESMARAIS: I would like also to ask Dr. Keane from MGH comment on
that.

DR. KEANE: My name is David Keane. I\'m an investigator, and I practice
at the Mass General Hospital in Boston. I have no equity, am not a
consultant, but my travel trip expenses, my flights, were paid for by
CryoCath.

The reason I came down here today is because I\'m strongly motivated to
see it be introduced to the clinical practice that we have in Boston,
and it has implications just not imminent to mapping but also ablation
alone.

I get a call once every two to three weeks from New England physicians
with patients who have -‑ typically, younger patients than older
patients with parahisian pathways ‑‑ and I have over 10 patients whom I
have sort of held off over the last five years on the basis that I was
involved in the animal work with this system and have always told them
that it is only a matter of time before you will see this thing come
through.

They have been holding out for a number of years with recurrent SVT,
treated on medication, and a lot of these are teenagers who are treated
with beta blocker and anti-arrhythmic drugs. Some of them are young
females who wish to become pregnant and they continue to take their
anti-arrhythmic drugs. That is the real downside for them. I think it is
a shame that they have to wait, in particular, for this system to come
along and kind of eradicate their arrhythmia on a permanent basis.

For us, it is really key to see an approval for parahisian pathways
because they are the folks that suffer the most in that they have had
enough SVT to come for ablation; they have turned down. They have been
brought all the way, almost like being a horse to the water, but they
haven\'t been allowed to drink. We have mapped these very accurately and
found them to be truly parahisian.

There are a lot of patients out there waiting in the wings, not only
directly on our own waiting list, but also on the referring docs. So the
answer today has been for AVNRT. I think the real value for cryomapping,
actually the relevant importance of cryomapping greatly exceeds the
AVNRT group for people with parahisian pathways.

As Dr. Waldo referred to it, it is a negative predictive value of a
cryomap that has been more important than a positive predictive value
for these people with parahisian pathways. The issue is that you have
total adhesion to the spot. It is the same with the mahine fiber. If you
have mahine fiber, if you do a bump map, there is a good possibility
that by the time you go on and your tachycardia terminates, again, it is
like Dr. Ruskin\'s video this morning: If the tachycardia terminates,
the catheter moves, you never get it back there again.

With the adhesion, the ability to do a map down to 30 degrees, go on at
that spot, if you have elimination of your target physiological
endpoint, to be able to go straight on from minus 30 to minus 69 or
minus 70 without having to rewarm is the biggest plus of this system,
because you are guaranteed that your spot is exactly where you mapped.
If you do it with an RF, either by bump mapping or even a low
temperature, 10-watt output, you are still getting smudge lesion. With
every other system, you are constantly smudging, the same way with
microwave and ultrasound.

With this cryo, because it is a pinpoint lesion, as you point out, they
are very small lesions, and that\'s why it is critical for these
accessory pathways that they are precisely mapped. Perhaps that was
underappreciated in the trial, the critical importance because you get
so much collateral damage with an RF. If you\'re not exactly on the spot
but close to it, you have success. With cryo, you have to be absolutely
on the spot. I think that may have been underappreciated when we were
performing this trial.

But, for me, the biggest issue about mapping is the ability to map a
parahisian pathway, particularly for these teenagers and young people
who have been waiting now for several years to see this system come
through.

Thanks.

DR. TRACY: I appreciate that comment, but I think that the device isn\'t
being considered for parahisian pathways at this point. I think our
discussion is just related to AVNRT.

DR. DESMARAIS: I think Dr. Lehmann has a final comment on that.

DR. LEHMANN: I have just redisplayed this slide from this morning\'s
presentation that I think relates to your question.

First, I would like to point out that this display doesn\'t relate to
our indications for use, but we thought it was a fascinating finding
from the study. In the effective cryomap column, at the bottom you see
the 94 percent success rate for those 87 subjects who had an effective
cryomap. For the 48 subjects who had cryomapping attempted but didn\'t
think demonstrated, they had a 67 percent complete procedural success.
For subjects, the 29 who had no cryomapping attempted, it was 76
percent. The comparison of the first to the second and third columns is
clearly significant.

So there is this positive predictive value. That is really all we were
saying, that if you do happen to cryomap and get an effective cryomap,
your certainty about ultimate success is high, and so that is really the
remark.

DR. TRACY: Thank you.

Moving on to the cryoablation itself, it strikes me that 11 of 103
patients had transient heart block, and that is high for even ‑‑ I would
not expect that high of a level of transient heart block with RF energy.
What explains that, and what explains the development of a right bundle
branch block when you\'re working in a slow pathway zone? I can\'t quite
figure that piece out.

DR. DESMARAIS: I will ask Peter, Dr. Friedman, to answer that.

DR. FRIEDMAN: You have touched on a number of important issues, and I
think, Dr. Lehmann, if we could have that one slide that I had asked you
to show, we will talk about this.

With regard to the right bundle branch block, there is a spectrum of
catheter stiffness or flexibility among the catheters that are available
in the marketplace, with EPT catheters being probably the most flexible
and on the other end of the spectrum maybe a Biosense Webster being less
flexible. Different catheters are used to different degrees in different
institutions, and people are accustomed to certain kinds of handling
characteristics.

This catheter is probably in the middle part of that spectrum, but
tending toward the Biosense Webster. I think if someone is used to an
EPT catheter, which is very flexible, then all of a sudden picks this
catheter up, it is a little bit stiffer and it takes a little time to
get accustomed to.

I think some of the right bundle branch blocks that you are seeing there
are not necessarily related to ablation or mapping. It is just the
mechanical handling characteristic of the catheter. After all, we see
right bundle branch block just with diagnostic his catheters on
occasion. So I think those are my comments about the right bundle branch
block.

With regard to the high incidence of transient AV block, I think this
relates to the fact again that this was an investigational procedure
with a new technology, and the investigators really were set on giving
this technology a good test. So, for example, this is a case actually
that we did at our institution. A woman with AVNRT ‑‑ I don\'t have a
laser pointer ‑‑ but a woman with AVNRT who had, I don\'t remember the
exact number, a few cryoablations, and after the last of those, the
sustained SVT was no longer inducible. There were still single echo
beeps that were inducible.

Now in radiofrequency ablation, that would be an endpoint. Most people
would stop at that point and not go on. But this is a new technology,
and we didn\'t know whether that was an adequate endpoint or not. So we
persisted, and we did ablations closer and closer to the compact AV
node.

So here\'s an ablation actually in the high to mid-portion of the
septum, fairly close to the compact AV node. You see the artifact on the
ablation catheter because of the ice formation around the catheter, and
you see here the surface ECG, and here\'s an atrial electrogram. That\'s
conducted; that\'s conducted. Here\'s a blocked P wave.

The first blocked P wave is right there, and you can see within one or
two seconds the ablation was turned off and you see disappearance of the
ice ball this quickly. Now this is a continuous strip, and you can see
that this transient AV block now is gone within four or five seconds.

So this may relate to why we saw transient AV block perhaps more
frequently than you would have expected, because people were using this
technology aggressively, knowing that if AV block occurred, it would
disappear.

I would conclude by just drawing your attention to the Calkins data in a
previous submission with a different kind of catheter, where if one
looks at the ‑‑ yes, and here we have the data for you.

So this is the previously-submitted Calkins data that was reviewed prior
to that catheter\'s approval. This shows you the incidence of any block
during ablation of AVNRT or AVRT. The incidence was 3.4 percent, so
maybe a little bit higher than people are accustomed to seeing. Ours was
7.2 percent.

But here\'s where the major difference resides, and I alluded to this in
my comments earlier. Of this 3.4 percent, you know, nearly a third or a
half went on to have persistent AV block and needed a pacemaker. Here is
where our difference is: that AV block is transient.

DR. TRACY: It is interesting, the electrophysiologic definition of the
substrate is not the traditional thing that we look at for success. It
talks about the success being measured as not inducible to 15 seconds or
more of SVT. I would never stop with 15 seconds of AVNRT residual. Why
was that chosen, and how often did you see an effect on both slow and
fast in the cryo?

DR. FRIEDMAN: That endpoint was chosen not for its own value, but we
struggled with what were the appropriate inclusion criteria. We didn\'t
want to do ablation in people who had non-sustained arrhythmia at
baseline because it would be so difficult to judge the effect of the
intervention.

So we arbitrarily chose greater than 15 seconds\' duration as a
definition for sustained SVT at baseline. Once we established that, then
the endpoint of a successful ablation was anything less than that. But I
would argue that the success rate long term attested to the fact that
that was a clinically-useful endpoint.

DR. TRACY: And the 94 percent long-term success rate, that\'s of the
cryo patients, not of those cryo-plus-rescue? That is cryo alone?

DR. FRIEDMAN: That\'s correct, that is just the cryoablation alone.

DR. TRACY: Okay. In patients with recurrence, at what point was that
seen? Is that an early recurrence, within a day or two, or is that ‑‑
it\'s early?

DR. FRIEDMAN: It is usually within a day or two, certainly within the
first month. No recurrences after three months.

DR. TRACY: Okay. How many patients had first re-AV block following
ablation?

DR. FRIEDMAN: I think we have the slide. None of them was permanent. I
think the table that I showed you there ‑‑ go back. So there was one,
two, three, four, and all of them resolved with 24 hours.

DR. TRACY: None were permanent? And none developed first re-AV block in
the first month or at a point later?

DR. FRIEDMAN: No, no.

DR. TRACY: Okay. There was sort of a ‑‑ we didn\'t talk about it in your
presentation this morning, but the learning curve seems to be ‑‑ it
seems to take quite a bit of learning to get to use this catheter
correctly. It looked like there was an acute success rate of 85 percent
early versus 97 percent late.

How hard is it to learn how to use this catheter and what does that mean
in terms of how you would train physicians to use the system?

DR. DESMARAIS: I think I\'ll have a multiple answer to that question.
I\'d like to start with Dr. Friedman to discuss how to use the device.
Secondly, there is a real number where we have Dr. Lehmann that can
answer some of that.

Then, in real practice, Dr. Ruskin. In the real practice, then we can
talk, Dr. Dubuc can, who has been using the catheter now for over 150
cases, as he reported earlier.

DR. FRIEDMAN: As a clinician who has been around longer than I care to
recall, I think it is fair to say that there is a learning curve with
any new technology, and that was true of radiofrequency ablation. If one
goes back and looks at acute procedural success in some of the older
trials, you know, 85 percent was acceptable. Now we use an OPC of 92 or
93 percent. So, seemingly, there is an evolution in the field as people
do more and more and get more comfortable, but that is true of also the
cryoablation catheter.

It is difficult to demonstrate that statistically within the confines of
a small study. So we actually didn\'t demonstrate statistically a
learning curve. Maybe Dr. Lehmann can comment on that further.

DR. LEHMANN: I think it is worth just keeping it very simple. There was
a very minor trend. There were a couple of difficulties.

One is there were a number of subinvestigators, and when you take 166 or
164 cases and divide them amongst 13 sites with multiple
subinvestigators, it is just impossible to do any ‑‑ you don\'t get
enough case accrual. That was really a major issue. When we did it on a
per-site basis, there was nothing significant.

DR. DESMARAIS: And Dr. Dubuc?

DR. DUBUC: As I said before, we did more than 150 cases in our
institution. I did myself 100 cases of these. When we switched to ‑‑ we
decided to go for cryo for all our AV node reentry cases afterwards, I
mean since last August; my colleagues started doing it, but they knew
about the technology; they knew about the result of the studies we
performed in Canada previously. And they quickly got it. Right after
three or four cases, they were able to do these things by themselves.

You have to realize that actually the thing you learn from the
technology is that you don\'t expect the same response from the energy
source. Like when you do RF ablation, you expect irradiated junctional
rhythm during the ablate. You don\'t have that.

The catheter adheres to the under-cardial surface. So it is different.
You don\'t have to monitor on the fluoroscopy. This is what you have to
learn.

More than my colleagues, also the personnel working in the lab, they
know what to expect and they make the connection quickly, and we know
what to expect from the technology. So it comes very, very quickly, if
you have somebody ‑‑ not everybody has to go through the same learning
curve, I would say, you know, like I did. My colleagues near me, they
did it very quickly.

In closing, your question about the complexity of the system itself, you
have a catheter; you have, compared to RF, you have two connections
instead of one, and you have an on-and-off button. So from a complexity
standpoint, it is not very complex.

DR. TRACY: Okay, thanks. Just to return to some of the labeling issues,
I don\'t know if you want to look at your labeling section, but I think
that, based on what you have presented today, I agree these are the
appropriate indications that you should be seeking approval for.

Under the precautions, just a couple of statements: The one, two, three,
four, fifth bullet down, \"Consider periprocedural coagulation therapy
for patients undergoing left-sided and transeptal catheter procedure and
for selected patients undergoing right-sided procedure.\" That doesn\'t
quite fit with the indication, but I understand why that might be there.

DR. DESMARAIS: Well, obviously, when we wrote the indication originally,
we understood that indications and instructions for use is something
that has to be worked on at a later date, obviously.

DR. TRACY: Okay. And down further, the third-from-the-bottom precaution:
If patients need to be defibrillated during the procedure, disconnect
the catheter\'s electrical connection part to do defibrillation. Why?

DR. DESMARAIS: I would have Marwan Abboud to answer that question. He is
our Director of Engineering.

DR. TRACY: Okay

MR. ABBOUD: Ladies and gentlemen, Mr. Chairman and Panel members, I am
Director of Engineering.

The different relation issue is mainly ‑‑

DR. TRACY: Excuse me. Could you please tell what your conflict of
interest is?

DR. DESMARAIS: Marwan Abboud is an employee of CryoCath.

DR. TRACY: Okay.

MR. ABBOUD: Director of Engineering at CryoCath.

DR. TRACY: Okay. I\'m sorry I didn\'t understand.

MR. ABBOUD: The defibrillator issue is mainly to protect the console. As
any equipment, when you defibrillate, since we have a thermocouple
measurement, in order to prevent destroying the temperature measurement
circuit, we recommended to disconnect the catheter.

DR. TRACY: Okay. That\'s fine. All right, that\'s basically all the
questions I have at this point, but I sort of reserve the issue of the
statistical questions, might come back to that. I am hoping others will
do that, too.

CHAIRMAN LASKEY: Great. Thank you, Cynthia.

While Dr. Tracy had the luxury and prerogative of spending 15 minutes,
you can appreciate the number of people up here who need their moment in
the sun. So I would like to ask the Panel members to share their
thoughts and direct their questions to the sponsor and the principal
investigators in less than five minutes, five minutes or less, if they
can summarize the key issues that they have before us. That way,
everyone can have a fair shake.

MS. WOOD: Actually, at this time it would be general questions for
either the FDA or the sponsor. We would ask the sponsor to vacate the
table at this time, please.

CHAIRMAN LASKEY: I would like to begin the Panel\'s questions and
comments with Dr. Gilliam.

DR. GILLIAM: I have a few questions related. I think Cindy touched on
several, but I am looking at your labeling. You do say, \"The foot
switch is available only in Europe.\" Is that the plan? I am just
wondering, why was that set up that way, your foot switch for your
console?

DR. DESMARAIS: Obviously, every device has design evolution. When we
designed this trial, we designed it with the current product that we
had. At that time there was no foot switch that existed with the design
of the console that we have, but the design evolution in Europe is
moving faster. So it is available there. But, in due course, when it is
time to file amendments to the current product, we will do so within the
boundaries of the FDA regulations.

DR. GILLIAM: Another thing, looking at the first panel of your labeling,
I guess that is on the first page on the righthand side, the third point
down: \"Do not connect CryoCath to radiofrequency generations as it may
result in patient electrocution.\" It seems pretty drastic.

Is there a real possibility of that? I guess I would direct that to your
engineering.

DR. DESMARAIS: I will ask now our Director of Engineering to answer
that.

MR. ABBOUD: I think, as any RF, you, even for the eruption rater, they
do recommend not to put a diagnostic catheter. Since our catheter
printout on the connection are different from regular RF catheter, we
recommend not to do it at this time. Thus, we are using different
thermocouple. Since we have a cold temperature, we use a different
thermocouple.

DR. GILLIAM: I\'m not opposed to not hooking up to an RF. It was just
quite drastic when you saw electrocution. Have you all had some
experience with that perhaps? You don\'t have to answer.

(Laughter.)

While you are there, I do have one question.

MR. ABBOUD: Yes.

DR. GILLIAM: Your panel that you viewed the temperature that is right on
the console, is that exportable to any type of monitor that an operator
could see if they are not directly looking at the console?

DR. DESMARAIS: At the current time, it is not exportable. It is not
designed to be in such a way. However, again, in Europe we are looking
to introducing that concept. Whenever it is ready for us to introduce in
the USA, we will do so again, within the boundaries of the FDA
regulations.

DR. GILLIAM: This may be one of your investigators could answer this.
Looking at your AV node reentry population, is it typical that you would
be doing the slow pathway ablation while the patient would be in
tachycardia insofar as you will not have the junctional rhythm that we
typically see with RF? How would you, other than looking at a negative
map, cryomap, how would you know you have achieved some degree of
success with slow pathway modification during an ablation run?

DR. FRIEDMAN: There are a number of ways that one can do that. The
example I showed you this morning was cryomapping, just to illustrate
how the tachycardia would terminate, and in the anterograde slope
pathway direction.

During ablation, most typically, the ablation is actually during a sinus
rhythm. The advantage to that is that the patient\'s in sinus; you can
monitor the PR interval. Indeed, you can even do atrial pacing or
programmed atrial stimulation during the ablation application.

That catheter tip is fixed to the myocardium and will not move, and that
allows you to monitor during sinus rhythm or during atrial pacing, while
the ablation is going on, when the slow pathway disappears.

DR. GILLIAM: As far as the shipping and storage of the catheters, are
there any special precautions of this catheter, given it is sort of a
multi-lumen catheter? I notice the kinking is a concern, obviously, for
reasons, but how does the catheter come in storage?

DR. DESMARAIS: The catheter is packaged into a tray system. It is
packaged flat and it is not coiled on itself, and the storage conditions
for catheters and console is standard of any ablation catheter out
there.

DR. GILLIAM: Those are all the questions that I have right now.

CHAIRMAN LASKEY: Thank you, sir. Thank you twice. Mitch?

DR. KRUCOFF: I also will try to be brief. I guess I am most interested
in the use of the OPC-based trial design. Obviously, that is consistent
with the precedence in this area of industry.

But I think it has been remarkable to me, in listening to your
presentation, the difference between the fascinating findings from this
study, which is to me the investigator\'s view of what happens in a
patient and how it works, versus what you have welded yourself to with
an OPC-based trial design that I think Dr. Yue did a very eloquent job
of illuminating. It is really a population kind of statistic.

So the observed behavior of the catheter in individual patients, the PI
sort of view, and how it will behave in the population, and whether or
not you qualify based on boundaries for your endpoints as successful or
not are two very different worlds.

I guess what I would like to hear is, why do you think you failed to
show the boundary outcomes?

DR. FRIEDMAN: I think there are a couple of points to mention in
answering that question. When the protocol was being designed, we were
faced with a choice of either using an OPC, an historically-derived OPC,
or doing a randomized comparison between cryo and RF. The randomized
comparison would not have allowed us to look at cryomapping because
there is no way to map with radiofrequency. So we were, basically, stuck
with the OPC comparator for the purpose of this trial.

I would point out that that OPC is derived from results recently, and RF
is a very mature technology. It has been around for nearly 20 years now.
This is a very young technology. So we are comparing ourselves to a very
high bar.

Beyond that, I think that the technology was demonstrated to be
clinically effective in the group for which an indication is being
sought: Ninety-one percent in the AVNRT patients is a
clinically-valuable result.

The reasons why the OPC weren\'t met I think relate to the fact that
some of the ablations were in AVRT, left-sided accessory pathways. This
technology is very different than radiofrequency. I think you saw the
acute effectiveness results were less dramatic in the AVRT group than
the AV nodal reentry group.

I think you have to think about the biophysics of ablation and the
differences between these two technologies to understand that. With
radiofrequency ablation of the left free-wall pathway, typically done
along the mitral valve annulus, this is a high blood-flow area. That
high blood-flow actually serves to cool the radiofrequency tip, and in a
way it is almost akin to a saline-irrigated RF ablation.

From Dr. Dubuc\'s animal studies, we know that radiofrequency ablation
causes a larger area of damage on the endocardial surface. That relates
to the fact that the catheter is moving. It is not stuck to a certain
point. It paints back and forth across the endocardial. So that one
doesn\'t need to be exactly on the accessory pathway to achieve a
successful ablation.

It is very different for cryoablation. Cryoablation adheres to the point
and does not move from that point. That high blood-flow along the mitral
valve actually acts as a heat source that minimizes the efficiency of
the cryoablation. I think that relates to why there may be a difference
in effectiveness in that group, which affected the overall results.

But, conversely, I would look at it a different way, because in
high-flow areas where cryoablation may not have an advantage, in
contrast to low-flow areas, it may have a very real advantage, and
specifically in post-receptal accessory pathways within the coronary
sinus, for example, where radiofrequency often can\'t be done because of
high impedance and low-energy delivery, and in the slow pathway
position, which is not as high a blood-flow area. It results, I think,
in the fact that in that circumstance it is highly effective.

DR. KRUCOFF: Well, I mean, I hear you, but I\'m honestly not sure to
which side of my question this ‑‑ you know, again, to me, what I hear is
an enormous amount of conceptual and intellectual fascination in why and
where this technology really might be an advance beyond RF.

But how much of that is reflected in this clinical trial or can be
deduced, or even in the 91 percent in AVNRT, is the actual observation?
It is the boundaries around that that become even relevant to talk about
with an OPC. As was described, it is not the boundaries around the whole
population. It would be the boundaries around the RF population and
AVNRT. Again, at least my understanding of the data, unless I missed
something, is that even the boundaries around the 91 percent for AVNRT
do not compare favorably to the RF historical boundaries that you would
pre-define if you had prospectively pre-defined for that population.

So, I mean, I get that there are a lot of theoretical both safety and
effectiveness possible subpopulations that this instrument might be
terrific for. On the other hand, I also get that, like so many things
that we do, it is possible that the more damaging milia that RF creates
may have areas where it is actually more effective.

The fact that I saw two different sets of numbers, but whether it is 23
out of 25 or 25 out of 27 of the cryo failures that were successfully
done with RF, I don\'t need an explanation of that. To me, it just says
that one is more histologically pleasing to look at than the other. It
ultimately begs the question of when you start applying this to a
population of human beings, where is the data that gives you confidence
that this is a safe and effective approach?

And with an OPC set of boundaries that, even in the group who you are
asking for an indication, if you drill down retrospectively to your
point control population, you still don\'t make the boundaries for the
AVNRT.

So I am just missing a link as to, if you bought into this trial design
from the beginning, which obviously you must have at some level, how do
you come to see the data supporting the fascination? The fascination is
self-evident? The data that this is safe and effective compared to a
well-established, as you say, mature technology is, I think, what the
patient or user side question is.

I am really interested in why you think, both in the safety and in the
effectiveness, you failed to make your boundaries?

DR. LEHMANN: I will just briefly comment on the design. As you do know,
sponsors don\'t have a free hand in choosing a clinical study design. It
is negotiation with the agency.

We either had the choice of a ‑‑

DR. KRUCOFF: Well, you could have done a randomized trial.

DR. LEHMANN: Yes, we could have done a randomized trial, but there are a
number of problems with that, including standardizing RF therapy
procedures and equipment, which is actually rather hard to do ‑‑ it will
cause a large study ‑‑ and the difficulty with cryomapping.

As to the implications of what we have demonstrated, I think Dr.
Friedman will just have a few remarks.

DR. FRIEDMAN: I will try to answer your question. I understand what you
are wrestling with, and it is a difficult issue. I will try to answer it
by putting it in clinical perspective.

I think it is very helpful to step back and try to look at things from
the perspective of the patient. If I\'m a 20-year-old patient with AV
nodal reentry that is interfering with my lifestyle and a physician gave
me two choices: One choice, I can have radiofrequency ablation with a 94
percent chance of acute success; however, there is a 1 to 2 percent
chance that I am going to wind up with a permanent pacemaker. Or I could
have a cryoablation with a 91 percent acute procedural success rate and
no chance ‑‑ no chance ‑‑ for a pacemaker. It is very clear in my mind
what I would choose, and I would venture to say that most individuals
faced with that decision would make the same decision that I have just
made.

CHAIRMAN LASKEY: I must say I need to object to that last statement. It
is not zero. The confidence intervals of zero events observed in 150
patients go out on my back-of-the-envelope, amateur stat. program here
to 2 percent. It\'s not zero. I think you do need to be rather
intellectually honest to some of these questions.

I think we are on the threshold of perseverating as well. So I\'m not
sure we are going to get to what you really need to know.

DR. KRUCOFF: I think a question is on the table, and I think, you know,
again, I am just going to move on because I only have a couple of other
brief questions.

In your European experience, are you aware of any instances where RF
ablation has failed and cryoablation has succeeded?

DR. DESMARAIS: Well, in fact, every time that there has been ablation in
AVNRT and do defibrillation near the aveno where the physician either
pulled back, because of fear of I think an AV block and subsequently
tried trial, there is a lot of data that concurs that we have successful
cryoablation after RF.

DR. KRUCOFF: Okay. Thank you. So what I am hearing is, in situations
that the operator sort of judged to be too risky to actually fire RF
energy ‑‑

DR. DESMARAIS: Or has fired RF and failed in that, as well I think
there\'s a current trial in the U.S. Again, this was filed initially by
the PMA. The data we have, we know that these are patients that failed
RF, that the study conducted by Dr. Chapman right now, which is a small
subset study, but we don\'t have any data to present on that.

DR. KRUCOFF: Okay, and are you aware of any experience with cryo
patients that were not durable, that came back, that were redone with
cryoablation? Can you go back and freeze the same site twice. Do you
have any experience with that?

DR. DESMARAIS: Yes, and I think Dr. Dubuc can answer that. He has done
some of those patients.

DR. DUBUC: I think I have two parts of this question, if we have
patients who have failed RF and they went to cryo or if they had two
sessions of cryo?

DR. KRUCOFF: Yes.

DR. DUBUC: Okay. Well, yes, with no problem. No problem at all.

DR. KRUCOFF: Have you looked at that in animals, if you repeatedly
cryoablate the same tissue?

DR. DUBUC: Nothing will happen because the process is already in
evolution. Actually, I could say that, even if you stand there, and why
we picked that time of four minutes is because we know that after three
minutes you reach a plateau that the ice ball inside the tissue will not
grow anymore. It will stop there, and that has been proven by cardia
ultrasound, because you can see the ice ball with ultrasound, with
intracardiac ultrasound. Actually, we can monitor that. Actually, the
correlation coefficient between the measurement done by echo and the
histology was .95.

DR. KRUCOFF: Okay, I have no other questions.

CHAIRMAN LASKEY: Thank you, Mitch. Dr. Page?

DR. PAGE: Thank you. I will try to keep this as short as possible.

The first question is ‑‑ actually, the first two questions have to do
with the footprint of this device. Peter, maybe you could answer this,
Dr. Friedman.

In terms of looking for biological plausibility for why you found what
was, I guess, an unexpected result, that AVNRT was successful and AVRT
was not, as I wrestled with the biological plausibility of that finding,
as opposed to just chance, which is what we always have to be concerned
about with a post-hoc analysis. Would you say it has to do with the
footprint of this device being smaller and being adherent at the time of
ablation lesion?

DR. FRIEDMAN: I think those are the answers, as I alluded to earlier,
yes.

DR. PAGE: Okay, fair enough. Do you have an idea, how long is it before
you get adherence of this catheter at the ablation site?

DR. FRIEDMAN: It occurs within a matter of 10 or 15 seconds. It depends
a little bit on how stable the catheter is to begin with and what kind
of contact one has with the tissue.

But by the time the artifact on the catheter that I showed you there
indicating freezing appears, that catheter is stuck.

DR. PAGE: And, likewise, would you say that it detaches at about the
same interval that we saw on that electrogram? So a few seconds, but
pretty promptly?

DR. FRIEDMAN: Within three or four seconds.

DR. PAGE: Within three or four seconds, good.

And as someone who performs ablation, I recognize the advantage of
having an adherent catheter at the spot you are burning or freezing in
this case, because, especially if you are burning during tachycardia ‑‑

DR. FRIEDMAN: Yes.

DR. PAGE: \-- then it will stay put when the geometry and the motion of
the heart changes as you break the tachycardia.

Let me flip that around. I have spent the last 10 years doing ablations
in Texas, and every once in a while a patient would get up off the table
in the middle of a burn or grab or move a leg. What data do we have in
terms of, if a catheter is pulled when adherent to the tissue \-- you
understand my question?

DR. FRIEDMAN: I do.

DR. PAGE: We\'ve all been through this, being in a busy lab, and
suddenly a patient moves, and your catheter might move with him. With
the standard RF catheter, it may perforate or it may more likely pull
away from where you are burning.

But if you are attached and someone took a tug at that catheter, what
happens to the tissue?

DR. FRIEDMAN: Well, there are some animal studies that we could cite,
but I would follow up just by saying that, if the patient moved,
injection can be halted within a matter of seconds.

DR. PAGE: I understand that, but this happens so fast, and we have
already agreed that it sticks for a couple of seconds. This happens in
less than half a second, as we all ‑‑ anybody who has been in an EP lab
recognizes sometimes the patient will suddenly come up off the table.

DR. FRIEDMAN: Yes.

DR. PAGE: So if that does occur with adherence, what happens to the
underlying tissue?

DR. DUBUC: I mean, if the range of motion you are talking about is
rather small, I mean I don\'t think that the patient would start running
from the table.

DR. PAGE: No, but imagine ‑‑ let me put it clearly because it happens.

DR. DUBUC: Yes, I know.

DR. PAGE: Imagine someone in the middle of the burn tugs it forcefully.
I mean, what comes with the tip?

DR. DUBUC: Okay. If the patient moves, nothing will ‑‑

DR. PAGE: That\'s not my question.

DR. DUBUC: Okay. If somebody tugs really just a little ‑‑

DR. PAGE: No, I\'m saying a good, strong tug.

DR. DUBUC: Well, you can do damage to the tissue underlying the ‑‑

DR. PAGE: The underlying tissue?

DR. DUBUC: Yes.

DR. PAGE: Okay. And my only caution being, you know, we have had
physician experts talking about looking forward ‑‑ I should just
mention, first of all, that at the AV node slow pathway area, this
probably would not be a major catastrophe. If someone is taking this to
other places ‑‑ we have talked about parahisian. What if we wanted to
outflow track ablations, something like this, where the tissue is thin,
atrial tachycardias where the tissue is thin, do we have any data on
what would happen then?

DR. DUBUC: Well, something wrong can happen because, you know, we made
animal studies on that or on purpose we pulled ‑‑

DR. PAGE: Sure.

DR. DUBUC: \-- you know, strongly on the catheter. Actually, if you pull
a lot, you can bring part of the heart inside the IVC and even have
avulsion of the tissue. Really, if you have two people on the ‑‑ we did
that testing.

DR. PAGE: Sure. It doesn\'t happen often, but it does happen rarely.

DR. DUBUC: Yes.

DR. PAGE: Okay, thank you.

One question I had, and I just have one other question after this: We
seem to agree that there were no catheter-related complications, but
there were a number of complications that I think related to procedure
time and DVT, atrial clots, and bladder infection related to a Foley
that you don\'t need for an hour-and-a-half procedure, but you might
need for a 260 average minute procedure, the average number of burns is
7.5, and those were four-minute burns? Is that right?

DR. FRIEDMAN: Four-minute freezes, yes.

DR. PAGE: Thank you.

(Laughter.)

I am so old-fashioned.

So four-minute ablations, if you will. So that is about 30 minutes of
actual ablating time. So this is, indeed, a longer procedure, related to
whether it is the experimental condition or not, it is a longer
procedure. I think the length of the procedure related to the
experimental protocol, indeed, was responsible for increased
complications.

I would mention that the European data you showed us, which I never had
a chance to see before today, was reassuring in terms of number of
lesions as well as duration of the procedure. So I could presume that
those wouldn\'t be ongoing complications, and the procedure time would,
indeed, shorten.

My last question was, in terms of the comment on parahisian pacing,
which, as I mentioned, concerns me because we are talking about a very
limited indication here, and with approval, I am already hearing that
people are looking forward to using off-label use of the device and
potentially in tissues where we have already discussed could be a
problem if the catheter weren\'t handled properly.

But if I saw the data properly, when you have a failed cryomap, that
still translated to a 67 burn success at that site?

DR. KRUCOFF: Ablation.

DR. PAGE: Ablation. The slide, it was like 90 percent ablation when you
have a successful cryomap, but even a failed cryomap, you ended up
getting successful ablation 67 percent of the time. So my only caution
is, with these 20-year-olds that are waiting to have their parahisian
pathways ablated, a negative test pulse, cryomap, will not necessarily
translate to failure to ablate the his bundle. Am I interpreting the
data correctly?

DR. LEHMANN: I would make one minor correction. The figures that you are
quoting that were recently up there were on a per-patient basis. The
distinction between a subject with one or more effective cryomaps versus
subjects who were attempted but had not effective cryomaps, versus the
group that was never attempted.

So that isn\'t on a ‑‑

DR. PAGE: So on a per-burn basis, it is lower than that?

DR. LEHMANN: Well, the overall is ‑‑ we would have to go back and look.
I don\'t have that on the tip of my tongue.

DR. PAGE: I think you\'re right, it\'s significantly lower.

DR. LEHMANN: Yes.

DR. PAGE: My only caution being that I don\'t know what comfort I have
that the test pulse, indeed, will not result in true ablation of the
normal conduction system.

And my last question is, the reversibility of the heart block that you
have seen, that wasn\'t just with cryomapping; that was also during an
attempted ablation, is that right? And then you turned off in time and,
indeed, conduction returned?

DR. LEHMANN: There are two aspects to this. One is the straight
cryomapping where we had 162 effective cryomaps, of which only around 64
of them, 62 of them were warmed for reassessment. That is where we got
the 90-plus percent reversibility of an individual intended cryomap
effect.

Then we had 11 adverse events, these device-related transient AV block,
of which one was related to cryomapping and led to a death. It was
intended. It wasn\'t the therapy, they contend. They were trying to go
after one of the slow pathways, and that subject had unintended AV block
that lasted 20 seconds. So that was an adverse event.

DR. PAGE: But in terms of when you are therapeutically ablating, those
do also, if you see heart block, they tend to get better?

DR. LEHMANN: Those, we had the 14 instances in 11 subjects all reverted.

DR. PAGE: And that is reassuring. Thank you very much.

CHAIRMAN LASKEY: Nobody in this room is more sensitized to the off-label
use of the material that we\'re discussing. So could we please restrict
our comments to the material at hand and not encourage off-label use?
But thank you very much.

Dr. Aziz?

DR. AZIZ: I, too, enjoyed the presentation, and I must say I learned a
little more electrophysiology today.

Let me just address a few questions. Looking at the number of patients
who actually developed either arterial or a venous clot, I guess part of
that may be related to the time that the catheters were in place, and it
seems that the times with experience do decrease.

Do you put these patients on any anti-platelet agents or anything that
you suggest that that should be done?

DR. FRIEDMAN: In the study protocol, decisions about anticoagulation
during and after the procedure were left to the investigator based on
the practice in that laboratory and, as you might imagine, varied widely
from one institution to another.

For example, the one case of a pulmonary embolism that I mentioned as an
AMC was a woman who actually had a fairly short procedure and did not
get heparin during her procedure, but she went home and spent two days
in bed and developed a deep venous thrombitis that embolized,
undoubtedly related to the catheter insertion site, but in a sedentary,
bed-ridden person.

These other procedures that I showed you, one of them I mentioned
specifically was a very, very long procedure where no heparin had been
given for some eight hours.

So our own practice at our institution is that patients get
anti-coagulation during right- and left-sided ablations, and they all
get sent home on aspirin, but I think that that is going to vary from
investigator to investigator.

DR. AZIZ: And you have seen the histological slides of the difference in
damage done with cryoablation versus RF. In clinical usage, did you see
that translate into better or less CPK leakage with cryoablation versus
RF, or you didn\'t think about that?

DR. LEHMANN: We did see some CPK rise and we didn\'t compare it to any
RF experience, but there is some CPK rise with ‑‑

DR. AZIZ: In somebody who had a prior, let\'s say, tricuspid valve
repair or a tricuspid valve replacement, could you still use this
technology, depending on, obviously, the type of ‑‑

DR. LEHMANN: These subjects were excluded from this trial.

DR. AZIZ: I guess, when it does come out, could you see it being used in
somebody who has had prior tricuspid valve surgical procedures done?

DR. FRIEDMAN: That\'s a problem even with radiofrequency ablation. I
don\'t know the answer to that. As I think about the biophysics of this
technology, nothing occurs to me right away that would make me think
that it would be contraindicated. If there is a sewing ring in the
tricuspid valve and you are trying to ablate beneath that, I am not sure
how effectively the cryo energy would be transmitted. It might not be
that effective, but I don\'t think there would be any particular safety
concern.

DR. AZIZ: Let me just go over ‑‑ there were one or two patients. On page
85, Subject 0917, could you just have a look at that? This was actually
a 76-year-old male who had the procedure performed. Echo post-procedure
showed that his EF had increased and he had quite significant mitral
regurgitation, and that the left atrial size had actually also
increased. The dimensions had increased by 9 millimeters.

DR. LEHMANN: Which document?

DR. AZIZ: Page 85, Subject 0917.

CHAIRMAN LASKEY: In the general packet itself, the patient descriptions.

DR. LEHMANN: I can\'t find the reference.

DR. AZIZ: The patient was 0917.

DR. FRIEDMAN: I\'m reading here from the report. I don\'t know this
patient, but let me just read the details of what we know.

DR. AZIZ: Okay.

DR. FRIEDMAN: An 89-year-old female had a baseline echo which showed
aortic stenosis, mild tricuspid, and mitral regurgitation and inject ‑‑

DR. AZIZ: Actually, it is the next one.

DR. FRIEDMAN: Okay. Seventy-six-year-old male, baseline echo showed
thickened aortic valve leaflets, mild MR, mild TR, and an injection
fracture of 63 percent, underwent successful AV node ablation for rate
control and permanent pacemaker without adverse event. Post-procedure
echo demonstrated dilated left atrium; the pacemaker in the right
ventricle.

I think it is difficult to compare those two echoes for a couple of
reasons. No. 1, baseline, the patient had a very rapid ventricular
response and, presumably, a normal QRS because of rapid conduction
through the AV conduction system.

Post-ablation, clearly, had a much slower heart rate, which by itself
would increase cardiac dimensions by any measure, and, in addition, had
a right ventricular pacemaker, because there was no intrinsic AV
conduction. Pacemaker implantation alone in someone with AV block could
lead to ventricular dilation and even some degree of mitral
regurgitation.

My guess is that that is related to the pacemaker implant and the
presence of AV block post-procedure as compared to pre-, not a function
specifically of cryoablation.

DR. AZIZ: Thanks.

DR. WALDO: I just had a few short questions. The histology that you
showed us, the iced lesions looked like ventricle. Am I correct? Have
you done that at atrium? Is there any more of the same, because ‑‑

DR. DUBUC: For the purpose of presentation, we showed mainly ventricle
lesions. Those lesions are all ventricular, the lesions you saw this
morning in the presentation, but we did the same in the atrium.
Naturally, all these lesions were transmural.

DR. WALDO: That was my point; they are transmural?

DR. DUBUC: Yes.

DR. WALDO: And no other problems? Okay. How do you decide on 4
millimeters being necessary duration of the application of freezing? For
minutes? I\'m sorry.

DR. DUBUC: The four minutes, yes. Well, we ‑‑ and this work is already
published, but we demonstrated with the ultrasound we can monitor the
ice ball growth within the tissue, and we can monitor the size and it is
growing for about three minutes, and then you reach a plateau after
three minutes.

So we decided that four minutes was okay. This, as I said previously,
the size of the ice ball correlated very well with the coefficient, the
correlation coefficient of .95, when we compare histology to the size we
found by ultrasound.

DR. WALDO: Okay, two other very brief questions: Peter, when you
answered an earlier question, you didn\'t address the issue of the
relatively surprising to me poor success rate for his cryoablation.

DR. FRIEDMAN: Yes, that does stand out, Dr. Waldo, though I am not sure
why. The numbers are small, and those confidence intervals are fairly
wide. I think it is hard to make any definite conclusions.

DR. WALDO: Okay, now just a little heresy from me: I don\'t know, I
think this is a philosophical point I would like to make in considering
this. I think the statistics here have been very well presented. I am
not a statistician. We are going to hear a lot of more, and I think if
you just took a statistic, there are some real questions, and Mitch
addressed some of them.

But, for me, that is why it is heresy, because I hope ‑‑ I have been a
scientist in my time, and I think data are very important, but I look at
this, do look at this in part as a clinician. I think one of the things
I look upon this as another option. There are not a lot of secrets about
AV nodal ablation. We know the mechanism. We know how to go about it.
There are not a lot of secrets about hisp ablation, even about getting
accessory AV connections.

I just see that there are times when one would want to have an
alternative technique. And what becomes important there is safety. And
if I understand the data, I think we have seen that it is remarkably
safe.

I think efficacy is always important, but I haven\'t seen a terrible
efficacy really. I have seen quite a good efficacy, maybe not as good as
some of us would like to see, especially statistically or if you look at
ITT and a lot of other things. I understand that thing.

But I think that we shouldn\'t lose sight of the fact that this provides
the clinician with an alternative therapy that may be very important
sometimes, and it is safe. I would just like to leave it at that.

CHAIRMAN LASKEY: Not heretical at all, Dr. Waldo.

Dr. Bailey?

DR. BAILEY: Well, I feel like everyone\'s waiting for my remarks here.

(Laughter.)

As a statistician, I guess I belong to the group that we don\'t allow
second chances; we don\'t allow rescue procedures for analysis. If you
miss it on your first shot, we don\'t bail you out, although I think the
sponsors were well motivated to try because it certainly looks like a
very interesting device.

However, as a patient or as a consumer, I am certainly interested in
rescue procedures. I guess most of my remarks tend to be on the
philosophical.

I agree, if you accept the design of the study, the OPC pretty much
ropes you in and you don\'t even need to think about it. I agree, I
thought both the sponsor and the FDA made excellent, clear presentations
of the data, with obviously some differences in interpretation.

Of course, the subgroups, you know, we don\'t let you look at subgroups,
but, of course, you have to look at subgroups. You have to; they are
interesting.

I guess, what does it mean to have an overall OPC if, indeed, the
efficacy is intimately linked to the composition of the study
population? Now I don\'t know how much of the variability would have
been known ahead of time, but I understand in the radiofrequency
literature there\'s also variability of efficacy of ablating these three
different entities.

So I guess from a philosophical point of view, how do you come up with
an overall OPC when you have heterogeneity that may influence what the
result is in any given population?

There was a little bit of vagueness in the way the protocol was written,
but I think, to be hard-nosed, you have to accept that the overall
results are what count. However, this thing about the rescue procedures,
I mean, as a consumer, you know, if I am being offered a procedure that
has much better safety in some sense, but I agree with the comment that
that\'s not necessarily been shown, then I might be willing to have a
lower efficacy, initial efficacy rate, if I can also, then, get the RF
procedure as a backup.

I guess it has sort of surprised me that we weren\'t looking at the
overall success rate of the strategy. Now the RF procedure, is it done
in the same catheterization or do you have to come back later for it?

DR. FRIEDMAN: It was done at the time of the same procedure.

DR. BAILEY: I presume it adds quite a bit of time though to the overall
procedure.

DR. FRIEDMAN: It depended on the patient. Some patients who failed cryo
also failed RF. They, obviously, tended to be longer procedures. Some
had a successful RF very quickly, and it was a short procedure.

DR. BAILEY: I had thought that the complications weren\'t related, but,
as I understand, they could be related to the length, overall length, of
the procedure. So it would be important to know whether the complication
rate was, indeed, related to the length of the procedure and, indeed, to
the performance of the back-up procedure or two procedures rather than
just one.

But, subject to that, I would think that, from the point of view of
seeing where this fits in or if it fits in, it is not really fair to
compare the initial efficacy to the efficacy of radiofrequency ablation,
unless you are proposing this procedure as a substitute for it without
the opportunity to perform RF ablation.

But if you are proposing a strategy, then now that may imply that we
need a higher limit than 85 percent, but I think that, as a consumer,
not a statistician but a consumer who happens to have a Ph.D. in
statistics, that is what I would be looking at, is, you know, what\'s
the efficacy, given that I am going to be able to have a rescue
procedure, if necessary? Not rescue, a back-up procedure.

That is why I would have been interested in ‑‑ well, we were given that
initial success rate, and it was well over 90 percent. I would have been
interested in the success rate at three months, and so forth.

In terms of the safety issue, it is also amazing how different, again,
the OPC is from the way the data seem to be that are most relevant, in
that although ‑‑ again, that was probably from naivety ‑‑ I didn\'t
realize that it is possible that it may be somewhat actually difficult
to determine which complications are related to the procedure versus
just the device.

But the one thing that stands out is that, in order to achieve your OPC,
you had to have four events ‑‑ I\'m sorry ‑‑ you needed to have a rate
such that you were expecting four events, four complications, five was
the limit, and then you actually observed seven.

I guess what is striking is how little tolerance there is between those
numbers. So I think this gets at the point that this is a very small
study on which to base safety, given the vagaries of what causes these
complications, and the extent to which they are dependent on the devices
is unknown. That is why either large numbers or a comparison group or
something.

In terms of the randomized trial, I didn\'t follow the argument why the
cryomapping prevents you from doing a randomization. You can still look
at the efficacy and safety of the strategy of cryoablation. You could
even randomize the use of cryomapping or not, if you wanted to, versus
radiofrequency without the alternative of ‑‑ of course, on the
cryoablation side, you would have the opportunity to use radiofrequency,
if necessary. Then you would be comparing efficacy immediately at three
months and, of course, complications.

But I didn\'t follow the ‑‑ I heard you say that the cryomapping made it
impossible, but I didn\'t follow the logic of that.

And I agree with all the comments that have been said, that the
cryomapping really, in order to understand it, you really have to
compare the groups that get cryomapping versus groups that don\'t, if
you are trying to look at the efficacy of it from a strategy point of
view, and probably even in this study, even doing that analysis is very
fraught with the usual observational biases.

So those are my questions.

CHAIRMAN LASKEY: If they were questions, do you want comments or
questions or more thoughts?

DR. BAILEY: They are comments that are questions.

CHAIRMAN LASKEY: Oh, I see.

DR. BAILEY: We should give the sponsors an opportunity to respond then,
starting with ‑‑

CHAIRMAN LASKEY: Why couldn\'t you do a trial?

DR. LEHMANN: Well, it could be possible to do that. I rose to just
respond to a few of the numbers, if I could address those.

Just to the overall strategy of cryo and then RF, if cryo failed,
resulted in a rate of 97 percent for every study subject, and in each
instance RF was undertaken in the same procedure.

Any measure of adverse events was not correlated with either the number
of cryoapplications, the number of cryomaps, the number of
cryoablations, nor procedure duration.

In descending order of certainty, we have 151 IDE subjects in this trial
with no AV block. In a prior IDE trial of a 9 French device, otherwise
essentially identical to this one in its mode of action, and two trials
done in Canada under essentially the identical protocol, using the same
monitoring group and submitted to the TPT, and filed with the FDA in the
PMA.

So we have almost 300 very-carefully-observed patients followed for many
months, and the number AV block in that population was zero. Zero out of
300 is, back of the envelope, is about 1 percent upper limit.

Now with lesser degree of certainty, there\'s another 300 AV node
reentrant tachycardia, AV reentrant tachycardia subjects in a European
registry, where they do get more attention than normal. It is not
carefully monitored in a classic sense, and that is about 600 no AV
block. Then, of course, there is the commercial experience, which, as we
all know, has its issues on reporting. So those are some numbers in
relationship to some of the remarks you make.

CHAIRMAN LASKEY: Thank you. Dr. White?

DR. WHITE: You\'re not going to take a turn?

CHAIRMAN LASKEY: I\'m not allowed to speak.

(Laughter.)

DR. WHITE: I would like to echo, without repeating the words, what Dr.
Krucoff said. I think we hold very similar opinions about understanding
the magic or the theoretic nice pieces of this procedure, but wondering
why the device didn\'t actually perform.

Could I just ask a specific question about the IFU, about the
instructions for use? Could you clarify for me whether it is possible
for this device to be connected to an RF generator?

DR. DESMARAIS: The answer is no.

DR. WHITE: Then why did you take the time to write it in here?

DR. DESMARAIS: I think, you know, you want to address from when we do a
risk hazard analysis, which is a technique used in the industry when you
look at all the potential hazards. By design we\'ve mitigated that, but
it\'s always there and a good practice to put all kinds of warnings and
precautions to address the risk analysis that you conduct.

DR. WHITE: Is the criteria for LV ejection fraction being greater than
35 percent, I think, in your protocol, is that necessary for clinical
practice?

DR. DESMARAIS: I will ask Dr. Friedman.

DR. FRIEDMAN: As a practicing electrophysiologist, I wouldn\'t see that
as an exclusion. I think for the purposes of the trial, the intent was
to identify healthy patients who were less likely to have co-morbid
conditions.

DR. WHITE: How do you feel about IVC filters and working through them?

DR. DESMARAIS: Dr. Friedman?

DR. WHITE: Is that a problem or no problem for this device?

DR. FRIEDMAN: With other catheters, radiofrequency catheters, we
traverse IVC filters without difficulty. The average dimension in this
catheter is really 7 French, the same size. I don\'t foresee a problem.

DR. WHITE: And for aortic valves retrograde, do you mean mechanical
valves or do you mean a pig valve as well?

DR. FRIEDMAN: No, we don\'t think we would advocate traversing
retrograde a mechanical aortic valve. Those patients would have to be
done transeptally. But for a porcine prosthetic valve or a native valve,
this catheter could be used retrograde.

DR. WHITE: Because the contraindication simply says any aortic valve
replacement, you may want to be more specific about that.

In the demographics, in slide No. 46 that you showed, it struck me that
you had excess of women in the trial. Is it that women have more of
these arrhythmias than men?

DR. FRIEDMAN: That\'s a very good question actually, but that mirrors
clinical practice. Women present with AVNRT and AVRT more commonly than
men. I don\'t know whether it is a genetic difference or there is a
difference in diagnosis. Maybe men don\'t complain of palpitation or are
less troubled by the palpitation. There could be a host of explanations,
but ‑‑

DR. WHITE: But you would agree that percentage would be representative
of the clinical practice.

DR. FRIEDMAN: I think that is representative of clinical practice.

DR. WHITE: And the minorities were not represented in an adequate
fashion here. I mean, is there a reason why American Indians, Blacks,
Hispanics were not represented in percentages that are reflected in our
population?

DR. FRIEDMAN: I don\'t have an explanation for that, but I would point
out that overall it was a fairly small trial, and you might not expect
to see it reflected in those small numbers.

DR. WHITE: We have heard today, I think, a lot of reasons to think that,
because the device attaches and because the device has a smaller
footprint, that there may be some theoretical safety benefits, but I am
not sure I am convinced that the device has been proven to be safer
because it has not been directly compared.

As I think Dr. Page mentioned, I think some of the complications which
are not catheter-related certainly appear to be procedure-related. And I
think that if, as you are comparing the patient who is going to have one
or the other of these procedures, those complications need to be taken
into account.

The other issue is that I am not an electrophysiologist, so I am hearing
so much about AV block and how terrible this is with RF, but in the
paper that you provided us in the Panel pack, the Calkins paper that
looked at the thousand patients with radiofrequency ablation, the
incidence of heart block was only 1 percent in that population.

So I guess I am not being struck with ‑‑ I am not convinced that in 151
patients that you have actually convinced me that AV block will happen
in less than 1 percent of your patients.

DR. FRIEDMAN: I think there are a couple of points to mention there.
First of all, if one actually does a careful literature search, the
incidence ranges from 1 percent even to as high as 14 percent in some
series actually reported from fairly busy laboratories with experienced
investigators. So 1 percent is probably the lower bound, if you will. It
is the best that you would expect.

The other point I would mention is that it does not include patients who
were referred for AVNRT ablation, who may get one or two ablation
attempts, and then because of proximity to the compact AV node, the
procedure is stopped. I have seen patients, like every one of us who
does these procedures have patients like that. They don\'t develop AV
block, but they also don\'t have a successful procedure, and they\'re
not reflected in those data.

DR. WHITE: The other thing I would like to ask you about is in slide 64
and 66, which were the Kaplan-Meier curves for long-term success. It
appears that the patients drop out of your Kaplan-Meier curve, and it is
not clear to me why you haven\'t retained the patients in the
Kaplan-Meier curve.

You\'ve got at six months, for the long-term success of all subjects, 77
patients being measured in the Kaplan-Meier curve, whereas your flow
sheet at six months you\'ve got, I believe, 119 patients who were
available. It is slide 64.

DR. FRIEDMAN: Well, I will see if we can find the slide. Sixty-four.

DR. WHITE: Actually, 64 and 66 both show it.

DR. FRIEDMAN: Right. So just bring that one up.

DR. WHITE: You see at six months you have 77 patients when in your flow
sheet here you have accounted for 119.

DR. LEHMANN: First of all, here\'s the three-month point, starting here,
and the effect is stable. This six-month telephone followup, here is a
dispersion, because there was a window of following the subjects. The
software, of course, takes the exact number as of the exact point. When
you do a live table, you take the inferred endpoints. So you\'ve got all
of these subjects with the nominal six months, but in this subject
attrition line it stops dead right there, losing ‑‑ so that is why you
do both of the assessments.

But really with this curve you can see that there has been absolutely no
change, and all of the six-month follows are represented, although they
don\'t come to that number.

Have I addressed the question? No?

DR. WHITE: Am I dumb as a rock or what?

(Laughter.)

I mean, how many patients got measured at six months?

DR. LEHMANN: A hundred and twenty something.

DR. WHITE: Then how come it says 77 at the bottom?

DR. LEHMANN: Because if the phone call occurred at six months and one
day, then it doesn\'t show up in that six-month number in the
Kaplan-Meier; in the survival analysis it measures every day as a
distinct event. In the life table analysis it measures the increment,
the normal increment.

DR. WHITE: All right.

DR. BAILEY: So, technically, it shows the status of that patient.

DR. WHITE: That is not the way I do my Kaplan-Meier curves. I don\'t
understand them, I guess. Are you telling me that\'s right?

CHAIRMAN LASKEY: Dr. Bailey?

DR. BAILEY: No, in a way, I think you might want to consider interval
censoring there. If you assume that you don\'t get recurrence that goes
away, if you just assume that the later time point is representative of
the earlier time point, you could sort of back it ‑‑

DR. WHITE: I guess I would like to be assured that all of the patients
have been followed and that their events are being accounted for. So
when I see 40 percent of the patients not being accounted for, I am
concerned that you are not seeing them.

DR. LEHMANN: No, I forget the exact number, but over 95 percent of the
subjects with acute procedural success were followed.

DR. WHITE: Right. Well, no, they are here in your flow sheet.

DR. LEHMANN: Yes.

DR. WHITE: And they are identified here. So I am just wondering why they
are not showing up.

DR. LEHMANN: Well, go back to the live table. Go up to the live table. I
think if you look at the life table, here you see we start with 136, and
these are the subjects that are lost. So by month six we have lost three
out of 136 from analysis. There\'s 122 who remain successful ‑‑

DR. WHITE: So does it strike you as strange that your graph doesn\'t
show 122 at six months?

DR. LEHMANN: It doesn\'t strike me as strange at all. That is just the
way it works in the two different analyses.

DR. WHITE: Okay. What do I know? I\'m dumb.

CHAIRMAN LASKEY: No, Chris, you\'re just rebelling against how computers
constrain our thinking.

(Laughter.)

That\'s the output of the tests. Thanks.

DR. WHITE: Yes.

CHAIRMAN LASKEY: George?

DR. VETROVEC: Very briefly, was there any evidence that procedure time
got shorter by the number of procedures done? In other words, in the
second half of the study, is the average procedure length less?

DR. LEHMANN: We haven\'t assessed that.

DR. VETROVEC: And then in terms of training, the observation was made
that, \"I learned to do a hundred of them and then I could teach the
other fellows in four or five procedures.\" What is it that you have to
teach them that is unique about this, because this is going to be
important, if you come down to, what do you specify as a training issue?
What is it that\'s different?

Even if you couldn\'t document a learning curve, there was something, it
sounds like, you had to train the other personnel in doing. What was it?

DR. DESMARAIS: I will let Dr. Dubuc answer that, specifically what has
to be done for training of the person.

DR. DUBUC: I think you can call it training or teaching. People doing
this procedure with this new technology, they have to acknowledge that
it is different from RF, and that is the only point here.

The thing is, like I said previously, when you do AV nodal reentry
ablation and you are going into a slow pathway area, you expect the
technology to produce, when you are successful, to do rapid junctional
rhythm. This you don\'t have with cryo. So this is different. So the
operator has to know more than that; their catheter will stick to the
wall, adheres to the endocardial surface. So during that time you can do
pacing or program stimulation, which you cannot do with radiofrequency.
So this is different.

And, third, you have the attachments. So you cannot move the catheter
during the position, and the catheter is very, very stable. It will stay
there, not like RF, when you have this slippage from the area.

So those are the three main reasons, and the people doing the
procedures, they have to acknowledge that it is different from RF from
the beginning. So it takes time because you change the way you ablate
and you make your procedure.

DR. VETROVEC: I don\'t disagree with you, but it just is an issue in
terms of, how has this been disseminated into the practicing population?

DR. DESMARAIS: In that respect, I will put up just a few slides. I
don\'t even need that.

But we believe that through instruction for use, operator manual, and we
believe that there is a need for didactic training, as Dr. Dubuc just
alluded.

We will utilize skilled physicians experienced with Freezor to train and
initiate at new sites. We have learned that from our experience in
Europe, and we will provide ongoing support with clinical support
specialists, which we are doing in Europe as well. We are convinced that
this is a need.

DR. VETROVEC: Are you talking about physicians proctoring this or are
you talking about ‑‑

DR. DESMARAIS: Yes, yes.

DR. VETROVEC: And how many procedures do you anticipate as necessary?

DR. DESMARAIS: That is very difficult. It depends on the site in terms
of the volume, the number of physicians. So it is a very difficult to
estimate at this point in time.

DR. VETROVEC: I don\'t have anything else.

DR. DULLUM: You said that in the ice ball you saw after three minutes
stayed stable, so that is why you chose four minutes. In surgery there
is usually a dry field in this aspect that a little bit was talked
about, that there is going to be warm blood going by. So that was
monitored, and you still know that at three minutes with warm blood that
it stays the same?

DR. DUBUC: Well, we know in a beating heart, which could be different
from surgery sometimes, in a beating heart we know that it is very
stable after two minutes. Even if you keep the catheter there for six,
seven, or eight minutes, there will be no change. But if you go in the
preparation, like a fine muscle preparation, you will see that the ice
ball will still grow after three minutes. The longer you will keep the
catheter there, the bigger will get the lesion, which does not happen,
actually, in a beating heart.

DR. DULLUM: So you basically have a cool sink.

So did I understand that it took an average of seven-and-a-half
cryoablation procedure times with your catheter? Is that the same with
RF?

DR. DUBUC: I would say it is about the same, yes. It is the same range.

DR. DULLUM: So are you going to recommend that in clinical practice
then, when do you know when to stop? Do you say, okay, after
seven-and-a-half or do you just keep going until you get tired or the
patient gets tired?

DR. DUBUC: I think it is like our effort goes with the clinical
judgment. I mean, you are doing the procedure and sometimes you know
that on the average it will take, four, five, six lesions, but sometimes
it takes more. I mean, even with RF, I have seen cases you do 30, 40
applications. So that can happen also with cryo, I imagine. I mean, that
goes with the clinical judgment.

DR. DULLUM: And my last question: Are you going to recommend that if you
go with cryo and you don\'t ablate, then you switch to RF, or vice
versa? I think, as someone said, there was an RF that was not successful
and then you used cryo.

DR. DUBUC: I think we had no safety problems with that in this clinical
trial, doing RF after cryo.

DR. DULLUM: And vice versa?

DR. DUBUC: Well, we did not ‑‑ just to correct, there were no subjects
in the study who got RF first. Everyone, out of 166, 164 had cryo first.
Some failed; some succeeded, and some of the failures were RF. Two of
the subjects did not have a cryoapplication; they had RF alone without
any cryo following.

We did look at the complications, any measure of adverse events in the
group of cryo and followed with RF, and there was no difference between
those two groups.

Furthermore, in terms of the number of cryoapplications, either mapping
or ablation, they had no relationship with measures of adverse events as
well. So that bears a little bit on some of your questions.

CHAIRMAN LASKEY: Thank you. Mark?

DR. HAIGNEY: Okay, I will be brief.

I am still confused about your indication. You are asking for an
indication for parahisian pathways? You\'re not? Just AV node?

DR. DESMARAIS: As presented today, the indications for it ‑‑

DR. HAIGNEY: AV node ‑‑

DR. DESMARAIS: Correct, AVRT indication.

DR. HAIGNEY: Okay, so not mid-septal pathways?

DR. DESMARAIS: Correct.

DR. HAIGNEY: Okay. On page 62 of the final report, there is something
that really confused me. It said, under adverse events, it says,
\"Thirty-one of 42 Canadian subjects and eight of 124 United States
subjects were reported with these AEs.\" Is that what I think it is
saying?

DR. LEHMANN: We believe that the three Canadian sites had a very
different view of what constituted an adverse event. No, we don\'t feel
there was any ‑‑ other than sequelae that would indicate they had had a
much different means of accessing the circulation, and I know it was
quite consistent across the Canadian sites. So we think it is a
reporting anomaly.

DR. HAIGNEY: Well, it is a reporting anomaly with somebody. Whether it
is with the Canadians or the Americans, they\'re not going to say.

Finally, I have one more weird comment to make. Have you considered as a
possible contraindication patients with known cryoglobulinemia anemia?
It just occurred to me over breakfast, and it seems to me that that
would probably be ‑‑ if you had a patient who had known
cryoglobulinemia, that it is probably not the technique you would want
to use. So I would suggest putting that in as a contraindication.

On the whole, I think the device represents an important contribution
potentially to the progress of EP. It\'s a niche device, and it doesn\'t
replace RF ablation. So I am not as bothered by the fact that you
didn\'t make your OPCs. I agree that there are no clear
device-associated complications. So given the fact that this is not
replacing RF ablation, I think I\'m inclined to be a little more lenient
than perhaps Dr. Krucoff. I usually am.

(Laughter.)

CHAIRMAN LASKEY: You\'re not supposed to spill the beans until after the
break.

(Laughter.)

We\'re about to take a short break, following which we will reconvene
and do the voting. However, I would like to raise one point here in my
prerogative.

I think in the future ‑‑ and I think it is unfortunate in this trial,
but in the future when we have these sorts of interventional trials
requiring prolonged fluoroscopy, we should have some measure of dose. I
think all of the agencies around, there\'s none that I can think of that
should be more aware of patient dose. Procedures that have up to
whatever the estimate is, many, many minutes of fluoro time, that is not
a surrogate for dose. I think we should require that of the studies down
the road, because we are going to see more and more prolonged laboratory
time. So let\'s build that into the protocol. It might even be a measure
of safety as well.

Thank you. So let\'s take a 10-minute break. Let\'s reconvene. Then we
will go over the questions to the Panel and the Panel\'s preferences.

Thank you again, Panelists, for sticking to the schedule.

(Whereupon, the foregoing matter went off the record at 3:48 p.m. and
went back on the record at 4:05 p.m.)

CHAIRMAN LASKEY: Good, thank you.

At this point I would like to proceed with reviewing the questions put
to the Panel, if we can have them up.

As we go through these, I will do my best to summarize points of
agreement and disagreement amongst the Panel members.

\"The results of this clinical trial were compared to objective
performance criteria, OPCs, established for the study for both safety
and effectiveness. The OPCs were determined from the radiofrequency
ablation medical literature.\"

The first question to the Panel with respect to safety: \"The safety
endpoint was the occurrence of major complications, as defined in the
study protocol. The FDA interprets the definition of major complications
to include all adverse events requiring treatment which occurred within
seven days of the procedure. The upper 95 percent confidence bound for
the major complication rate was 8.5 percent.

\"This exceeded the safety OPC, which specified an upper 95 percent
confidence bound of less than 7 percent. Please comment on the
following:

\"a. Please discuss whether the results of the clinical study provide a
reasonable assurance of device safety for the intended patient
population.\"

To paraphrase Dr. Bailey, I think that you certainly were roped into
these constraints by the OPCs in that there is not a lot of wiggle room
in a small study. One patient either way could have made the difference,
and, unfortunately, it didn\'t work in your favor.

\"b. Please discuss the applicability of a safety OPC for cryoablation
which was based on reported clinical experience with radiofrequency
ablation.\"

I think that the Panel alluded to this in some of their comments. That
is basically all we have to fall back on as a benchmark. It may or may
not be appropriate, but that serves as a benchmark and it is a not
unreasonable benchmark.

Question 2, with respect to effectiveness of ablation: \"The device did
not meet the effectiveness OPC for the overall study population or for
any patient subgroup. The lower 95 percent confidence bound for acute
success for the entire study population was 76 percent. The OPC for
acute success specified a lower 95 percent confidence bound greater than
85 percent.

\"a. Please discuss whether the results of the clinical study provide a
reasonable assurance of effectiveness in (a) the overall patient
population or (b) in any individual patient subgroup.\"

I think that both statisticians have spoken cogently to this point.
Again, you are constrained by your boundaries. One patient either way
could have made the difference. Again, it\'s an awfully small study to
allow for that kind of non-leeway.

With respect to the individual patient subgroups, I think that the Panel
has done a good job, as well as the FDA statistician, at pointing out
the foibles of doing post-hoc subgroup analysis. It\'s really
treacherous, and you really live or die by the limitations of this
technique.

\"b. If the clinical trial does not provide enough evidence of
effectiveness, please discuss what would be needed.\"

I think we need to hear really how people are voting before we can give
you an answer to that.

DR. ZUCKERMAN: Could we, for Question 2, which really gets to the heart
of the matter, could we hear from several other Panel members? Is there
a consensus on this summary as you presented it?

CHAIRMAN LASKEY: Let\'s go back to a and b with ‑‑ both parts, a and b?

DR. ZUCKERMAN: Yes.

CHAIRMAN LASKEY: Okay, well, feel free to chime in, Panelists, if I
didn\'t quote you correctly. Cindy?

DR. TRACY: I would like to jump in, because this is sort of the crux of
the struggle with this thing: What would it take ‑‑ can you construct a
study that would look at AVNRT or do the data that we have ‑‑ how close
are we to defining safety and effectiveness in AVNRT?

I have whole issues with the safety, given the way there is such a
variance in reporting between the Canadian side, just the variance in
reporting in this study.

But, anyway, in terms of effectiveness, what has to be done? I mean, are
we close?

CHAIRMAN LASKEY: So this is \"b\"? This is really 2b?

DR. TRACY: \"Or not to be.\"

(Laughter.)

CHAIRMAN LASKEY: Please discuss what would be needed, because we have
before us a negative trial.

DR. TRACY: Dr. Bailey was struggling with this. Maybe he can struggle
some more for me.

DR. BAILEY: Well, yes, as a true/false question, the answer is false,
but if it\'s an open-ended question, I mean the data do seem to support
efficacy, but only if you look at the strategy of cryoablation with the
possibility of RF as a backup. That\'s to say nothing of the safety, but
in terms of efficacy, you get 161 successes out of a 166, which seems
pretty reasonable.

DR. WHITE: Well, but the problem, though, Ken, is that\'s not what we
were being asked to judge because you have no comparer.

DR. BAILEY: Right, but that\'s why I say, if it is a true/false
question, the answer is false.

DR. WHITE: The question is, what Cynthia is asking is, what would it
take to make us say that they have satisfied efficacy? Is it because
there were so few patients that the margins were so narrow and the lower
bounds were not met? If there were another hundred patients enrolled,
would the bounds narrow?

DR. BAILEY: No, no, I think the OPC as stated doomed them to the result
because that was not a quirk of sample size. You can\'t get that high an
efficacy with this technique. But in terms of the overall clinical
application, it\'s pretty high.

DR. KRUCOFF: I think that is a really key point. I think we have
actually heard it stated several times, but it seems like when this
trial was first designed, that the catheter behavior and performance was
expected to be the same as an RF catheter. Yet, it sounds more like the
actual experience that\'s evolved out of the trial is that the catheter
performance may be a little inferior to an RF catheter.

When it is, you can bail out with an RF catheter, but the other safety
elements and the potential to pre-map and to protect more vulnerable
areas, that\'s what gets actually into an area where you\'re suggesting
a trial design that would look at a potentially slightly inferior
efficacy from the device, but at least an equivalent behavior in an
intention to treat, which includes the RF backup, where overall the
safety would be better. I don\'t see that it would be very complicated
to design that kind of a trial.

The trouble is that that\'s not how that OPC was designed. That\'s,
unfortunately, I guess the question that we\'re going to be asked today
in 2a, and then in the 2, bottom \"b,\" I think it would be pretty
straightforward, based on this experience, to see a design where you
would do an intention-to-treat analysis for efficacy and really
concentrate on safety, and whether these are catheter or dwell time or
radiation time safety issues or not.

DR. WHITE: But without a comparison group, I have a hard time
understanding the safety ‑‑

DR. KRUCOFF: No, not in a randomized trial.

DR. WHITE: Because I don\'t see the safety in 151 patients.

DR. GILLIAM: I don\'t think you can see the safety in 150 patients, but
I also don\'t think it would change if they had 650 patients or a
thousand patients, because the comparison that we really are talking
about is looking at, for instance, use of radiofrequency in an AV nodal
reentry group and skilled operators today. I mean your heart block risk,
if you will, is something less than 1 percent. I mean it is.

If we start looking at the comp. we\'re seeing, no one is saying that
there is something intrinsically not safe with this catheter. I mean we
are getting complications because they only had 150 patients, and if we
probably take 150 patients from any of the procedures, we may have like
complications. These are procedure-related but not catheter-related. It
may very well have been RF cases we were looking at to get the same type
of complications.

I think the reality is that this is a procedure that potentially may be
less likelihood of creating complete heart block in an AV node reentry
population, and, ultimately, the overall efficacy of this one alone may
not be as good, but taken with the option of using RF, it may provide an
additional tool.

That\'s saying a clinical trial ‑‑ I\'m not sure what we\'re going to
compare it with. I think it would be very difficult to provide such a
study. I don\'t see how it could be done easily.

DR. WHITE: Well, I don\'t understand why you say that because there is a
standard clinical procedure now to treat these patients. So you take the
experimental procedure, you compare it to the standard clinical
procedure, you get a comparison.

DR. GILLIAM: If we were going to replace the procedure, I would agree
with you. But I don\'t think that anyone would suggest that cryoablation
is intent to replace radiofrequency ablation. I think that that\'s where
I think it would be difficult because it may very well be that you can
go in and just look at RF, you know, first or second.

You may go in with cryo first, and if you find an easy point, you map
and you get it right away, then fine, you may just go with it. If you
need a bigger lesion, if you will, or you just use RF, I just don\'t
think that you are going to be able to compare one to the other because
they\'re not going to be used the same.

I don\'t think you\'re going to replace RF with cryo. It\'s a smaller,
more discrete lesion. That means that you\'re likely to have less
efficacy, I mean all things being even. But, on the other hand,
potentially that one or two people that surprise the heck out of you,
that when you step on the pedal, they all of a sudden develop heart
block, and you jump off the pedal real quick, you know, if you\'re
lucky, as we most of the time, frankly, are ‑‑ I mean that we don\'t get
permanent heart block.

But every now and then you look at it happen, and you say, \"Oh, my God,
I wish it was reversible.\" Maybe this is reversible. You know, I don\'t
think they\'ve proved that, but I don\'t think they\'ve proved that it
is any more dangerous.

CHAIRMAN LASKEY: But, again, we\'re not here to talk about replacement.
We have heard the word \"supplement\" and \"adjunct to.\" Whether that
lends itself to non-inferiority versus class RCT is, I guess, what Dr.
Zuckerman needs to know here in Question 2b.

DR. VETROVEC: But let me ask you, if the goal, based on what you say, is
to look at this as something to prevent it, then it will become your
first choice. Otherwise, you\'re going to have heart block the whole
time.

So now you\'re suddenly substituting this as a first choice, and RF is
becoming second choice, and do you know that that\'s a fair trade?
That\'s what you\'re suggesting, if you\'re going to use a hundred times
to prevent one or two heart blocks.

DR. TRACY: Do we have data that ‑‑ is there a way to look at this data
for non-inferiority?

CHAIRMAN LASKEY: Which data?

DR. TRACY: The effectiveness data.

CHAIRMAN LASKEY: The way I look at this trial, this was a
non-inferiority trial. That\'s the study design to me.

DR. KRUCOFF: Well, it didn\'t make its boundaries on ‑‑

CHAIRMAN LASKEY: No, exactly, but ‑‑

DR. KRUCOFF: It is a negative non-inferiority on a safety compared to an
historical. So a classic non-inferiority, this is not a randomized
dataset.

DR. TRACY: Effectiveness, not inferiority.

DR. GILLIAM: But if we\'re looking at heart block, let\'s just look at
just heart block. Then, in effect, this study doesn\'t ‑‑

CHAIRMAN LASKEY: We need numbers. We don\'t have numbers here. There\'s
no precision of the estimate, and maybe I guess, Dr. Page, you said
something during the break about adding some precision to the number. We
know it\'s not zero. Nothing is zero. But could it conceivably be on the
same order of magnitude as RF and is it, therefore, as safe from that
standpoint?

DR. PAGE: Yes, I would just like to comment that, first of all, I think
in all fairness, as Rosie Gilliam said, in good hands the risk of heart
block, and I would say there are a number of good EPs in this room, and
please speak up if your heart block is over 1 percent, but most of us
are less than that, I believe.

That being said, I believe that the cryo is probably as low or lower in
terms of heart block. I see this as another arrow in the quiver, if you
will, as being supplemental.

In addition, one thing that has to be mentioned is we\'ve focused on the
specific indication for AV nodal reentry, but, in addition, to have this
other tool in terms of cryomapping is going to be valuable in a number
of circumstances.

If I understand the indication as it is written, we are not limited to
the device being used in the AV node reentry for the cryomapping, is
that correct?

DR. ZUCKERMAN: No. Dr. Page, your comments are well-founded, but I think
you\'re getting into Question 3. Perhaps if we could go back to Question
2 and take it in an ordered fashion, it will help us decide what the
trial showed and what can be done with this device.

I would like, Dr. Laskey, first of all, to know, for Question 2a, the
overall patient population. Is there a Panel consensus as to whether
there\'s reasonable assurance of effectiveness?

DR. PAGE: Just so I\'m clear, is effectiveness only in successful
ablation, having nothing to do with the second indication, effectiveness
as a mapping tool?

DR. ZUCKERMAN: That\'s correct. Right. For acute procedure success; we
would all agree that they didn\'t meet it for the overall patient
population.

CHAIRMAN LASKEY: I think we all agree with that.

DR. ZUCKERMAN: Good. Okay.

CHAIRMAN LASKEY: It would be hard to say otherwise, yes.

DR. ZUCKERMAN: Now Question 2b asks ‑‑ a subgroup analysis was done.
You\'ve heard multiple comments as to whether or not the subgroup
analysis is valid for AVNRT. It\'s important for the agency to get a
consensus, if there is one, or just a response from the Panel as to the
validity of the result, of the effectiveness results for the AVNRT
population.

DR. BAILEY: I thought your statistician made the excellent point that
the OPC was for the overall mixed population, and we don\'t know what
would have been specified, had it been this one subgroup that was
recruited.

CHAIRMAN LASKEY: As a non-expert in this area, though, it did look as
though the AVNRT group is the group most likely to do well of the three
groups anyway. So, therefore, the bar would be even higher. So that we
would expect this procedure to do better in that group which tends to do
better.

So I think that you need to sit down with the applicant and go over the
applicability of OPCs. There must be data in the literature on the
success rate of AVNRT only rather than all-comers, and that may be
helpful, although retrospective still.

DR. ZUCKERMAN: Okay, that\'s one way to look at it, but the
electrophysiologists here in the Panel have offered the suggestion that
these two devices, cryoablation plus RF ablation, could be used in a
treatment strategy approach because of a comfort level associated with
cryoablation.

So another approach which is similar, Dr. Laskey, to what we do with
guide wires to cross-total occlusions is, if we do believe the first
device has some intrinsic merit, might be safer, we may accept a lower
success rate with a first device, and then if it doesn\'t work, you go
to your next device.

So I\'m not sure I have heard from the electrophysiologists that for the
subpopulation called AVNRT we necessarily need a higher bar, given the
risk/benefit profile. Can the electrophysiologists comment?

CHAIRMAN LASKEY: You don\'t need a higher bar.

DR. TRACY: I\'ll speak now as an electrophysiologist, and I would be
happy with this level of success, knowing that there are certain
patients with very narrow ‑‑ there are some people with very narrow
anatomic windows between the slow and fast pathway, that this would be a
very nice thing, very stable catheters used.

There would be certain circumstances where I would use this as a first
line, and I would be very comfortable knowing that I had a backup of RF,
and in my lab the chance of heart block is less than one-half of 1
percent. So it\'s not high, but in those patients that have the funky
windows, those are the ones that, if they are going to get into trouble,
those would be the ones that would have the problems with heart block.
So there\'s a group of people where this device would have a distinct
advantage to use.

So if it is a 91 percent success rate with this device, that\'s not that
far off from reported data on other AVNRT studies, although our success
rate is 98 percent. If I took this catheter and put it in a heart, what
my success rate would be ‑‑ presumably, it would be better after the
tenth case than on the first two or three.

To me, it\'s in shooting range of what would be acceptable for any
device.

DR. WHITE: But the problem I have is that there is one option to approve
this device for ‑‑ what is it called when there is a very narrow
indication for this, like we use for the atrial septal closure devices?

MR. MORTON: Those are HDEs, and the population is way ‑‑

DR. WHITE: Right. Well, you\'re talking about a very small population
that you would choose this device for. So it would be a very narrow
window. But when this device fails, the OPC, the lower bound, then I
don\'t understand how we can say that we\'re in the neighborhood and we
ought to let that go.

I don\'t see the purpose of the OPC if you\'re going to ignore the
OPC\'s lower bound. I mean, once it is set, once it is agreed and we
proceed with that, then I find it a specious argument to work around the
number, if the device fails the lower bound.

MR. MORTON: I think that\'s the hardest thing about this, is that,
obviously, there\'s a patient population who it seems to be a real
consensus would benefit from doing cryos first, but if, as a plumber,
I\'m understanding what I\'m hearing, that patient population isn\'t
identifiable upfront.

DR. TRACY: It is. In short order it is.

MR. MORTON: It is? So when you get into the lab, you can see when the
window\'s ‑‑

DR. TRACY: It is. Once you have the catheters in place and you\'ve done
your baseline study, then you know who you would pull which catheter out
for. And if you had both available in your lab, you would have a very
clear distinction which catheter would be appropriate to use.

In terms of the OPC, I think that the OPC is not appropriate.

DR. GILLIAM: I agree. I think that the question isn\'t ‑‑ I think the
OPC is a high standard, which is good.

DR. WHITE: A high standard?

DR. GILLIAM: I think it\'s very high.

DR. WHITE: For AVR? I mean, I don\'t think you can ‑‑ that\'s not true.
I don\'t know how you came to that conclusion.

DR. WALDO: You know, I think if you\'re introducing a brand-new concept
‑‑ ablation is not a new concept. I mean if you\'re introducing a
brand-new concept, if you\'re doing a mated one, or maybe if suddenly
you\'re taking a new technology and introducing it to a new treatment
mode, you have to be extremely ‑‑ well, you should be rigorous always,
but this is something very different. This is ablation.

We have several tools for ablation. There is not just one RF ablation
technique. There are many RF ablation techniques, from the size of the
catheter to cool tip, to, you know, saline irrigation. There are all
kinds of ways to do these sorts of things, but the concept is clear.
This is a concept of ablation. It\'s another way to do ablation.

I think we can even get some information from Dr. Dubuc, because what if
your laboratory switched to only ‑‑

DR. WHITE: Well, I don\'t think that\'s relevant.

DR. WALDO: I\'m going to suggest an answer then. If you don\'t think it
is relevant, I\'m going to think that they decided in their group ‑‑
I\'m guessing because I haven\'t talked about it, but they decided in
their group that it was worth doing the cryo technique because they
found it very, very effective and they found it safe.

DR. WHITE: I disagree. He\'s conflicted. He\'s a paid consultant for
that company.

DR. KRUCOFF: I think we\'ve got to recognize that there\'s a difference
between what these numbers are from the study and what these numbers
potentially mean when they are applied to a population. Kent, please
correct me if this wrong, but I think that\'s really what boundaries are
about.

The OPC historical control creates a non-randomized clinical trial
venue. What that means is that the 91 percent doesn\'t mean ‑‑ I mean
it\'s 91 percent for this 130 patients; when you get to 136,000
patients, the boundary is what you may see. You may see that\'s 97
percent or the upper boundary or you may see that it\'s 83 percent or
the lower boundary, and that 83 percent, if that\'s what happens in
136,000 patients compared to your 98 percent with radiofrequency
ablation, that is my understanding of what an historical boundary
branded number is telling us for application of population.

That\'s, to me, what is so difficult and what we seem to be wrestling
with. Ninety-one percent sounds really good, and certainly if it\'s
safer and there\'s a population who would benefit from it, you know,
that\'s where the consumer side of a Kent Bailey steps up and says,
\"Maybe that\'s what I would like to have used.\" But 91 percent is what
happens in this 130-ish patients. The boundaries tell us what might
happen at 136,000 patients, and that\'s why if the trial design pays
attention to the boundaries rather than to the number ‑‑ and somewhere
we\'ve got to figure out how to digest that into whether this is just
another neat arrow for the quiver or whether what this trial may be
telling us by failing its boundaries both in safety and efficacy is
that, when you really get out there and start using this thing, compared
to what you\'re already getting with radiofrequency ablation in your
lab, there\'s going to be a bigger gap than the 91 percent kind of
number indicates. That seems to me to be what we are wrestling with.

So we\'ve come full circle. We basically all agree that they failed to
meet all their pre-specified endpoints, and we\'re not being terribly
helpful here to the agency or to the vendor. But I would have to say, if
we did 136,000 or million, the confidence limits would shrink. They
wouldn\'t stay that way. They would be awfully tight. Is that right?
They wouldn\'t stay where they are?

DR. BAILEY: The learning curve.

CHAIRMAN LASKEY: But to get back to what your needs are, you know, the
Panel is torn. We have a body of scientific evidence before us which
meets the null hypothesis, which has not been rejected. Yet, as
clinicians we have a gut feeling that this probably is safe. If you take
out the prosthetist and you take out a few other weird things that can
happen, it probably is safe and it probably is effective.

But you\'re asking us, and we need to qualify that again and again and
again, that we vote as clinicians and not as methodologists or
statisticians. If you want a positive study, it needs to redone in some
manner with a larger sample.

Does that reflect ‑‑

DR. ZUCKERMAN: That\'s helpful as a start because it helps us through
2a. We have a difference of opinion as to what the data show in terms of
effectiveness right now.

So then we go to 2b. Given this difference of opinion, is there any
consensus on what would be required in terms of replication of results
or new dataset that could help everyone here concerned?

DR. WALDO: Well, you\'re not going to get a trial of a thousand
patients. I mean you know that.

DR. ZUCKERMAN: No, but I don\'t think the agency would require a trial
of a thousand patients for RF ablation. I think we have to go through
the usual panoply.

One is you always start with a randomized trial. There\'s a difference
of opinion there. But at the other end of the spectrum, do we need
another registry experience where we can replicate a number that was
developed in a post-hoc analysis to make everyone feel that we\'ve
reached a bar that\'s acceptable? I mean there\'s always a wide range of
designs when we\'re talking about device trials.

CHAIRMAN LASKEY: And I, for one, would suggest that. I think that if
post-hoc analysis is all about hypothesis-generating, then certainly
registry of AVNRT only, which is what the indication here ‑‑ it looks
like that\'s the indication they\'re going for. If that\'s the
indication, then a registry of some reasonable number of patients, less
than a thousand but greater than a hundred, would answer the question as
to the safety and efficacy track record.

I think that we\'re sort of jumping the gun here.

DR. TRACY: What registry are we talking about?

CHAIRMAN LASKEY: A registry such as has been suggested to add to the
qualifications of a vote, for example.

DR. TRACY: You\'re talking about a registry that this catheter would be
entered ‑‑ or patients would be entered into who had their ablations
performed with a cryocatheter versus a registry that we would pull out
of the shelf in the library and say, let\'s compare this data to a bunch
of AVNRTs?

CHAIRMAN LASKEY: Prospective.

DR. TRACY: We\'re talking about a prospective though.

DR. ZUCKERMAN: I would just take a step back. I\'m looking at the
screen, and we\'ve dealt with Question 2a, which suggests that there\'s
a difference of opinion as to effectiveness. So then we go to 2b, which
is, how much more might be necessary to go to the goal line?

I think it\'s important for folks on this Panel to understand that it
doesn\'t imply that needs to be a randomized trial. It doesn\'t imply
that needs to be a single-arm registry. We\'re just looking for ideas
here for those who feel uncomfortable with the present dataset,
realistic ideas.

DR. KRUCOFF: I think one thing that has been said a couple of times is
that the size of the current dataset plus or minus one or two patients
flirts source. One way to consider going forward, it would seem to me,
would be to focus on your indication population and sit down with a
calculator and see how many patients enrolled in the identical protocol,
but with just that one indication, treated in the same way, could be
potentially appended to take away some of the flirtation with the
boundaries and really find out whether you\'re at or better than the
boundary or whether you\'re not.

DR. WALDO: Can I ask a point of information? In terms of safety, we
heard that the events, when they adjudicated all the cases, that none of
these things were device-related. Isn\'t that my understanding?

Now I understand that there are procedure-related problems in all
things, and the real issue, then, if I understand it correctly, is that,
is the device indirectly the cause of some of the problems? That\'s what
you\'re struggling with, is that right?

Because I read through. I pulled it out a couple of times, and I read
through all the things. I don\'t know how to answer that because I\'m
not a statistician, but as a clinician I thought a lot of those things,
the countings we see anyway, most people don\'t look that hard.

I recently sat on an events committee where we found some things that
were newly-recognized because they were looking very hard. When we
started looking at other patients who were not in this kind of study,
they found the same thing these other patients had, a very, very good
laboratory.

So I don\'t know, I would not like to ‑‑ I mean, what I hear a couple of
things, and I think our Chairman has stated them very well earlier ‑‑ I
really think there is a comfort level for me, and I\'ll speak only for
myself, about the safety of this device. I think it has a utility.

Then the question is, do we want to just disregard that at this point
because it is a small study and there are ‑‑ I don\'t know if I\'m using
the right term ‑‑ secondary concerns because it\'s not the device per se
that has been associated with the safety concerns; it\'s the procedure,
and we don\'t know if the procedure of the use of the device or if there
is something unique about the device and the procedure. My suspicion is
that it isn\'t, but I don\'t know that I can say.

I don\'t know if I have made myself clear, but I think we\'re focusing
on numbers, and we\'re not focusing on what I think is the substance of
something that we in electrophysiology deal with a whole lot, and
that\'s ablation. I think the ablation, the results of ablation are
clear.

For me, a 91 percent and 97 percent and 96 percent, it\'s still an
option for a physician and there are times you want to use it. That\'s
why I made that remark earlier. I think that it\'s an option that I
think is legitimate, and I think the data are sufficient to me to
suggest that there\'s an adequate efficacy, and the safety problems that
I see here are not the kind problems ‑‑ I haven\'t seen life-threatening
things. I\'ve seen things ‑‑ you\'ve proselytized the most obvious, but
someone had a problem with a sheath in a diagnostic catheter. I mean
those things happen from time to time. There are a bunch of other things
like that.

So I think the forest and the trees thing here is what I\'m talking
about. I think seeing the forest, I think this is something useful. If
you look at all the trees, then you haven\'t got a sense of what the
forest is about here. That\'s what I see.

DR. WHITE: I guess my problem is that they failed on every single
boundary. They failed every one. It wasn\'t like two were good and one
was bad, and shouldn\'t we overlook that? I mean, we\'re talking about
rescuing the ‑‑

DR. WALDO: But you\'re focusing on efficacy. I mean, I don\'t think 91
percent and 97 percent is to be ignored, but we\'re not talking about
life-threatening rhythms. We\'re not talking about something terrible.

I think Dr. Bailey really had a very ‑‑ he saw it immediately, and he
called it as a consumer, but I think really the approach, if you take
the approach if you want to start with cryo, and if it doesn\'t work, go
on to RF, you\'ve got an enormously good success rate. I think that is
how we think as clinicians. That\'s how they did it in the study.

You have to ask yourself then, why do OPC trials at all if you\'re not
going to accept the data?

DR. WHITE: I haven\'t thought about it forever, but just off the top of
my head, I mean if you\'re breaking new ground, if you bringing in a
whole new direction of therapy, if you\'re introducing your first
implantable defibrillator or your first bimitricular pacer, talking in
my own area of devices, I think you\'re breaking new ground. But we\'re
not really breaking new ground in terms of ablation. We\'re playing with
the technology of ablation; that\'s all. That\'s how I see it.

CHAIRMAN LASKEY: Well, but this is not a 510(k) either. This is a new ‑‑

DR. WALDO: Well, it\'s not 510(k).

CHAIRMAN LASKEY: This is a new energy source.

DR. WALDO: I mean, the safety issues to me are not safety issues that
are out of my cage; put it that way.

CHAIRMAN LASKEY: No, I would agree with you that these are
procedure-related complications, but these are the chances you take when
you do a study. You roll the dice and that\'s it. If you win, great, but
in this case they didn\'t.

But they\'re procedure-related and they\'re often hard to disassociate
from any device. It\'s in the hands of the operator, and there\'s seven
or so variables that go into procedural complications. Nevertheless, I
tend to agree with you that I think we do see the forest through the
trees, but the trees are awfully big.

DR. TRACY: Does anybody have a rough estimate of what it would take to
achieve an effectiveness endpoint? Is it five patients or is it 5,000
patients?

DR. PAGE: If I may just ask, I think it troubles the heck out of me that
an OPC trial was done and it failed, but in retrospect I don\'t think it
was the right trial. I think it was too small, and given what I believe
the safety is of this device, then I think the bar was set too high in
terms of efficacy.

Then we\'re looking back at the safety issue. When we dissect out the
safety issue, which I think is fair in this case, because one or two
going the other direction changes the whole result, when we dissect out
the safety, then it doesn\'t look like it is the catheter that\'s
responsible for it.

So I feel like I\'m totally schizophrenic here because, as a
statistician, if I were one, I would not accept what I just said, but as
a clinician I think we would be wasting our time to do another
pre-approval trial because I don\'t know if this Committee could even
figure out what our endpoint was, then much less go through all the time
of running a trial.

I think a registry afterwards of this type of patient would be very
valuable, the first thousand cases, and really look at it.

DR. ZUCKERMAN: Right, but the problem is you need the data before
approval to label a device for a certain indication. So to respond to
Dr. Tracy\'s question, though, I think we need to remember that with the
approximate number of AVNRT patients that were in this trial, the lower
bound was about 82 percent. So if you were going to do a subsequent
trial, where you could accept a lower OPC, for some of the reasons
alluded to, you\'re in the same ball park, not as exactly, as to what
was studied, what was retrospectively determined to AVNRT patients,
around a hundred or so.

MR. MORTON: Dr. Laskey, just a quick comment: I know that we\'re all
looking at the same screen, but one thing that I would emphasize that
the agency and the sponsor have come before the Panel to ask is, is
there proof of reasonable safety and effectiveness? And that is exactly
what I\'m hearing you wrestle with.

DR. GILLIAM: My concern is, just looking at the OPC, I mean I\'m not so
certain that if we were to do this study with 5,000 patients and it
didn\'t meet the OPC, does it mean that we should not approve the
device? I guess at the end of the day we have to take a vote.

As Dr. Waldo said, I sort of feel that, if you were to say, \"Is this
device as effective as RF for ablation,\" then I would probably say RF
is probably a little bit better. I mean, it\'s a bigger lesion maybe,
and maybe that\'s why it\'s better or maybe quicker, whatever.

But is this an effective treatment? I would have to say, yes, it\'s
effective. Maybe it\'s not as good as RF, but it\'s different. It\'s not
the same thing.

So I think using the OPC standards we have for RF may not fully be
applicable to this type of therapy. I mean it\'s an ablation, but it\'s
different. I mean, maybe the efficacy is not as good, but it doesn\'t
mean that it is still not effective. I think that\'s the distinction
that I make.

DR. HAIGNEY: Would it be possible to have a registry that would be
aiming at safety? I think it\'s quite possible that this isn\'t as good
as RF, but RF is darn good and it has been developed over 10-11 years.
If it turned out, after looking at a thousand patients, it had an 85
percent success rate, I would say fine, that doesn\'t bother me because
there are certain patients who I want to use it in.

It would bother me, however, if we did a registry and we started getting
more heart blocks. Then I would say, well, wait a minute, maybe this
isn\'t the thing I want to try in the area of the AV node. In a
registry, couldn\'t we design a registry that was a couple hundred
patients with the express purpose of being sensitive to detecting AV
node block and other ‑‑ the sort of device-related complications that
we\'re all ‑‑

DR. WHITE: If we haven\'t seen heart blocking in over 600 patients I
heard, how are you going to find it? This is going to be very hard to
find.

DR. WALDO: Well, that\'s terrific. I don\'t want to find it.

DR. WHITE: No, no, no, but I mean for pre-approval. We already have
600 ‑‑

DR. WALDO: You\'ve only had 150 patients to look at. You\'ve had 150
European experience.

DR. WHITE: Well, I would love to see that data. I would love to see it,
but it wasn\'t presented to us. So I have 150 patients with a 1 percent
incidence.

DR. WALDO: If the prevalence is zero, the confidence is because the
numbers are small, is what we\'re talking about.

DR. WHITE: But it would only take one or two patients. The next two
patients have heart block, and all of a sudden ‑‑

DR. WALDO: AVNRT has fewer patients than that, but I think we have to
decide what the agenda of the Panel is. If, ultimately, there\'s a
regulatory process that\'s asking a question about an indication based
on data, then that\'s one conversation.

I think you could probably put this catheter in the hands of any of the
EP people sitting here, and in about five or ten cases they would know
99 percent of what we have been talking about today, but that\'s not
data.

I think ultimately we have to decide whether there is information here
sufficient to support a regulatory approval and/or indication or not,
and if not, then what would provide that, I think is what I interpret to
be the part of this question to allude to.

DR. WHITE: I may be confused, but what I\'m hearing from the EP group
here is that this may not be as good as RF, but it has a niche. But, on
the other hand, what the sponsor, I think, asked the FDA was, how could
we have this approved that it\'s at least equivalent to using the
guidelines of RF ablation?

We didn\'t quite hit that, and that is the problem we are struggling
with. I have sat on a number of these panels, and I\'m always startled
by the fact that somehow the studies really never have the power to
answer the question you would really like. I think when you go back and
look at these in the future, you hope that people will do the studies
that are going to answers the questions you want or design the question,
design the trial to answer the question.

Maybe it should have been designed as a niche device trial in some way
rather than the way it is being presented, but somehow the position of
the product needs to fit the study that\'s done, and an adequate study
ought to be done to answer that question.

DR. KRUCOFF: Well, the OPC questions are on the safety side that the
boundary established tells us that the use of this catheter is not going
to do more harm than radiofrequency.

And on the effectiveness side, the other boundary basically tells us
that this catheter is at least as good as, within a range, the point of
comparison. The reality is I think what we are hearing is that
clinicians who do these procedures would be happy to have this
instrument in their lab, even if it was not as good as. The trouble is
that\'s not what this trial addresses.

Either we have an approval process based on the trial or we have an
approval process based on what, unfortunately, may or may not be some
degree of bias, having looked at the data as to where you think, in
fact, the right trial design might have been, if you were to go
backwards. It\'s a little head spin.

CHAIRMAN LASKEY: Does it help the agency at all for the Panel to at
least say with some unanimity, I think, that the OPC criteria, these
criteria chosen are not applicable, and, therefore, need to be evaluated
in that context?

That gives us the room in which to make a clinically-driven decision
rather than the one that we\'re agonizing over, which is our clinical
horse sense says one thing, but our methodologic rigor says another. But
if we were all willing to discount or to freely acknowledge the known
limitations of the OPC criteria as to another device, to this device,
that would make us all feel better in terms of our final
recommendations.

DR. WHITE: I\'m not sure I feel guilty about this. I mean, I\'m not the
one who choose to do the OPC trial.

CHAIRMAN LASKEY: No, but having done it, you know, we\'re trying to be
fair here to everyone, and it is fair, I think, to acknowledge the
limitations of somewhat arbitrary criteria that act as a benchmark,
which is a moving target, and perhaps if done in 2003, and not in 1990,
would be different.

DR. BAILEY: But I think the considerations that make people think that
it has a niche are the heart block issue and things like that. It seems
it might theoretically have a better safety profile, but we don\'t have
data ‑‑

CHAIRMAN LASKEY: There are no numbers to support that.

DR. BAILEY: We don\'t have enough precision on the thing that gives it
the niche that it needs. It has to be better at something.

CHAIRMAN LASKEY: You keep putting us back in the hole. We need to get
out of the hole.

DR. ZUCKERMAN: Oh, but that\'s fair. I think it\'s fair to summarize
there\'s a difference of opinion on Question 2a and b regarding the
effectiveness shown presently. We\'ll get into it later with the Panel
voting, but I\'m not sure there\'s more to say about this question more.

CHAIRMAN LASKEY: Thank you. Agreed.

(Laughter.)

There are so many ways to rephrase it.

Question 3, effectiveness in the cryomapping area: \"The submission
describes the use of cryomapping technology and effectiveness
evaluation. Please discuss whether the study results show that the
cryomapping technology is effective for use in the intended patient
population.\"

First of all, the intended patient population is now AVNRT. So to answer
that question, we need to delimit the Panel\'s response to AVNRT, not to
AVRT or AF, is that correct?

DR. HAIGNEY: No, I don\'t think so.

CHAIRMAN LASKEY: No?

DR. HAIGNEY: I believe the indication is for cryomapping around the AV
node for accessory pathways, as well as AV node reentry. Isn\'t that
correct?

DR. WALDO: No, it says, essentially, says for AV-conducting tissues.
That would include ‑‑

DR. ZUCKERMAN: Dr. Haigney, do you have Section 3 of the label?

DR. HAIGNEY: Yes. It says, \"Cryomapping of conducting tissue near the
AV node.\"

CHAIRMAN LASKEY: You\'re correct. That\'s absolutely correct. That\'s my
misread, uh-hum.

DR. TRACY: I think that is, in fact, what that says, but when it was
asked earlier of the sponsor, maybe that would need to be clarified, but
their answer was pertaining to the AV node. You could say, well, that is
anterioseptal pathways conducting tissue near the AV node. So that it\'s
not ‑‑ if you want to limit this specifically to AV nodes, you have AV
nodes or peri-AV nodal tissue, something to more specifically state
that.

MR. MORTON: I have a question. Shouldn\'t we be looking at the slides
that were presented today by the sponsor and the agency, rather than
what was in the labeling, because this labeling was presented or
actually was what was used to start the study, as I understand? Is that
not correct, when we\'re talking about the indications for use?

CHAIRMAN LASKEY: I suppose that\'s a good point, Mike. We need to make
sure we\'re on the same page.

DR. TRACY: It\'s actually on page 4 of the sponsor\'s ‑‑ the
identification of a variant conducting tissue responsible for SVT using
reversible electrophysiologic cryomapping of conducting tissue near the
AV node. It doesn\'t really narrow it down any further. In fact, it
broadens it if you consider aberrant conduction to mean accessory
pathway.

DR. HUGHES: To me, that means that you could use it to cryomap accessory
pathways where you think there\'s danger of causing AV block, but not
ablate those accessory pathways with the cryoablation catheter. Just a
little bit odd. I guess you would pull the catheter out at that point.

CHAIRMAN LASKEY: Well, that\'s right. I mean that\'s the problem with
the semantics here, and it does need to be reworded. You can\'t reword
it on the fly? Can we reword it on the fly, because as it is it\'s
not ‑‑

DR. GILLIAM: Did they show that cryomapping was successful at any point
for anything?

CHAIRMAN LASKEY: No, the results were the same with and without.

DR. GILLIAM: My question, really to be on the other hand, I think I\'m
kind of liberal with the first area. As a clinician, I want to go that
way. But the second area, I think I might be the guy with the dagger to
put into it because I think at that point ‑‑ I mean, I haven\'t seen
anything in any of the study, in any subgroup, in any way that suggests
that cryomapping has been effective in any way.

DR. HAIGNEY: Didn\'t they show that they had a higher percentage of
successful burn for efficacy in the sites with positive cryomaps? Is
that correct, the 95 compared to 67, which they had positive or negative
in the seventies if they didn\'t do a cryomap?

DR. TRACY: I think the problem was it was more effective than a negative
cryomap, but it was particularly more effective than if you had not done
a map. But if you had done a map in the places where you had not done a
map, you might have had further data in one direction or another.

So it was only a piece of the data that was collected, and it was not
mandatory to collect cryomapping. So it makes it a little hard to say
too much definitive about it.

DR. WALDO: But having more rigorous and selective ‑‑ I mean savvy, it
would have been really nice to focus specifically on the patient groups
of interest, but I think we all know why we would love to have this, if
it really works, which theoretically it ought to.

CHAIRMAN LASKEY: But just to remind everybody, it was P equals NS. I
think it was .59 or something from the chi square result, that was just
not even close, the efficacy with and without mapping. So they chose to
do the analysis and it was way off.

All right, can we move on?

This study did not show it\'s effective, at least if we talk about the
intended patient population, which was the chi square that they gave us.

No. 4 ‑‑ oh, sorry. I will read on. With respect to the training and
learning curve, \"Acute success rate varied per institution in this
study,\" albeit the numbers were also variable. \"Acute success rate per
institution ranged between zero and 100 percent.

\"a. Please discuss the concept of the site-based and physician-based
learning curves.\" Can you go back to A? Thank you.

DR. WHITE: You know, in our world there are roll-ins, and that\'s how we
take care of learning curves with plumbing devices, is we decide how
many you need to get comfortable with this, and then you have roll-ins
and then you start your pivotal trial. So I think that\'s the way that
you handle a learning curve with any new device, which we all agree is
there.

The only question is, how many roll-ins do you need to feel comfortable?
Three? Five? Seven?

DR. WALDO: But maybe to demonstrate this, I thought that they admitted
that they didn\'t demonstrate any learning curve. The numbers are so
small.

DR. WHITE: But I think it was because they had multiple operators at the
sites, and so they didn\'t have numbers ‑‑ it kept changing over time,
too.

DR. WALDO: But I don\'t think there\'s any question among us that a new
device requires some training and some comfortability, and that you
don\'t want to hit the deck with the first time that it ever touches
your hand, impacting the safety and efficacy pivotal trial, and that\'s
the purpose of a roll-in. So you get to try it and it doesn\'t count you
if you have a problem until you get comfortable.

CHAIRMAN LASKEY: So the Panel agrees with the concept of physician-based
learning curves. What the number is is up for grabs. I think we all
espouse that.

\"b. All new devices inherently involve a learning curve in their
evaluation. Please discuss whether the concept of a learning curve,
either per site or per physician, may be considered in the evaluation of
device safety and effectiveness.\"

Yes, it may be considered. Some trials actually do allow for that in
terms of looking at roll-in patients and not counting them in a
randomized but still analyzing them in the same way. So I think we all
would agree that they may be considered in the evaluation, and, in fact,
should be. Roll-in patients should be followed in every detail the same
way as the rest of the trial.

\"c. Please discuss whether and/or what type of physician training
should be required for this device if approved.\"

Here I think there was lots of discussion. So, Cindy, do you want to
lead off whatever consensus you took away from the recommendations for
training?

DR. TRACY: I think there has to be some physician training. I don\'t
know whether that has to be a visitor come to your lab and show you how
to use the equipment versus you go and observe the use of the equipment
someplace else.

I think it would be preferable to have somebody come and train onsite.
I\'m not sure it needs to be a physician. It could be a well-trained
clinical field engineer or something like that. But I think there should
be some specific individual physician training as well as training of
the staff in the laboratory on how to use the device correctly.

I think I would hesitate to mandate the specific number of cases that
would have to be performed with an observer in the lab with you. I think
it would depend on the individual expertise of the person learning.

CHAIRMAN LASKEY: It sounds reasonable.

DR. PAGE: Will you forgive my addressing Question No. 3 one more time,
and just to point out, because I think what we just agreed on wasn\'t
what I remembered and isn\'t supported by the FDA slide series?

If I can just draw your attention to slide No. 70, which shows a p‑value
of .0001 in terms of the analysis of cryomap. The overall group ‑‑ so
the prospectively-defined, overall, no subanalysis group is .001.

The next slide, 71, points out that it\'s driven by the AVRT patients,
but, in fact, that\'s where I see the mapping as being useful. Actually,
that\'s where the proposed indication is. The second proposed indication
reads, to my interpretation, and maybe it needs to be clarified, but
reads to my interpretation exactly the issue of mapping AVRT around the
AV node.

So it seems to me that, at least my impression was, we dismissed the
idea of cryomapping showing any efficacy, and it seems to me we have
both an indication of efficacy on slide 70 and a request for indication
for that exact purpose on slide four.

CHAIRMAN LASKEY: The request for the indication calls for the
identification of tissue.

DR. PAGE: Right, for mapping.

CHAIRMAN LASKEY: Period, right.

DR. PAGE: But, as I interpret that, aren\'t they talking about
parahisian conduction in and around the AV node?

CHAIRMAN LASKEY: They didn\'t specify.

DR. TRACY: It\'s not specified, and it\'s inconceivable that somebody
would put in a catheter, map an anterioseptal accessory pathway
successfully, pull that catheter out, and put another catheter in and
try to get it in the same place. I mean it\'s a can of worms that you
open there.

DR. PAGE: Well, I didn\'t open it.

(Laughter.)

But that\'s the request that they have. Indeed, the data are the data.

CHAIRMAN LASKEY: Lilly, could you help me out here? What was the results
of your analysis in the 2-by-2 table of the outcomes by mapping or no
mapping?

DR. YUE: Okay. Now please remember we have three subgroups: effective,
ineffective, and no attempts. The sponsor combined effective ‑‑ sorry,
the sponsor combined \"ineffective\" with \"no attempts,\" correlated
without cryomapping, then compared this without effective cryomapping
with effective cryomapping.

Okay, now here the overall p‑value, the p‑value for the overall analysis
is less than .0001, but you\'ll see it is driven by 49 AVRT patients.
This subgroup is not the group that the sponsor is, it is occurring to
me, claiming for. Instead, the AVNRT group is the only group they are
claiming for. We have a concern about this grouping.

DR. GILLIAM: I think you\'re asking what ablation ‑‑

DR. YUE: What is the meaning of the comparison? Why are they grouping
\"ineffective\" with \"no attempts\"? Is the subgroup classification
\"effective\" versus \"without effective\" biologically plausible?

It seems if we try to test the impact of effective cryomatching ablation
with success, we could compare the effective group with the ineffective
group, then use \"no attempts\" as a control.

Now from here, we can see the acute success rate is 94 percent for
effective group. It is much better than 50-65 percent for the
ineffective group, but the chance of having an effective cryomatching is
only 64 percent. On the other side, if we try to test the impact of our
attempt cryomatching on ablation with success, we could compare attempts
with no attempts. Attempts include effective and ineffective here.

We performed this study. Then we found there\'s no significant
difference in ablation acute success between attempt and no attempts.

Now here the p‑value is .59 here.

DR. BAILEY: The point is, if you were doing a randomized trial, it would
be use of cryomapping or not using cryomapping. You can\'t just take the
people that are positive and say, because their success rate is high,
that shows that cryomapping is a good thing to do.

DR. WALDO: You know, this is the problem. We understand the statistic
very clearly, and there\'s no challenge to that. But the specific thing
that we are talking about is very unique. What you are trying to do is
avoid the his bundle, and I\'m not sure they presented that specific
data.

We are not talking about ablating ‑‑ this is very, very unique, and you
can\'t apply it the same as looking at pathway on the left side with a
his bundle. This is a very unique application where we have nothing at
the moment to help us, and, fortunately, it is not the most common type
of Wolf Parkinson-wide or accessory AV connection problem, but it\'s
very, very real.

The hope is, and maybe we heard some of it anecdotal, unfortunately,
here, but the hope is that you can use this cryomapping technique to
find the sweet spot and avoid the his bundle and help the patient
effectively and safely. That is as simple as that.

That\'s not going to come out of anything we say about the statistics
here because it is just not going to. It\'s not there.

DR. TRACY: It\'s also not necessarily something that needs regulating.
This is something that people over time can find out: If I attempt, I\'m
successful, I ablate; what is my success at ablation at that spot?

So I think this is something that you can do with this catheter that is
unique. You can\'t do it with anything else, but it doesn\'t seem to be
the make or break whether this catheter is useful or not.

DR. KRUCOFF: I think this is also a good illustration of the difference
between the data we actually have to discuss and the questions that go
through your mind. In fact, I think the sponsors during their
presentation came up with a discussion that actually the inability to
show any effect may be a great way to show that it\'s safe to ablate in
certain patients, but while it\'s a great concept, you know, this trial
doesn\'t give us the basis to address it with data. I mean it\'s a great
concept.

CHAIRMAN LASKEY: Frankly, all bets are off with the cryomapping because
there was an arbitrary selection criteria that we were not privy to as
to who were mapped and who were not. It is really difficult to take any
lessons home from that. I just wish it weren\'t here, but it\'s the
second bullet in their IFU. So sorry.

Labeling: \"Labeling for a new device should indicate which patients are
appropriate for treatment, should identify potential device-related
adverse events, and should explain how the device should be used to
optimize its risk/benefit profile. If you recommend device approval,
please address the following:

\"a. Please discuss whether the proposed warnings, precautions, and
contraindications are acceptable, based on the study results.\"

Let\'s be clear about one thing: We\'re now back to the AVNRT group, is
that right, Panel members? Right.

Are the warnings, precautions, and contraindications acceptable, based
on the study results?

DR. GILLIAM: I\'m going to go back to my electrocution question still. I
still have real issues with that, and maybe I\'m not electrocuting a
dead horse. But it is not clear to me how this device can electrocute a
patient if it were hooked to an RF generator. I think if it is possible,
then maybe a little sterner warning needs to be connected, because I
can\'t see how you can avoid or prevent me from hooking this device to
an RF generator.

DR. TRACY: I don\'t think it fits.

DR. WHITE: I asked them specifically that.

DR. GILLIAM: You said they can\'t do it, but if you\'re going to be able
to record, I assume at some point you record an electrogram from the end
of this catheter some way. That means it\'s got to plug into your
recording machinery you have. So at some point there\'s a pin that gets
to my, if you will, Pruca or whatever system you have.

So that would suggest to me that I could plug it into an RF generator,
because all I need is one pin. If that is a significant risk, it may
need to be a little bit higher.

I mean I\'ve never seen anything like this in anything we\'ve done other
than plugging the pin directly into the shield, when we went to hooded
pins ‑‑

DR. TRACY: Well, but I\'m not sure, Rosie. You might, then, carry it to
the extreme of saying: Don\'t plug this into the wall because that could
be dangerous.

I think the connectors are simply not meant ‑‑ they don\'t fit into an
RF generator.

DR. GILLIAM: Okay. I think that\'s how we ended up with the hooded pins,
by the way, so people didn\'t plug them into the wall. But I\'m maybe
getting a little bit overboard here. I just find it very curious. I have
never seen that specific thing written out in any way.

CHAIRMAN LASKEY: Well, it\'s certainly a red flag, but can we settle
this one more time from the engineer? Can you explain the physical basis
for the inability to make this hazardous connection?

MR. ABBOUD: Actually, technically, you can connect anything to an RF
generator, right? You can take any wire and connect it to the RF
generator.

The catheter has a tip, a metal tip, and has a wire on it. And like you
said, you can take that wire and put an adapter and put it on the RF
generator, but no electrocution can happen. That catheter is not
designed to deliver enough energy, and there is no reference electrode
first to connect it. That means someone has to take that catheter, that
second end wire, make all the adaptation and put it to the right pin to
an RF generator and make it work, right?

CHAIRMAN LASKEY: Okay. All right, and we do have a big warning with a
box around it, is that right, in the IFU?

Let me just go back to identify potential device-related adverse events.
I think Dr. Waldo, in the lead, explained it is very difficult to
pinpoint specific device-related AEs when they are procedure-related. So
I might suggest modifying that language to get us off the hook. We
can\'t look at device-related AEs unless it\'s heart block, and that
didn\'t occur.

So other than Rosie\'s concern ‑‑

DR. ZUCKERMAN: Okay, Dr. Laskey, maybe I can take you and the Panel
through the labeling because we do need some comment on the big ticket
items. I\'m looking at the label which is in Section 3, \"Indications
for Use,\" Mr. Morton, which is the same as on our slide.

This is the key point. The first bullet regarding cryoablation, is that
still acceptable to the Panel, and the second bullet should be removed?

CHAIRMAN LASKEY: What page are you on?

DR. ZUCKERMAN: I\'m in Section 3, \"Labeling of the Panel Pack,\" and
page 2 starts with, \"Device description\" and then \"Indications for
Use.\"

The \"Indications for Use\" somehow got deleted from Question 5, but is
our major question here: Is the device appropriately labeled?

DR. TRACY: I think it would save a lot of angst simply to remove that
second bullet.

DR. ZUCKERMAN: Okay. Part \"b\" would be: \"Is the Panel satisfied with
the current contraindications? Should some be removed? Are there others
that are important?\"

DR. TRACY: Didn\'t we decide that we could put it through a
bioprosthetic aortic valve, so that that slight change in the wording in
the retrograde ‑‑ but then again, why are you going retrograde for the
AV node? I suppose you could, if you were ablating it on the left side.

I mean, it\'s there. It\'s not pertaining to this population, but ‑‑

DR. VETROVEC: If I\'m correct, if one reads the package insert for a
porcine bioprosthetic valve, it says it should not be crossed by a
catheter, not to say that we haven\'t, most of us in this room, done
that, but ‑‑

MR. MORTON: I think the valve manufacturers would definitely not want
you crossing anything across prosthetic valves.

DR. GILLIAM: Do we have guidance from other like RF catheters and their
ablation systems? The contraindications, are these substantively
different from that in any way? I guess I\'m asking FDA.

DR. EWING: The indications for all the non-generic-indicated RF
catheters include accessory pathway and adrophobe.

DR. GILLIAM: I was thinking more of the contraindication, not the
indications. I mean, the indications I will grant here a specific
arrhythmia, but are there any specific contraindications to RF systems?

DR. DESMARAIS: I can answer that. We based the contraindication of this
indication for use based on prior RF ablation safety and effectiveness
data that we lifted from the FDA website, and this is the model we used
to create this impression for use and this labeling.

DR. WALDO: By eliminating your angst, we eliminated the one potential
advantage of this because we haven\'t had data, and we\'ve made our
peace with that, is that what we\'re saying, unhappily, but that\'s the
way it is? Is that we\'re saying?

DR. TRACY: Yes, that\'s what that means.

DR. PAGE: Does everybody agree with that? I personally think that having
this as a mapping device for cryomapping is a potentially useful
indication.

DR. HAIGNEY: I agree with that. I think it does require us to have
certain amount of faith in our fellow man that they will map and then
pull the catheter out, but I don\'t think ‑‑ I think it depends on
whether you have a Hobbesian view of man or not.

CHAIRMAN LASKEY: Again, we\'re straying from the data. I think it always
helps to go back to homeplate, and I think we all understand its
attractiveness, but we\'re straying from the data to support that. We
all know that you\'re going to do it anyway.

DR. WALDO: That\'s an easy thing to recommend, a recommendation on how
to focus them on identifying a bunch of patients like this ‑‑

CHAIRMAN LASKEY: Yes.

DR. WALDO: \-- and giving us the data. That\'s the one easy thing I
think of all the things we talked about so far.

CHAIRMAN LASKEY: Well, we\'ll get to that.

Brian, do you want to lead us through the wilderness some more?

DR. ZUCKERMAN: Okay, now we\'re dealing with warnings. Dr. Gilliam has
expressed an opinion on one warning. Are there any other warnings that
are of concern here for the precaution section?

DR. HAIGNEY: The cryoglobulinemia contraindication I think should be
included.

CHAIRMAN LASKEY: I think we\'re all in agreement about what not to do.
There\'s confusion about what to do, but I think Part a is pretty easy
here for the labeling. Do you agree? Yes?

Do we feel the IFU described how the device should be used? From a
technical standpoint, I think so, yes. Agree? Good.

Are we awake?

No. 6, from a post-marketing standpoint: \"If you recommend approval,
please discuss whether a post-market study should be performed to
address any issues that are unresolved, but not essential to the
pre-market approval of the device.\"

DR. KRUCOFF: Were one to approve the device, then one might append a
post-market look at the value of mapping, for instance, if it\'s built
into the same device. That might be ‑‑

DR. WALDO: Specifically, the parahisian mapping.

CHAIRMAN LASKEY: One might, agreed. What else one might recommend?

DR. VETROVEC: Can you look for things that aren\'t necessarily
indicated? If we talked about removing one of the indications, then that
wouldn\'t be a legitimate question to ask someone to do.

DR. ZUCKERMAN: I think Dr. Vetrovec\'s viewpoint is correct. The
parahisian question is an important one, but that could be studied in a
new IDE study with the intent to get that on the label. We\'re really
talking about some issues for the intended indication which are not
show-stoppers for making a decision today, but would be nice
subsequently to study because there would be utility for having that
additional data.

DR. TRACY: This is a dreadful suggestion because it just goes full
circle to where we were earlier in terms of our registry on
effectiveness.

DR. AZIZ: What about monitoring the instance of heart block that people
have spoken about?

CHAIRMAN LASKEY: Sorry?

DR. AZIZ: The instance of heart block that people have spoken about?

CHAIRMAN LASKEY: Yes, I couldn\'t agree more. I am very enthusiastic
about ‑‑ I would go further than one might. I would strongly suggest a
prospectively-designed registry, designed for a safety outcome analysis.
I think the efficacy is believed by most, but safety is the issue, if
this is a complementary or an alternative technique.

DR. ZUCKERMAN: I think, again, in understanding the nature and intent of
post-market surveillance for a problem like complete heart block, which
has an extremely low incidence, while that information might be
interesting to clinicians, it would really require several thousand
patients perhaps to make a definitive determination. That\'s not the
intent usually of post-market surveillance.

What we are asking here is for the intended use indication under study,
are there some additional points where we still feel very uncomfortable,
not where we still want to dot an \"i\" rather than get an A-plus-plus
on a paper?

DR. GILLIAM: I think the utilization of cryomapping even in the AVNRT
patients could be effectively shown. I mean, you could show, when you
achieve an effective cryomap in a specific place, I mean in the study
here it suggests that it wasn\'t particularly useful, but I think the
data are really suspect because we don\'t know how those patients were
selected or, you know, in any way. I think that is something post-market
could be handled within the study population.

DR. BAILEY: I don\'t see how you could learn about the efficacy unless
you design a study to look at it. I mean, post-marketing, some people
will get cryomapping and some won\'t, but how do you know, what does
that show?

DR. GILLIAM: I mean specifically design a study to look at that.

DR. BAILEY: But that\'s not post-marketing.

DR. ZUCKERMAN: Right. Again, that\'s a traditional IDE study for a new
indication on the label. Perhaps to put this in perspective and allow
the Panel to better appreciate what we\'re getting at here, if this was
a traditional RF ablation catheter, there wouldn\'t be any post-market
study required because, as several people have pointed out, this is a
tried-and-true technology.

Is there something unusual here that has been indicated in the dataset
about a safety issue that would make you really want post-market data?

CHAIRMAN LASKEY: The consensus seems to be no, but ‑‑

DR. VETROVEC: Heart block seems to be the obvious.

CHAIRMAN LASKEY: Heart block seems to be the obvious one, yes.

DR. BAILEY: Yes, I think heart block would be ‑‑

CHAIRMAN LASKEY: With due respect to the precision of the estimate, I
would think that a thousand cases could be done across the country in a
reasonable period of time.

DR. BAILEY: And if the incidence is zero, the estimate will be quite
precise?

CHAIRMAN LASKEY: Yes.

DR. KRUCOFF: The other part of this is the premise of approval based on
current data, because while device-related safety looks pretty good,
procedure-related safety, if a significant percentage of these
procedures end up being bailout RF ablations, you\'re going to have
catheters in the blood ‑‑ I mean the safety, the potential safety issues
from a procedural point of view, if this was approved for use, might
well be worth tracking in the post-market, but that begs the question of
whether you see the safety issues as sufficient to approve the device in
the first place.

So the way this question is stated, it\'s a little hard to ‑‑

DR. TRACY: Does it make any sense to look at how the catheter is used,
how many times it is a bailout for RF versus how many times RF is used
to bail out from a cryo? Is that something that would be ‑‑ I know it
would be interesting. Is it something that\'s worthwhile?

CHAIRMAN LASKEY: Or easy to do. I mean, recording that kind of stuff is
just one more thing to record. Generally, the surveillance studies are
just do it and we\'ll look at the outcomes, but this is yet another
iteration. So it\'s one more thing to do. It\'s getting closer to a
study than just an observational kind of thing. I would think it\'s a
good idea, but it just requires one more thing to do and puts the
sponsor on the hook for paying for that information.

DR. KRUCOFF: I think what we are wrestling are ideas for actually it
would just be better studies to do. Maybe pertinent to the agency\'s
interest, I haven\'t heard anyone suggest that there\'s anything about
the lesion in animals or the behavior of the catheter, or whatever, that
ought to spook us in some way that would make you want to keep watching
longer.

I would suggest that the real question here is approval, not sort of
unique post-market kind of issues.

CHAIRMAN LASKEY: So as we get ever closer ‑‑ at this point I would like
to ask the sponsor ‑‑ at this point I would like to ask the agency and
then the sponsor if they have any additional comments or questions
before the vote. So the agency first?

DR. ZUCKERMAN: The agency doesn\'t have any additional comments.

CHAIRMAN LASKEY: Again, on behalf of the Panel members, I thank the
various contributors who have helped us out significantly.

Any final comments from the sponsor?

DR. DESMARAIS: Yes.

CHAIRMAN LASKEY: Brief?

DR. DESMARAIS: Very brief.

CHAIRMAN LASKEY: Thank you.

DR. DESMARAIS: We really appreciate and are fortunate to be here and to
present our technology to the Panel. We are very grateful to the Panel
and FDA for their thoughtful comments.

We believe that the risk/benefit profile for this product for this
profile is favorable and that the technology will play an important role
in the patient care.

Once again, on behalf of CryoCath, I would like to thank the Chairman,
Panel members, and ladies and gentlemen for letting us present our
technology. Thank you.

CHAIRMAN LASKEY: Thank you, sir.

Before we proceed with the motion, I would like to ask our industry and
consumer representatives if they have any final thoughts, beginning with
Mr. Morton.

MR. MORTON: Just to thank the sponsor for a clear and good presentation
of data and clinical utility of the device, and thank the Panel. This is
exactly the sort of decision that the agency needs Panel input on, new
technology and the outcomes not being crystal-clear. So thanks very
much.

CHAIRMAN LASKEY: Mr. Hughes?

DR. HUGHES: Thank you Dr. Laskey. Let\'s see, I know it\'s late in the
day and I would like to be brief, should be brief. If it wasn\'t for
spring break, I would have done a three-hour lecture at my institution.

I think that, first of all, I appreciate the presentation by the
manufacturer and the FDA, as well as the comments and discussion by my
colleagues. I think that there were a couple of points that I really
would like to highlight some that have come around.

That is one with regards to learning curves and being able to translate
whatever level of success the device has to other physicians, other
surgeons, and certainly a concern when it comes to the consumer. The
consumer I think of as being the patient, as opposed to his or her
learned agent; that is, the surgeon or physician.

I also appreciate the comments of Dr. White having to do with labeling
and mechanical valves; that is, making sure that the labeling does not
say specifically or does not indicate that it might be okay to traverse
mechanical valves, as well as representativeness of any studies,
minority representation, gender representation, things like that.

I think overall, though, this particular device does need in some form
more study, more statistical study to assure its efficacy for the
patient. This particular kind of study or set of studies I would think
could take the form of perhaps post-approval studies. But, otherwise, I
think that from the perspective of alternatives, the consumer/the
patient should have alternatives, and in that regard the physician, of
course, should have alternatives at his or her disposal.

I think that this device conceptually theoretically looks very, very
promising, but I think that there are additional studies more specific
to the intent as opposed to taking the OPCs and applying them. Anyway,
more specific studies would be nice and they could take the form of
post-approval studies.

Thank you.

CHAIRMAN LASKEY: Thank you, sir.

I would like to quickly, hopefully, open the public hearing. Anyone in
the audience who wishes to address the Panel on today\'s topic before we
vote?

(No response.)

Thank you. If not, we will close the open public hearing.

I would like to ask Geretta to read the voting options.

MS. WOOD: \"The medical device amendments to the Federal Food, Drug, and
Cosmetic Act, as amended by the Safe Medical Devices Act of 1999, allows
the Food and Drug Administration to obtain a recommendation from an
expert advisory panel on designated medical device Pre-Market Approval
Applications, PMAs, that are filed with the agency.

\"The PMA must stand on its own merits, and your recommendation must be
supported by safety and effectiveness data in the application or by
applicable publicly-available information.

\"Safety is defined in the Act as reasonable assurance, based on valid,
scientific evidence, that the probable benefits to health under
conditions on intended use outweigh any probable risks.

\"Effectiveness is defined as reasonable assurance that in a significant
portion of the population the use of the device for its intended uses
and conditions of use, when labeled, will provide clinically-significant
results.

\"Your recommendation options for the vote are as follows: approval if
there are no conditions attached, approvable with conditions. The Panel
may recommend that the PMA be found approvable subject to specified
conditions such as physician or patient education, labeling changes, or
a further analysis of existing data. Prior to voting, all of the
conditions should be discussed by the Panel.

\"Not approvable. The Panel may recommend that the PMA is not approvable
if the data do not provide a reasonable assurance that the device is
safe, or if a reasonable assurance has not been given that the device is
effective, under the conditions of use prescribed, recommended, or
suggested in the proposed labeling.

\"Following the voting, the Chair will ask each Panel member to present
a brief statement outlining the reasons for their vote.\"

CHAIRMAN LASKEY: I now ask for a motion on the PMA. Anyone? I now ask
for a motion on the PMA. May I have a motion?

DR. TRACY: I am making this motion as an electrophysiologist with the
understanding that the reasonable safety and effectiveness of this
device has been shown. I move to approve with conditions.

CHAIRMAN LASKEY: Is there a second?

DR. GILLIAM: I second.

CHAIRMAN LASKEY: It has been moved and seconded that the motion to
approve with conditions move forward. May I have condition one for the
PMA?

DR. TRACY: The first condition would be some minor modification in the
labeling to include cryoglobulinemia as a contraindication to
cryoablation.

CHAIRMAN LASKEY: Do we have a second?

DR. GILLIAM: Second.

CHAIRMAN LASKEY: Do you need a count for these? Can we have a
hand-raising response to the second, the seconding of the first
condition that Cindy just raised?

All members in agreement with cryoglobulinemia to be added to the
labeling, please raise hands.

(Show of hands.)

It looks like unanimous.

This is new for me, too, Rosie.

DR. KRUCOFF: Can I ask a clarification, Mr. Chairman?

CHAIRMAN LASKEY: Yes, I was just about to invite the Panel discussion on
this condition.

DR. KRUCOFF: Oh, it isn\'t about the condition.

CHAIRMAN LASKEY: Oh.

DR. KRUCOFF: I am trying to understand what we have moved in terms of
the indication for ablation and/or the indication for mapping.

DR. TRACY: That\'s a condition. We have moved for, what I was moving to
approve was for the condition of ablation in patients with AVNRT.

DR. KRUCOFF: And the other one was in the ‑‑

CHAIRMAN LASKEY: We had previously agreed, before we got to this point,
to strike the second bullet. Is that correct?

DR. ZUCKERMAN: Right, but right now we are voting to discuss each
condition. You\'re going to vote on each condition of approval, and
you\'re going to put the package together.

So you have started with labeling Condition No. 1, which refers back to
cryoglobulinemia. You want to discuss that and have a vote.

DR. TRACY: We had the vote. We did vote on that, yes.

CHAIRMAN LASKEY: We had the vote.

DR. ZUCKERMAN: Fine.

CHAIRMAN LASKEY: There didn\'t seem to be a lot of discussion.

DR. ZUCKERMAN: Then, Dr. Tracy, Condition No. 2?

DR. TRACY: Condition No. 2 is that we strike the cryomapping from the
indication.

CHAIRMAN LASKEY: Discuss first or before? Yes. Do we have a second?

DR. GILLIAM: Second.

CHAIRMAN LASKEY: We do.

DR. PAGE: I would just like to state that I think it\'s useful to have
that in there.

CHAIRMAN LASKEY: Okay, there\'s the discussion. Okay, let\'s vote on the
second condition then.

All in favor of striking the second bullet from the current IFU?

(Show of hands.)

One, two, three, four, five in favor.

All against?

(Show of hands.)

One, two, three, four, five against.

DR. ZUCKERMAN: Okay, it\'s important to state who is in favor and who is
against the vote for the record.

CHAIRMAN LASKEY: I have to name my colleagues in public?

DR. ZUCKERMAN: Yes.

(Laughter.)

CHAIRMAN LASKEY: How about we do it henceforth or do you want another
vote? Let\'s do this procedurally correct then. Let\'s just do the hand
vote again.

All in favor of Cindy\'s second condition, which is the elimination of
the second bullet?

(Show of hands.)

In favor are Cindy, Dr. Dullum, Kent Bailey, Mitch Krucoff, and Dr.
Gilliam.

Okay, and those against this condition?

(Show of hands.)

Drs. Haigney, Vetrovec, Waldo, Aziz, and Page.

I\'ve never had to do that. All right. It\'s five/five.

MS. WOOD: If you voted against the condition, could you please raise
your hand again? I missed ‑‑ okay.

CHAIRMAN LASKEY: One, two, three, four, five.

MS. WOOD: Okay.

CHAIRMAN LASKEY: It\'s five/five.

Okay, is there a third condition?

DR. TRACY: Yes, a third condition ‑‑

DR. ZUCKERMAN: Well, we need to decide what\'s going on with this
condition.

CHAIRMAN LASKEY: Of course.

(Laughter.)

You need a tie-breaker?

DR. ZUCKERMAN: Yes.

CHAIRMAN LASKEY: Well, I vote with the group that recommends striking
it.

The third?

DR. TRACY: I move that a formal training program, the details of which
can be worked out at a later date, be part of the approval.

CHAIRMAN LASKEY: A second?

DR. GILLIAM: Second.

CHAIRMAN LASKEY: Thank you. Do we have any discussion on this one?

(No response.)

Let\'s have a hand vote for all in favor of the training criteria to be
elaborated subsequently, articulated subsequently.

(Show of hands.)

Drs. Haigney, Cindy, Dullum, Vetrovec ‑‑ we have unanimous agreement on
this, and I would agree with that, too. That\'s the third condition.

Is there a fourth?

DR. TRACY: Maybe. I move that there be post-market surveillance to
monitor for the incidence of AV block.

CHAIRMAN LASKEY: May I have a second?

DR. HAIGNEY: Second.

CHAIRMAN LASKEY: And a vote?

DR. DULLUM: Can we have discussion?

CHAIRMAN LASKEY: Oh, I\'m sorry.

DR. DULLUM: Yes. I just want to go back to, is that going to require a
thousand patients, do we think, and how is that going to be trackable
and relevant, the less than 1 percent incidence most places?

CHAIRMAN LASKEY: It depends on what happens, I guess. All right,
surveillance for a relatively-rare event, although not astonishingly
rare, if we think it is on the order of 1 percent?

Kent, what would be a reasonable ‑‑

DR. BAILEY: Well, if it\'s really 1 percent, then you can never show
that it\'s less than 1 percent. If it\'s really very low, like one in a
thousand, then you should be able to show it in a few hundred patients.

CHAIRMAN LASKEY: And that would be the goal?

DR. BAILEY: But if it is a percent, then it sounds like what I\'m
hearing is that it\'s not necessarily any advantage over RF. So I think
you\'re really trying to show that it\'s better, which would lead to,
presumably, a lower sample size.

CHAIRMAN LASKEY: Than the equivalent, yes.

MR. MORTON: I have a question on this to the agency, Dr. Zuckerman. Is
post-market surveillance actually not an early-warning system, something
that we would look for for an event that we suspect could happen, an
adverse event that we suspect could happen? In this case, we actually
suspect just the opposite?

DR. ZUCKERMAN: Right. Again, I think there are two issues. One, we want
to distinguish the need for post-market surveillance versus the need for
addressing interesting scientific questions. Certainly, if someone wants
to go out and organize this registry of \"X\" thousand patients to
definitively prove that the incidence of heart block is less with one
form of therapy than the other, that\'s a very interesting scientific
question, but it\'s not necessarily in the purview of the FDA\'s
post-market authority.

The agency would be more interested in perhaps the following question:
Perhaps if you add a certain delta to that 1 percent level, and proposed
a registry and the incidence of heart block is unexpectedly a safety
problem because it is coming in at 3, 4, 5 percent, but I think one
needs to pose the right post-market question here initially: What is the
question?

DR. HAIGNEY: Yes, I think the question is not, is it better than RF
ablation? I think it is, is it worse than RF ablation? So I would be
interested if the incidents maybe blocked were 2 percent. I would
consider that an important factor that I would want to know before I
used the catheter.

DR. DULLUM: Well, wouldn\'t it be a reportable event anyway, MDR, or
not, AV block?

CHAIRMAN LASKEY: But, Mark, doesn\'t that presuppose some kind of
simultaneous or concurrent control or would you resort back to the
literature for comparison?

DR. HAIGNEY: I would resort to the literature.

CHAIRMAN LASKEY: I mean, I personally don\'t see what\'s wrong with a
surveillance that looks for the incidence of complete heart block in
\"X\" consecutive patients undergoing this procedure. I\'m not allowed
to ‑‑ right, but that\'s my concept of the surveillance; it\'s not
necessarily a study, but it\'s an observational approach to
event-collecting.

DR. HAIGNEY: We were having trouble trying to find a number of patients
that we want in the registry, and I\'m saying that I don\'t think we
need to look for the high standard of less than 1 percent incidence. Do
you see what I\'m saying? I\'m proposing a more liberal ‑‑

CHAIRMAN LASKEY: Yes, but my point is we can do better than 150
patients. I think we can come up with a better estimate with more than
150 patients, which is exactly what a post-marketing survey would do for
us.

DR. HAIGNEY: If I have learned anything today, Dr. Laskey, it\'s that we
need more than 150 patients.

DR. WALDO: Would it be permissible to use people in other countries or
would it only be people in the United States? My question is, in this
surveillance, would it only be post-marketing in the United States or
could they use worldwide information?

CHAIRMAN LASKEY: You would have to ask the agency for how they would
receive that data.

DR. ZUCKERMAN: Again, what is the question ‑‑

DR. WALDO: But you get it much faster with worldwide, the numbers
anyway.

DR. ZUCKERMAN: Right, but what is the question being asked? The question
that we would like to ask is, for the label indication, is there an
unusual safety problem that produces heart blocks, say, in 3 percent of
patients?

So if you were convinced that outside U.S. data was being utilized, was
being obtained in that intended patient population, then, yes, a large
simple registry, both U.S. and OUS patients, might be applicable. On the
other hand, if the OUS data contains patients who are being treated
multiple other indications, it\'s not going to help us answer the
question.

DR. TRACY: I think that the intent of the condition is to identify an
unusually large number of AV blocks, an unanticipated number of AV
blocks. I think that right now I\'m not certainly prepared to say what
that number of patients would be required, but I think we could
statistically come up with something that would be a reasonable number
of patients to survey for that phenomenon.

CHAIRMAN LASKEY: Yes, I agree. I don\'t think we should be on the hook
for the study design and the sample size, but I think we\'re simply
recommending that this be an additional condition. I think it is
designable. This is a study which is designable.

DR. WALDO: So can we move the question?

CHAIRMAN LASKEY: So, therefore, we need to vote on the fourth condition,
which calls for the configuration of a post-marketing surveillance for
the event of complete heart block in a sample size to be defined.

May I see all in favor?

(Show of hands.)

Drs. Haigney, Cindy, Dullum, Kent, Waldo, Aziz, Page, and Gilliam.

And those against?

(Show of hands.)

Dr. Vetrovec. Okay.

DR. VETROVEC: I guess I am supposed to state why. My position would be,
I think, reflecting the industry comment, which is we\'re really doing
this because of our interest. We don\'t think there is a problem with
heart block. We think there\'s not a problem with heart block, but
that\'s not sort of the spirit of a post-marketing surveillance.

DR. GILLIAM: But we don\'t know that there\'s not, and I think that\'s
why the post-marketing is necessary. We haven\'t been presented enough
data to show that this is, in fact ‑‑

DR. VETROVEC: I would suggest you not suggest that when you\'re trying
to convince some of us that, because you\'re already off the beam, that
may be one of its advantages.

CHAIRMAN LASKEY: Okay. Any further conditions, Cindy?

DR. TRACY: Not for me.

CHAIRMAN LASKEY: So we have a motion. We have conditions.

DR. ZUCKERMAN: Okay, so now you\'re going to ‑‑

CHAIRMAN LASKEY: Do we need to raise any other conditions? Are there any
other conditions that any other members of the Panel want to raise
besides Cindy?

(No response.)

Good. All right, and I think at this point we\'re ready to vote on the
motion presented, which is to move to approve with the following five
conditions:

To add the contraindication that patients with cryoglobulinemia be
excluded from consideration for this treatment.

The second condition being that we strike the second bullet on the IFU
pertaining to the mapping.

The third condition being the establishment of a better-articulated and
more-specific training criteria, perhaps including the number of cases
for a learning curve.

The fourth condition being ‑‑ there\'s only four conditions here ‑‑
being the post-market surveillance for heart block as a measure of
safety of the procedure.

So the one motion with four conditions.

DR. KRUCOFF: Do we discuss the motion itself?

DR. ZUCKERMAN: Sure.

CHAIRMAN LASKEY: Yes, we can, as is. That\'s en bloc now, yes, before we
vote. Sir?

DR. KRUCOFF: I would just like, before we vote, to encourage everybody
to think about what this vote means beyond just this product, but with
regard to the process of designing a trial prospectively between a
sponsor and the agency, and then having to expend this kind of energy to
really salvage what amounts to the wrong trial or a trial whose pivotal
data suggests the opposite of what you\'re intuitively inclined to do.

That may well be the right decision for this device, but what it will
stop is any ability to answer that question, and whether it will roll
over to then, as a precedent, for future studies to leave it to this
body to bail out trial designs that don\'t answer the questions that
actually are brought forward as an indication question, and I\'m really
concerned about that.

It\'s really not an issue of whether ‑‑ you know, I don\'t think
there\'s any question about the diligence with which this trial was
done, about the interest of the sponsor of bringing this device forward,
or about the interest and the passion of the investigators who have had
their hands on it. In fact, we\'re looking at a very similar situation
upcoming with a coronary device.

But I really do think that the process of prospectively designing a
clinical trial that actually addresses a question that has to do with an
indication is a vital process. If we decide to vote around that today,
that there\'s a bigger issue that impacts by setting that precedent that
ultimately this body would be put in a position to suggest to the FDA or
for a sponsor to rely on to bail out having done the wrong trial, or
whatever, to bring a device forward. So I\'m really concerned about
where we go with this.

CHAIRMAN LASKEY: I think we all appreciate that. The reason we\'re here
until six o\'clock is because we were giving due diligence to the
process and realizing how the serious the task is.

So it being six o\'clock and with those reminders, let\'s vote. May I
see, by a show of hands, all in favor for approval with the conditions
as enumerated?

(Show of hands.)

In favor for: Drs. Haigney, Tracy, Dullum, Waldo, Aziz, Page, and
Gilliam.

And those against?

Drs. Vetrovec, Bailey, and Krucoff.

How did Dr. White vote?

DR. ZUCKERMAN: He didn\'t vote.

CHAIRMAN LASKEY: He didn\'t? He did, but he didn\'t.

DR. ZUCKERMAN: But you could guess.

(Laughter.)

CHAIRMAN LASKEY: Okay.

DR. ZUCKERMAN: Dr. White, for the record, is no longer present.

CHAIRMAN LASKEY: So the motion passes by a vote of six to three.

I would like to spend 60 seconds or less for each member of the Panel to
please state your name and the reason for your vote, please. Dr.
Haigney?

DR. HAIGNEY: Mark Haigney. I thought the sponsor showed that the device
is safe. I think that the clinical trial, as it was designed, it was
entirely appropriate because of the way this device is going to be used.
I think I\'ll stop at that point.

DR. TRACY: Cindy Tracy, and I voted for approval because I think the
sponsor has shown reasonable safety and effectiveness for the device.

DR. DULLUM: Mercedes Dullum. I voted for approval because of showing the
reasonable safety and efficacy.

DR. VETROVEC: I voted against because I think that every time we say
something is reasonable but it didn\'t hit the target that the sponsors
said they would hit, we\'re really leaving ourselves open for question
as to why we made that decision. I\'m not comfortable in this
circumstance, and would almost like to encourage this as a reason that
people really should answer the question that they set out to or set up
studies that approach that.

CHAIRMAN LASKEY: Yes, I think that today this has probably been one of
the more difficult sharp edges to sit on. We didn\'t have with support
what our clinical intuition suggested.

I would strongly recommend, just as a personal opinion, that we relook
at the concept of OPCs. They\'re moving targets, particularly in the
technologic arena, where things move awfully dramatically and they can
be better or worse within a six-month period of time as the numbers
accumulate. So I would be wary of those kinds of strawmen basically to
design a study, and there\'s nothing like a good, old, randomized,
controlled trial that, hopefully, will answer the question with more
statistical rigor.

DR. BAILEY: Kent Bailey. I voted against approval based on the evidence
that was presented today. Although I think the sponsor demonstrated
reasonable efficacy, that is not ‑‑ although the device works in a
vacuum, you can\'t look at that in a vacuum.

It\'s probably not as efficacious as the other conventional approach.
So, well, maybe it\'s safer. Well, it didn\'t met the safety standard
either. So we can\'t really say that it\'s safer.

But, well, it has less heart block, but we don\'t have the evidence to
show that either. So, potentially it\'s not as good in any of those
three categories.

I also agree with the process question, that this is a bad precedent to
set, although I think it is a very promising device and I would have
liked to have seen data presented that showed that it was as good or
superior in at least one category.

DR. WALDO: Dr. Waldo. I voted for. I would like to just second what Dr.
Laskey said. I think he said it succinctly and well after a long
afternoon.

I voted for it because I thought that the efficacy and safety was
reasonably presented and reasonably demonstrated. I really think that it
would serve us well to relook at some of the criteria that were the
strawmen in this target, the strawmen targets in this study. Thanks.

DR. AZIZ: Salim Aziz. I voted in favor of the device because I think,
firstly, it showed relative safety and efficacy. I think it adds a new
way of dealing with a somewhat difficult problem for the EP and people,
and, hopefully, with the surveillance the evidence will bear out the
fact that it has a low incidence of problem.

DR. PAGE: Rick Page. I was convinced by the evidence that there is
reasonable assuredness that this device is efficacious and safe, and I
think it will be a useful tool to the clinical electrophysiologist.

DR. KRUCOFF: Mitch Krucoff. I voted against because, while it is obvious
that from the user\'s point of view, this really does look like a
promising device, that the lesson we have is that intuition in medicine
is a very dangerous direction to follow exclusively, and that\'s why we
do clinical trials. In this particular clinical trial, neither the
safety or the efficacy data landmarks were hit.

An OPC trial, by and large, we consider to be an easier target to hit
than a randomized trial, and that\'s why I voted against it.

DR. GILLIAM: Roosevelt Gilliam. I voted for the motion, aware that it
did not meet the OPC trials of radiofrequency device, a device that has
an extraordinarily high standard of success and safety that\'s been
proven over years.

I recognize that this device, I felt, demonstrated it has a reasonable
degree of safety and efficacy, although both may be close to, or at
least falling short of, the accepted radiofrequency, it provides a
different approach to a very difficult problem. So it provides an
additional tool.

I think that insofar as this is not to replace radiofrequency ablation,
I think the data so we can have a relative appreciation of its safety
was there, and I was comfortable with that level of safety. Thus, I
voted for the device.

CHAIRMAN LASKEY: Mr. Morton, Mr. Hughes, any final words? No?

DR. HUGHES: Yes, I have just a quick comment to send out to the
manufacturer, and that is, with regards to the post-market surveillance,
I feel like in the long run that it will be a good thing for the
manufacturer.

In fact, I think we have been, or the Panel has been, somewhat mild with
regards to those recommendations with regards to post-market
surveillance. A very thorough kind of post-approval study I think would
be in order, including such things as the potential for cryomapping. I
think that, once again, in the long run this would be beneficial not
only to the consumer, to the patient, but also to the manufacturer
overall.

There are regulatory kinds of issues that have to be taken care of by
the FDA, but that does not preclude the manufacturer from taking
additional steps voluntarily, and I want to urge the manufacturer to
consider that as it goes forward.

Thank you.

CHAIRMAN LASKEY: Okay, on behalf of the Panel members, I want to thank
the sponsor for a superb presentation and for sitting here with us until
this late hour. Thank you again.

This concludes the report and recommendations of the Panel on PMA
P020045 from CryoCath Technologies for the Freezor Cardiac Cryoablation
Catheter for cryoablation of cardiac tissue to treat patients with AV
tachycardia.

Thank you again, and good evening.

(Whereupon, the foregoing matter was concluded at 6:06 p.m.)