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					                     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
                             NEAL R. GROSS
                      COURT REPORTERS AND TRANSCRIBERS
                          1323 RHODE ISLAND AVE., N.W.
(202) 234-4433            WASHINGTON, D.C. 20005-3701         www.nealrgross.com
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

                        NEAL R. GROSS
                 COURT REPORTERS AND TRANSCRIBERS
                     1323 RHODE ISLAND AVE., N.W.
(202) 234-4433       WASHINGTON, D.C. 20005-3701       www.nealrgross.com
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




                        NEAL R. GROSS
                 COURT REPORTERS AND TRANSCRIBERS
                     1323 RHODE ISLAND AVE., N.W.
(202) 234-4433       WASHINGTON, D.C. 20005-3701       www.nealrgross.com
                       C O N T E N T S


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




                        NEAL R. GROSS
                 COURT REPORTERS AND TRANSCRIBERS
                     1323 RHODE ISLAND AVE., N.W.
(202) 234-4433       WASHINGTON, D.C. 20005-3701    www.nealrgross.com
                       C O N T E N T S


Open Committee Discussion                                       188

Sponsor Comments                                                259

Industry and Consumer Representatives'                          259
Comments

Open Public Session                                             262

Recommendations and Vote                                        262




                        NEAL R. GROSS
                 COURT REPORTERS AND TRANSCRIBERS
                     1323 RHODE ISLAND AVE., N.W.
(202) 234-4433       WASHINGTON, D.C. 20005-3701    www.nealrgross.com
1                             P R O C E E D I N G S

2                                                                            10:41 a.m.

3                     CHAIRMAN LASKEY:                  Good morning.           I would

4    like to call us to order.

5                     The    topic       before         us    is   a    PMA     for     the

6    CryoCath         Technologies'            7        French     Freezor       Cardiac

7    Cryoablation Catheter, P020045.

8                     I would like to ask Ms. Wood to read the

9    paragraph         regarding           the          Chair,     Committee,           and

10   conflict-of-interest statement.                         Ms. Wood, please.

11                    MS. WOOD:         Just a couple of reminders:                      If

12   you haven't signed in at the table outside, please do

13   so.      Also, please turn your cell phones to silent or

14   off      during        the     meeting.              Thank        you    for     your

15   cooperation.

16                    Dr. Cynthia Tracy has been excluded from

17   chairing recent meetings as a result of the regulation

18   governing covered appearance relationships.                                Since it

19   is expected that for most future Panel meetings Dr.

20   Tracy's covered relationship will continue to preclude

21   her from functioning fully as the Panel Chair, she has

22   graciously        stepped         down        as    Chairperson,          but    will
                                     NEAL R. GROSS
                            COURT REPORTERS AND TRANSCRIBERS
                                  1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433               WASHINGTON, D.C. 20005-3701            www.nealrgross.com
1    continue as a voting member of the Panel until the

2    expiration of her term.                Dr. Warren Laskey will be the

3    Temporary Voting Chair for this meeting.

4                      The       following         announcement              addresses

5    conflict-of-interest               issues        associated           with       this

6    meeting and is made part of the record to preclude

7    even the appearance of an impropriety.                             To determine

8    if     any       conflict    existed,        the     agency        reviewed        the

9    submitted agenda for this meeting and all financial

10   interests reported by the Committee participants.

11                     The conflict-of-interest statutes prohibit

12   special          government     employees         from      participating           in

13   matters that could affect their or their employer's

14   financial          interest.           The     agency        has     determined,

15   however, that the participation of certain members and

16   consultants, the need for whose services outweighs the

17   potential          conflict-of-interest             involved,        is     in     the

18   best interest of the government.                           Therefore, waivers

19   have      been     granted      for     Drs.      George      Vetrovec,          Kent

20   Bailey, Mercedes Dullum, and Albert Waldo for their

21   interest          in    firms   that      could      be     affected        by     the

22   Panel's recommendations.
                                     NEAL R. GROSS
                             COURT REPORTERS AND TRANSCRIBERS
                                 1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433              WASHINGTON, D.C. 20005-3701             www.nealrgross.com
1                      Dr. Vetrovec's waiver involves stock in the

2    parent of a competitor.                       The stock is valued from

3    $50,001 to $100,000.

4                      Dr. Bailey's waiver involves a grant to his

5    institution for the sponsor's product study in which

6    he     had       no    involvement        and     for        which    funding        was

7    between $100,001 and $300,000 per year.

8                      Dr.    Dullum's        waiver       involves        stock      in        a

9    competitor.             The     stock      is    valued        from    $25,001        to

10   $50.000.

11                     Dr. Waldo's waiver involves consulting for a

12   competitor's unrelated product, for which he receives

13   an annual fee of less than $10,001.

14                     Copies of these waivers may be obtained from

15   the      agency's        Freedom        of    Information            Office,       Room

16   12A-15 of the Parklawn Building.

17                     We would like to note for the record that

18   the      agency        took     into     consideration           other        matters

19   involving             Drs.    Vetrovec,          Dullum,         Mark       Haigney,

20   Mitchell Krucoff, and F. Roosevelt Gilliam.                                  Each of

21   these panelists reported interests in firms at issue,

22   but in matters that are not related to today's agenda.
                                      NEAL R. GROSS
                              COURT REPORTERS AND TRANSCRIBERS
                                   1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433                WASHINGTON, D.C. 20005-3701             www.nealrgross.com
1                      The agency has determined, therefore, that

2    they may participate fully in all discussions.                               In the

3    event that the discussions involve any other products

4    or firms not already on the agenda for which an FDA

5    participant has a financial interest, the participant

6    should excuse him or herself from such involvement,

7    and the exclusion will be noted for the record.

8                      With respect to all other participants, we

9    ask     in       the    interest       of    fairness       that    all     persons

10   making           statements       or        presentations          disclose        any

11   current or previous financial involvement with any

12   firm whose products they may wish to comment upon.

13                     CHAIRMAN LASKEY:            Thanks, Geretta.

14                     At this point I would like to have the Panel

15   members introduce themselves, starting to my left,

16   please.

17                     DR.     ZUCKERMAN:             Brian       Zuckerman,          FDA,

18   Division Director, Cardiovascular Devices.

19                     DR. GILLIAM:              Roosevelt Gilliam with the

20   Virginia           Cardiovascular             Specialists           in      private

21   practice of electrophysiology, Richmond, Virginia.

22                     DR.       PAGE:                Rick        Page,          Cardiac
                                     NEAL R. GROSS
                              COURT REPORTERS AND TRANSCRIBERS
                                  1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433               WASHINGTON, D.C. 20005-3701            www.nealrgross.com
1    Electrophysiologist,               now       at     the      University         of

2    Washington in Seattle.

3                     DR.    WALDO:             I'm      Al      Waldo,      Cardiac

4    Electrophysiologist, Case Western Reserve University

5    in Cleveland.

6                     DR. BAILEY:       Kent Bailey, Biostatistician at

7    Mayo Clinic.

8                     MS. WOOD:       Geretta Wood, Exec. Sec. of the

9    Circulatory System Devices Panel.

10                    CHAIRMAN LASKEY:             Warren Laskey.            I'm an

11   Interventional          Cardiologist          at     the     National      Naval

12   Medical Center.

13                    DR.    WHITE:            Chris       White.           I'm      an

14   Interventional          Cardiologist          in     the     Ochsner     Clinic

15   Foundation in New Orleans, Louisiana.

16                    DR. VETROVEC:           George Vetrovec, Chairman,

17   Division          of     Cardiology,              Virginia      Commonwealth

18   University.

19                    DR.    DULLUM:           Mercedes         Dullum,      Cardiac

20   Surgeon, cryo practice, Washington Hospital Center.

21                    DR.   TRACY:          I'm     Cindy       Tracy.       I'm     at

22   Georgetown         University          Hospital,          and   I      not      so
                                   NEAL R. GROSS
                            COURT REPORTERS AND TRANSCRIBERS
                                1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433             WASHINGTON, D.C. 20005-3701          www.nealrgross.com
1    graciously did try to get my brother fired, but it

2    didn't work.

3                      (Laughter.)

4                      DR.    HAIGNEY:           I'm    Mark       Haigney.            I'm        a

5    Cardiac          Electrophysiologist              at    the       National         Naval

6    Medical Center and Director of Cardiology at Uniformed

7    Services University.

8                      DR.       HUGHES:            Alan          Hughes,        Assistant

9    Professor of Decision Sciences and MIS at George Mason

10   University, and I'm the consumer representative.

11                     MR. MORTON:            I'm Michael Morton.                     I'm an

12   employee of Sorin-COBE Cardiovascular, and I'm the

13   industry representative to the Panel.

14                     CHAIRMAN LASKEY:            Thank you, colleagues.

15                     Geretta, if you could read the voting status

16   statement, please?

17                     MS.       WOOD:        "Pursuant           to    the      authority

18   granted under the Medical Devices Advisory Committee

19   charter, dated October the 27th, 1990, and as amended

20   August           the    19th,       1999,     I    appoint         the      following

21   individuals            as    voting      members        of        the    Circulatory

22   System Devices Panel for this meeting on March the
                                      NEAL R. GROSS
                              COURT REPORTERS AND TRANSCRIBERS
                                   1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433                WASHINGTON, D.C. 20005-3701               www.nealrgross.com
1    6th, 2003:

2                       "Mark     C.     Haigney,        M.D.;          Christopher        J.

3    White, M.D.; George W. Vetrovec, M.D.; Kent R. Bailey,

4    Ph.D.; Mitchell W. Krucoff, M.D.; Richard L. Page,

5    M.D.; Albert L. Waldo, M.D.; Francis R. Gilliam, M.D.,

6    and Mercedes K. Dullum, M.D.

7                       "For     the     record,       these        individuals           are

8    special government employees and are consultants to

9    this       Panel        under       the      Medical          Devices       Advisory

10   Committee.                They      have      undergone            the    customary

11   conflict-of-interest                review        and    have        reviewed        the

12   material to be considered at this meeting.

13                      "In addition, I appoint Warren K. Laskey,

14   M.D., to act as Temporary Chairperson for the duration

15   of this meeting."

16                      And it is signed by David W. Feigal, Jr.,

17   M.D.,            MPH,     Director,         Center           for     Devices         and

18   Radiological Health, on February 26th, 2003.

19                      CHAIRMAN LASKEY:             I would like to open the

20   public hearing portion of this morning's program.                                     Is

21   there anyone in the audience who wishes to address the

22   Panel       on      today's       topic      or    any       reasonably-germane
                                       NEAL R. GROSS
                               COURT REPORTERS AND TRANSCRIBERS
                                   1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433                WASHINGTON, D.C. 20005-3701             www.nealrgross.com
1    topic?

2                       (No response.)

3                       If not, then I will close the open public

4    hearing session.

5                       I would like to begin with the sponsor's

6    presentation.

7                       MS. WOOD:         I would also like to remind the

8    speakers to introduce themselves and to state your

9    conflict of interest before speaking.

10                      DR. DESMARAIS:            Good morning, ladies and

11   gentleman, Mr. Chairman, and Panel members.

12                      My   name    is       Jean-Pierre Desmarais.            I am

13   CryoCath Vice President of Scientific Affairs.                            It is

14   my pleasure to present our technology to this Panel.

15   As well, we will present the results of our pivotal

16   study.           Here is the agenda of the meeting:

17                      I'm introducing the group.                 Then we will

18   present the evolution of technology, the details of

19   the     freezor         device,      a    brief    synopsis   of    the     pre-

20   clinical testing, the pivotal clinical study, and a

21   few concluding remarks.

22                      The presenters will be myself, Dr. Jeremy
                                     NEAL R. GROSS
                              COURT REPORTERS AND TRANSCRIBERS
                                  1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433               WASHINGTON, D.C. 20005-3701       www.nealrgross.com
1    Ruskin,          Director,        Cardiac          Arrhythmia         Service,

2    Massachusetts General Hospital.

3                     Dr. Marc Dubuc, Co-Principal Investigator,

4    Chief       of   Electrophysiology           Service,        Montreal      Heart

5    Institute.

6                     Dr.       Peter           Friedman,            Co-Principal

7    Investigator,          also     Professor         of      Medicine,     Harvard

8    Medical School, Brigham and Women's Hospital.

9                     Also available for questions will be from

10   CryoCath:          Marwan Abboud, Director of Engineering;

11   Patrick Chauvet, Pre-Clinical Scientist.                        Consultants:

12    Susan Bondy, VCRA, Cato Research; Andrew Skrylov,

13   Study Statistician, Cato; Richard Holcomb, Consulting

14   Statistician;           John      Lehmann,        Consultant,         CryoCath

15   Medical Director.

16                    Investigators present with us as well are:

17   Dr.     Jose     Nazari    from      Illinois       Masonic     Hospital        in

18   Chicago; Dr. Mark Neibauer, University of Nebraska,

19   Omaha, and Dr. David Keane from Massachusetts General

20   Hospital in Boston.

21                    CryoCath is a public-traded company that was

22   founded in 1995 and which counts over 150 employees
                                    NEAL R. GROSS
                            COURT REPORTERS AND TRANSCRIBERS
                                1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433             WASHINGTON, D.C. 20005-3701          www.nealrgross.com
1    now.         CryoCath designs, develops, manufactures, and

2    distributes products from its location in Montreal,

3    Canada, as well as the freezor catheter which is the

4    subject of this PMA.

5                     CryoCath              offers                products                  to

6    interventionalists              and      cardiac           surgeons         for       the

7    treatment of arrhythmia.

8                     Our     catheter         and      probe-based               products

9    include Freezor and Freezor Xtra for the treatment of

10   cardiac arrhythmia, Arctic Circler for the treatment

11   of      AF       originating          from      pulmonary              veins,         and

12   SurgiFrost,         a    cryosurgical          probe        for    the       surgical

13   treatment of cardiac arrhythmia.

14                    Our products have been on the market since

15   2001        in    Europe,        Canada,         Australia,             and       other

16   countries.              Several        clinical        trials            are      being

17   conducted in Europe and elsewhere with the Freezor

18   Catheter,         and      CryoCath          has      put         in      place        an

19   international patient registry to collect data from

20   the use of its various products, including Freezor.

21                    In the USA, a feasibility trial is underway

22   with the Freezor Catheter to assess the feasibility of
                                    NEAL R. GROSS
                             COURT REPORTERS AND TRANSCRIBERS
                                 1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433              WASHINGTON, D.C. 20005-3701                www.nealrgross.com
1    treating posterseptal pathways through the coronary

2    sinus.

3                       Today we will present the results of the

4    FROSTY           trial,    as    well        as    other       pre-clinical           and

5    clinical information related to this PMA.

6                       CryoCath         has       proposed          the        following

7    indications           for       use:          The       CryoCath       Freezor         is

8    indicated          for     the     cryoablation           of     the      conducting

9    tissues of the heart in the treatment of patients with

10   atrioventricular              node     reentrant         tachycardia,           AVNRT,

11   and for identification of aberrant tissue responsible

12   for      supraventricular              tachycardia,            using      reversible

13   electrophysiological cryomapping near the AV node to

14   minimize AV block.

15                      We will now show you the evidence that we

16   believe             supports           the         following            conclusion:

17   Cryoablation          with       Freezor          has   an     excellent        safety

18   profile.             No     permanent             AV    block    is       clinically

19   effective in AVNRT patients, has excellent long-term

20   success, and has reversible cryomapping.

21                      I would like to introduce Jeremy Ruskin, who

22   will present the evolution of cryoablation.
                                      NEAL R. GROSS
                               COURT REPORTERS AND TRANSCRIBERS
                                   1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433                WASHINGTON, D.C. 20005-3701              www.nealrgross.com
1                      DR. RUSKIN:           Thank you, and good morning.

2    Mr. Chairman, Panel members, ladies and gentlemen, I

3    am Jeremy Ruskin.             I am a paid consultant to and own a

4    small       equity    position          in   CryoCath,       and   my   travel

5    expenses are paid by CryoCath.

6                      The purpose of my talk is to address very

7    briefly with you some of the history and specific

8    technologic aspects of cryoablation therapy.                                This

9    form of ablation is not new.                     In fact, it dates back

10   over a century and currently is widely used in a

11   number of areas of clinical therapeutics, including

12   gynecology, urology, tumor surgery, and dermatology.

13                     There's        also    extensive         experience       with

14   cardiac surgery using cryoablation for the treatment

15   of cardiac arrhythmias, and this goes back more than

16   30 years.

17                     While they are working on the slides, in the

18   interest of time, I will try to do the best I can from

19   memory.          There are several areas of cardiac surgery in

20   which       cryoablation         therapy      has     been   applied.         The

21   first was intentional creation of AV block in patients

22   with       disabling        or     life-threatening          drug-resistant
                                      NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                                 1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433              WASHINGTON, D.C. 20005-3701        www.nealrgross.com
1    supraventricular               tachycardias.             It      became      obvious,

2    when the technique was applied in this setting, that

3    it was both safe and highly effective in producing

4    cold injury that would result in the induction of AV

5    block.

6                      It subsequently was applied to treatment of

7    both       AV         nodal     reentrant         tachycardias            and       Wolf

8    Parkinson-like                syndrome        and,      in      fact,        was        the

9    mainstay, the only nonpharmacological option available

10   for the curative treatment of AV node reentry and

11   accessory             AV   connections          until         catheter       ablation

12   emerged,          particularly             that       using          radiofrequency

13   current in the late 1980s.

14                     Cryoablation           has     also         been    used     in       the

15   treatment of ventricular tachycardia, primarily as an

16   adjunct          to    endocardial          resection,          but     also       as       a

17   primary therapy in some situations.

18                     That's it.           Thank you.             And I will note in

19   this particular indication, it became evident that,

20   because of the ability of cryoablation to preserve the

21   underlying             tissue        architecture              while      destroying

22   myocytes, one was left with intact tissue with good
                                       NEAL R. GROSS
                                COURT REPORTERS AND TRANSCRIBERS
                                    1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433                 WASHINGTON, D.C. 20005-3701             www.nealrgross.com
1    tensile          strength,     and     surgeons        became          comfortable

2    applying this therapy to the papillary muscles in the

3    intraventricular            septum,         sites    at     which         incisional

4    therapy and heat-based therapies could not be used

5    because of concerns about perforation.

6                      More recently, cryotherapy has been applied

7    for the treatment of atrial fibrillation by surgeons

8    using both open and minimally-invasive techniques.

9                      Next, please.          What I would like to do in

10   the     next      few     minutes      is    speak         briefly        about      the

11   mechanisms of tissue destruction, make a few comments

12   about the histologic characteristics of cryolesions,

13   and then comment briefly on two unique properties of

14   cryoablation, that of adhesion and reversibility.

15                     Next,     please.             When        applied          to      the

16   myocardium,          cold      energy        produces            a    very        well-

17   demarcated area of freezing that results in a zone of

18   irreversible cell injury.                    This, then, progresses to

19   replacement         fibrosis.           Interestingly,               as    mentioned

20   previously, despite the destruction of myocytes, the

21   integrity of fibrous stroma is preserved, so that the

22   underlying          tissue       architecture              and       the      tensile
                                    NEAL R. GROSS
                             COURT REPORTERS AND TRANSCRIBERS
                                 1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433              WASHINGTON, D.C. 20005-3701               www.nealrgross.com
1    strength of the tissue is maintained, even during the

2    acute application of cryoablation.

3                     Next, please.          This is an artist's rendition

4    of application of a cryocatheter to the endocardium of

5    the     heart,     resulting         in     a   zone       of    freezing          that

6    produces irreversible cell injury and results in the

7    long-term formation of a dense, fibrous scar.                                    There

8    is an outer halo which is cooled to lower temperatures

9    and at which the effects of the cryoapplication are

10   reversible.

11                    Next    slide,      please.           This       is     a    typical

12   histologic section.              This is taken from a canine heart

13   one week after application of cryo energy.                                   The key

14   features are illustrated here.

15                    First,     there      is    an    extremely           homogeneous

16   dense fibrous scar with very well-demarcated margins,

17   and there is preservation of the endocardial surface.

18    These features are relatively unique to cryotherapy.

19                    Next     slide,       please.             This        is    just          a

20   photograph        from     our     institution         in       the    late      1970s

21   illustrating the use of a surgical cryoprobe in a

22   patient with ventricular tachycardia, and you can see
                                    NEAL R. GROSS
                             COURT REPORTERS AND TRANSCRIBERS
                                 1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433              WASHINGTON, D.C. 20005-3701               www.nealrgross.com
1    the frost forming on the probe at this point.                                      As

2    mentioned, the surgeons were particularly comfortable

3    using this form of energy because of their ability to

4    treat tachycardias over the papillary muscles and also

5    the septum without major concerns about the risk of

6    perforation.

7                      Next slide, please.                 Cryo has a number of

8    unique properties, two of the most important of which

9    are illustrated in the next two slides.

10                     The     first     is    that,       when    a    cryoablation

11   device is applied to the myocardium, it adheres firmly

12   to that tissue during the freeze period.                                  Loss of

13   adhesion occurs immediately upon rewarming.                            This is a

14   unique           attribute     of     cryoablation,          and     it     allows

15   application          of    cold     energy       in    close      proximity        to

16   critical structures like the AV node without concern

17   about catheter migration or slippage.                             This property

18   is distinctly different from what is seen with heat-

19   based energy sources.

20                     Next, please.           This slide is a movie of a

21   cryocatheter, outlined in blue, introduced through the

22   neck       and      into     an     anterioseptal           position      on      the
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1    tricuspid annulus.

2                     I hope that this continues to play.                     If we

3    can run that one more time, what you will see during

4    this is remarkable stability of this catheter on the

5    tricuspid annulus in an anterioseptal position.                              You

6    see termination of the tachycardia, restoration of

7    sinus        rhythm   with      literally          no    movement    of      the

8    catheter except in conjunction with the cardiac cycle.

9     In that position, which is a very delicate position,

10   that kind of stability is almost impossible to achieve

11   with radiofrequency devices.                       That is a result of

12   adherence during the freeze.

13                    Next, please.        The other unique property is

14   that reversibility, which is defined as using warmer

15   temperatures or shorter durations of application to

16   cause reversible alterations in cardiac conduction.

17   This      is     currently    referred        to    as    cryomapping        and

18   historically was known as ice mapping, something that

19   was used extensively by the surgeons, and in some

20   cases still is.

21                    It is used most commonly when working in

22   close proximity to the AV conduction system, and is a
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1    unique attribute which allows reversible interruption

2    of     cardiac        conduction          without         creating      permanent

3    electrophysiologic effects.

4                       Next,   please.          This      is    another         artist's

5    rendition, just to emphasize the fact that cryomapping

6    and     cryoablation          are    part     of      a    spectrum      and     that

7    cryomapping, which is defined as a reversible change

8    in    the        electrophysiology         of    the       tissue,     occurs       at

9    warmer           temperatures       and   with     shorter      durations           of

10   exposure,           whereas     true      ablation         occurs      at      colder

11   temperatures and with longer durations of exposure.

12                      Next,    please.              In        conclusion,          then,

13   cryoablation is a unique technology that has been used

14   safely and effectively in the surgical treatment of

15   cardiac arrhythmias for more than 30 years.                                 So this

16   is not a new form of ablation.                        What is unique about

17   today's           presentation       is    the     availability           of     this

18   energy source in a catheter-based platform.

19                      Cryoablation has different properties from

20   heat-based energy and results in the following unique

21   attributes:                One,      it     produces         well-demarcated,

22   homogeneous, dense fibrous lesions with minimal to no
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1    disruption of the endocardium and a low propensity to

2    thrombus formation.

3                     Cryoablation         devices        adhere        to   cardiac

4    tissue, providing an inherent stability to catheters

5    during the ablation itself, and cryoablation provides

6    the ability to cause reversible alterations in cardiac

7    conduction, which provide operators with the potential

8    for      targeting     desirable          sites      for    ablation       while

9    avoiding undesirable sites, such as the AV conduction

10   system.

11                    Thank you for your attention, and I would

12   like to turn the podium back to Jean-Pierre Desmarais.

13                    DR. DESMARAIS:         Thank you, Dr. Ruskin.

14                    I would like to present a technical aspect

15   of     this      device.       First,       I    will      begin    with    some

16   definitions of cryoablation terms.                         Cryocatheter, an

17   ablation catheter which causes necrosis by application

18   of     low       temperature.          Cryoapplication,             cooling         a

19   specific portion of the heart with either diagnostic

20   mapping or therapeutic ablative intent.                       Cryoablation,

21   cryoapplication at the coldest attainable temperature

22   for a period sufficient to cause tissue necrosis.                              In
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1    the FROSTY study, cryoablation consisted of one four-

2    minute cryoapplication at a set temperature of minus

3    68 degrees Centigrade or colder.

4                      Cryoadhesion, the adherence of the tip of a

5    cryocatheter             to    tissue         during     a     cryoapplication.

6    Cryolesions, lesions created by cryoablation.                                   And,

7    finally,          cryomapping,            a     limited         cryoapplication

8    intended to cause reversible alteration in cardiac

9    conduction, achieved by using shorter times or warmer

10   temperatures.

11                     This    table       shows      the    differences        between

12   cryoablation and RF ablation catheters, and I would

13   like to point to the main difference.                                The energy

14   source is nitrous oxide for cryocatheters, which is

15   widely used as anesthesiology gas.                           The mode of action

16   and ablation mechanism cryofreezes tissue, leading to

17   ice formation and disruption of cellular membranes

18   while        RF     heats        tissues        and      denatures       protein.

19   Finally,          cryo    energy         has    the     ability     to     provide

20   reversible          mapping,         a    unique       feature,      unlike        RF

21   current energy.

22                     The system is comprised of a console which
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1    contains a refrigerate, the user interface, and the

2    safety-monitoring system, a 7 French catheter with a

3    4-millimeter               deflectable            tip,         electrical         and

4    mechanical umbilical to transport the refrigerant and

5    electrical            signals        between        the       console   and       the

6    catheter.

7                      The major safety features include a vacuum

8    system           that    maintains          the      catheter      shaft      under

9    negative pressure to prevent any potential release of

10   refrigerant gas into the bloodstream, flow detection

11   monitoring and vacuum sensors to monitor key operating

12   parameters to prevent catheter pressurization.

13                     A     leak      detection        system       which     disables

14   refrigerant             injection,       in    the     unlikely     event      of       a

15   catheter breach; a blood detector in the handle to

16   prevent the aspiration of blood through the catheter.

17    We      believe         these       were      well-designed        and     tested

18   features and will offer unparalleled safety for this

19   device.

20                     This     slide       presents       the     extensive     design

21   verification testing done on the safety system and the

22   device attribute.                  All the testing conformed to FDA
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1    guidance and industry standards.

2                       I would like now to introduce Dr. Marc Dubuc

3    from the Montreal Heart Institute, who will summarize

4    the pre-clinical experimentation.

5                       DR.       DUBUC:             Thank       you.          Ladies         and

6    gentlemen, Mr. Chairman, and Panel members, my name is

7    Marc Dubuc.                 I am Co-Principal Investigator of the

8    FROSTY           trial      and     I    am    also     a    paid       consultant        to

9    CryoCath.               I    do      not      have    an    equity       position         in

10   CryoCath.              My travel expenses for this meeting have

11   been paid by the company.

12                      I     would        like     to     present       a    pre-clinical

13   testing.           Extensive animal testing in over 250 animals

14   confirmed              cryocatheters'             handling         characteristics,

15   safety features, and ability to make cryolesions.

16                      In addition, we demonstrated the ability to

17   cryomap, and we compared cryolesions to RF lesions,

18   demonstrating reduced thrombogenicity compared to RF

19   lesions.

20                      We also have demonstrated the ability to

21   ablate safely adjacent to coronary vessels.                                          These

22   studies provided sufficient evidence of feasibility
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1    and safety to proceed to IDE clinical study.

2                     On     the      left       is     a   typical        cryolesion,

3    homogeneous,           sharply-demarcated,                and    dense.            This

4    lesion was made with the four-minute cryoapplications

5    at    minus      70     degrees       Centigrade.             Note    the      intact

6    endocardium.

7                     On the right is representative RF lesions

8    for comparison made with temperature-controlled RF at

9    70     degrees        Centigrade         for      60   seconds.           Note      the

10   adherent thrombus.

11                    Next    slide.           A study randomizing RF and

12   cryolesions in the canine heart demonstrated that the

13   median depth for cryoablation of 5 millimeters and RF

14   lesions 5.3 millimeters, shown in the first column,

15   were      the    same.           However,         lesion        volumes      for     RF

16   ablation, 95 cubic millimeters, were roughly twice as

17   large as cryoablation lesions at 49 cubic millimeters.

18    This resulted directly from the larger surface area

19   of RF lesions in comparison to cryolesions.

20                    Note       that      the        interquartile         range        for

21   cryolesions           are      much     smaller        than      those      for      RF

22   ablation.             Cryolesions         are      more      focused      at    equal
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1    lesion depths with less tissue destruction and have

2    much less dimensional variability than RF ablation

3    lesions.

4                     Next.     In this same study, lesion-associated

5    thrombus was compared using computerized morphometry.

6     Only 13 percent of cryolesions had lesion-associated

7    thrombus compared with 76 percent of the RF lesions.

8    This difference was highly significant.

9                     In addition, the median thrombus volume was

10   zero for cryolesions and 2.8 cubic millimeters for RF

11   ablation lesions.                This difference was also highly

12   significant.

13                    This     slide       shows       the      lesion-associated

14   thrombus         in     this    study.          On      the    left        you      see

15   cryoablation lesions of 23 lesions with no detected

16   thrombus and three lesions with thrombus volumes of

17   0.4, 0.6, and 5.5 cubic millimeters.

18                    On the right you see that the RF lesions at

19   over       75    percent       of    the     lesions          with      associated

20   thrombus ranging in size to several thrombi lighter

21   than 20 cubic millimeters.                       The association of RF

22   lesions with increased frequency and size of thrombus
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1    remain even after all other variables were controlled

2    for.

3                       Next.        The use of the freezor catheter to

4    ablate           accessory        pathways        via     the    coronary      sinus

5    system was also studied in a canine model.                                Ablation

6    was performed within 2 millimeters of the adjacent

7    coronary artery, using RF at 30 to 50 watts for 60

8    seconds.           Cryoablation was administered at minus 75

9    degrees Centigrade for either one or two four-minute

10   cycles.           Sacrifice was performed at one week for RF

11   and one week and three months for cryo.                              Assessments

12   were      made      for    transmurality             of    the   coronary      sinus

13   lesions and for stenosis by IVUS and geography and

14   histology.

15                      These slides depict the placement of the

16   ablation catheters in the coronary venous system .                                  On

17   the top, three angiograms of RF animals, we see the

18   development          of     a     significant         stenosis     in    the     left

19   coronary artery one week after RF ablation in the CS

20   adjacent to the artery.                        Compare this to the lower

21   panel in which no stenosis developed in cryolesion

22   animals one week and three months after cryoablation.
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1                     This     study       showed         that      both      RF      and

2    cryoablation led to transmural coronary sinus lesions.

3     At all subsequent time points, measures of stenosis

4    were much worse in the RF-ablated hearts as compared

5    to     cryoablated        hearts       with     no    cryoablated         lesions

6    showing atrial stenosis.                    Histology at three months

7    showed healed and endothelialized with no stenosis,

8    only minor intimal proliferation, two to three cell

9    layers.

10                    In summary, our animal experimentation with

11   the CryoCath cryoablation catheter demonstrated that

12   cryolesions         are        dense,        homogeneous,          and        well-

13   demarcated.         Cryolesions are focused as deep as RF

14   lesions with a smaller volume of tissue destruction.

15   Cryolesions        are     associated         with         significantly       less

16   frequent and significantly smaller thrombi, even when

17   lesion dimensions are controlled for.

18                    Cryoablation in proximity to coronaries is

19   significantly less likely to produce coronary artery

20   stenosis.         These studies provided sufficient evidence

21   of feasibility and safety to proceed to IDE clinical

22   study.
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1                     Now    I   would     like to introduce Dr. Peter

2    Friedman.

3                     DR. FRIEDMAN:          Thank you, Marc.                Ladies and

4    gentlemen, Mr. Chairman, and Panel members, my name is

5    Peter Friedman.               I am Co-Principal Investigator for

6    the FROSTY trial.                  I'm also a paid consultant to

7    CryoCath.           I    do    not     have     an    equity          position        in

8    CryoCath.           My travel expenses for this meeting have

9    been paid by the company.

10                    I would like to present the FROSTY study.

11   Next, please.            The FROSTY study was a non-randomized,

12   single-arm,          multicenter        study.             It    utilized        FDA's

13   previously-determined objective performance criteria,

14   or     OPCs,      that      were     developed        during          RF    catheter

15   testing.

16                    The primary safety endpoint was acute major

17   complications, or AMCs, and the primary effectiveness

18   endpoint,         acute       procedural       success,          or    APS.          The

19   safety secondary endpoint was the occurrence of long-

20   term        major       complications          and         the    effectiveness

21   secondary endpoint, freedom from recurrence of the

22   targeted         arrhythmia.           Furthermore,             this       study     was
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1    designed to investigate the cryomapping effect and the

2    reversibility of cryomapping.

3                      Next, please.         The inclusion criteria for

4    FROSTY were a documented history of supraventricular

5    tachycardia,          either      AV     nodal       reentrant   SVT,       AV

6    reentrant tachycardia utilizing a bypass track, or

7    atrial fibrillation requiring AV node ablation for

8    rate control.

9                      Patients       had          been       referred          for

10   radiofrequency ablation.               The ejection fraction had to

11   be greater than or equal to 35 percent, age greater

12   than or equal to 18 years.

13                     Finally, the diagnostic electrophysiologic

14   study had to document inducible sustained AVNRT or

15   AVRT in the baseline state or the presence of a rapid

16   ventricular response in the setting of AF, requiring

17   AV nodal ablation.

18                     Next slide, please.          These are the exclusion

19   criteria in the trial, typical for what one would

20   expect.          Note that atrial tachycardia was an exclusion

21   criterion, and the others are ones that you would

22   predict.
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1                     Next, please.            These are the FROSTY study

2    hypotheses for safety:                   the 95 percent, double-sided

3    upper confidence bound of the proportion of safety

4    subjects with AMCs was greater than 7 percent for the

5    null hypothesis and less than or equal to 7 percent

6    for the alternative hypothesis.

7                     For effectiveness, acutely, the 95 percent

8    double-sided            lower       confidence             bound      of      acute

9    procedural            success,      or     APS,      for      intent-to-treat

10   subjects         was    less     than      85    percent       for     the       null

11   hypothesis and greater than or equal to 85 percent for

12   the      alternative         hypothesis.               Long-term           clinical

13   success, freedom from recurrence at six months would

14   be greater than or equal to 85 percent.

15                    We    estimated         that   a    sample        size     of    165

16   evaluable safety subjects was required to establish a

17   95 percent upper confidence bound of less than or

18   equal to 7 percent, when the acute major complication

19   did not exceed a target value of 3 percent.

20                    We also estimated that a sample size of 150

21   subjects intent to treat was required to establish a

22   95 percent lower confidence bound of greater than or
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1    equal to 85 percent, when the acute procedural success

2    exceeded a target value of 91 percent.

3                       Next, please.             One hundred and sixty-six

4    subjects were enrolled at 14 sites.                           Eleven of these

5    were in the United States; three were Canadian.

6                       The first subject enrolled on March 23rd of

7    2001.       The last six-month followup was on October 23rd

8    of 2002.           Protocol compliance supported the scientific

9    validity of the study conclusions.

10                      Next, please.           Overall, 166 patients were

11   enrolled with a mean age of 48 years.                           Patients with

12   AVNRT and patients with AVRT tended to be older than

13   the atrial fibrillation patients.

14                      As one can see, the mean of body surface

15   indices were typical for what one would expect in

16   North America, and there was a female preponderance in

17   each of the three groups in a ratio of approximately

18   two to one.

19                      Next, please.            One hundred and sixty-six

20   subjects were enrolled.                   All of these are considered

21   safety           subjects,     and     they     were        comprised     of     103

22   patients with AVNRT, 51 patients with AVRT, and 12
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1    with       atrial      fibrillation.             This      distribution           of

2    diagnoses         closely      matches        that        seen    in      routine

3    clinical practice.

4                     Two   patients       with     AVRT       were    not     treated

5    because of equipment failures, which left a total of

6    164 intention-to-treat patients.                      One of the subjects

7    initially diagnosed as AVNRT turned out to have atrial

8    tachycardia, which was an excluded arrhythmia in this

9    trial, and, therefore, cryo treatment was abandoned in

10   that individual.             Six other subjects did not have a

11   protocol-specified,            qualifying         cryoablation;           namely,

12   one lasting for four minutes at less than or equal to

13   minus       68   degrees.         Excluding        these    seven       patients

14   yields 157 per-protocol patients who were correctly

15   diagnosed          and      had       at      least        one         qualifying

16   cryoablation.

17                    Next slide, please.             Basic study procedures

18   were      nearly       identical      to     standard       diagnostic           and

19   therapeutic RF ablation procedures with the addition

20   of      protocol-mandated            assessments.                All     of      the

21   preparation         of    these      patients        and    the        diagnostic

22   portion of the EP study were identical.
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1                      When the cryocatheter had been introduced

2    into the body and correctly positioned, the console

3    was activated, either for cooling to achieve ablation

4    or    for        mapping   at    the    ablation          catheter      tip.            A

5    physician monitored the response at the tip, noting

6    particularly          temperature         and     time      of     application.

7    When the cryoapplication was complete, the console

8    stopped the flow of refrigerant gas, the catheter was

9    allowed to thaw, and the catheter was then moved, if

10   desired.

11                     Next, please.          This slide shows a typical

12   panel from the cryo console during the cryoablation.

13   On the righthand side are the controls to set the pre-

14   determined           tip     temperature           and       the       time        of

15   application.          In the mid-panel note the orange tracing

16   which depicts the pre-determined tip temperature that

17   was set.          The white tracing represents the actual tip

18   temperature           in     the       catheter,           recorded         by          a

19   thermocouple.          We can see how closely it mirrors the

20   pre-determined             desired        temperature            during           the

21   cryoapplication.

22                     At the end of 240 seconds, the injection is
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1    halted and very quickly one sees a return of the tip

2    temperature to body temperature; namely, 37 degrees.

3    The total application here was 240 seconds.

4                     Next, please.         This slide illustrates the

5    procedural details for all the patients.                     One hundred

6    and sixty-four patients underwent cryoablation.                        There

7    were 1,230 cryoapplications for ablation with a mean

8    of 7.5, ranging between 1 and 36.                       One hundred and

9    thirty-five subjects had cryomapping with a total of

10   820 cryomapping attempts, a mean of 6.1 per patient,

11   ranging from 1 to 37.               Mean fluoroscopy time was 25

12   minutes, mean procedural duration 265 minutes.                             The

13   mean      cryoablation      temperature,           minus   71.2     degrees

14   Centigrade, and mean cryomapping temperature, minus

15   26.6 degrees Centigrade.

16                    Next, please.         I would like to now present

17   the     safety     results.        I   will     discuss    major     safety

18   outcomes; namely, acute major complications, or AMCs,

19   deaths and serious adverse events, SAEs, and other

20   device-related adverse events.                   I would then like to

21   present the safety results for the AV nodal reentry

22   tachycardia subjects specifically.
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1                      I would like to add that all adverse events

2    were reviewed by the investigators, study monitors,

3    and the medical monitor, and were then reviewed and

4    adjudicated             for      final        characterization             by      an

5    independent adverse event adjudication committee which

6    convened on three separate occasions.

7                      Next, please.           Seven subjects experienced a

8    total of eight acute major complications, for an AMC

9    rate      of     4.2    percent       with     a    95       percent    confidence

10   interval ranging from 1.7 to 8.5 percent.

11                     No AMC was device-related, as adjudicated by

12   the independent committee.                         All subjects recovered

13   completely.             However, the primary safety hypotheses

14   based on OPC with a 95 percent upper confidence bound

15   of less than or equal to 7 percent was, therefore, not

16   met.

17                     Next, please.             This slide illustrates the

18   AMC      in      each    subject.            One     subject      had    a      minor

19   pulmonary         embolism        requiring        brief       hospitalization.

20   One      subject        developed        prostatitis           after     traumatic

21   placement of a Foley catheter.

22                     One    subject,         after       a      lengthy     procedure
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1    utilizing         cryoablation           which      failed     and       then      RF

2    ablation, was found the day after the procedure by

3    echocardiography             to    have     adherent        thrombus       in     the

4    inferior vena cava.               This patient's procedure began at

5    9:00 in the morning, and heparin was not administered

6    until three or four o'clock in the afternoon.                                     The

7    patient          was   treated        with      anticoagulation,            and         a

8    follow-up echocardiogram revealed resolution of the

9    thrombus.

10                    One subject with a left lateral accessory

11   pathway failed cryoablation and then was treated with

12   radiofrequency catheter ablation.                       Several hours after

13   the       procedure         he      developed         evidence        of      acute

14   myocardial infarction.                 Emergency angiography revealed

15   occlusion of the right coronary artery, a site distant

16   from      the     site     of     ablation.          This    was    treated        by

17   angioplasty and stenting, with complete resolution of

18   the symptoms and of the evidence of infarction.                                    He

19   was discharged some days later with a normal ejection

20   fraction.

21                    One subject was noted to have a partially-

22   sheared          introducer         sheath       during      removal         of         a
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1    diagnostic catheter.             One subject had perforation of

2    the right ventricle during manipulation of the RV apex

3    diagnostic          catheter.             This          patient     required

4    pericardial centesis.            The same subject was also noted

5    to have deep venous thrombophlebitis on day two after

6    the procedure

7                     Finally,       one        subject          with       failed

8    cryoablation -- this was the subject with the atrial

9    tachycardia -- had the cryoablation catheter removed

10   from the body, and preparations were then initiated

11   for a transseptal catheterization because the focus

12   was located in the left atrium.                    An intracardiac echo

13   was performed that revealed thrombus that was adherent

14   to a diagnostic catheter extending down the IVC.                           That

15   catheter and the thrombus were removed.                            A small,

16   residual thrombus remained on the right atrial wall.

17   The patient was anticoagulated and had no permanent

18   sequelae.

19                    Next, please.        This slide shows deaths and

20   serious adverse events.               One unrelated death occurred

21   in an 89-year-old subject who was hospitalized for

22   cholecystectomy and who had a stroke.                       This was four
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1    months after successful cryoablation.

2                       Twenty subjects, or 12 percent of the total,

3    had a total of 26 serious adverse events.                                       None of

4    these        was     device-related,             as    adjudicated              by      the

5    independent           committee.             Seventeen            of    20     subjects

6    recovered completely and three did not:                                  the subject

7    who       died,           another       with       unrelated              compression

8    fractures, and a third unrelated depression.

9                       Next, please.            All device-related adverse

10   events            were     various         kinds        of         AV        conduction

11   disturbances.              The duration of these was a median of

12   45 seconds, ranging between 10 seconds and 24 hours.

13   All of the longer-duration AV conduction disturbances

14   were examples of incomplete or complete right bundle

15   branch           block.      No     patient       developed             permanent        AV

16   block.

17                      The       etiology           of           these           conduction

18   disturbances was felt to be related to cryoablation in

19   seven,           related      to     cryomapping             in        one,     due      to

20   mechanical trauma in one patient during pacing and was

21   noted post procedure in one patient.

22                      Next, please.           This table shows you all 14
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1    instances        of    AV    conduction         disturbance           in    the   11

2    patients.             You     see      that      the       longest         duration

3    abnormalities were those of incomplete or complete

4    right bundle branch block.                      AV block, ranging from

5    first degree to complete AV block, generally was very,

6    very short-lasting, often resolving within a matter of

7    seconds.         I would like to emphasize how dramatically

8    different this is compared to radiofrequency catheter

9    ablation.

10                    During        RF       ablation,           an        accelerated

11   junctional         rhythm       is     induced         which     impairs          the

12   operator's            ability        to       assess        anterograde           AV

13   conduction.           When transient AV block occurs during RF

14   ablation, 30 to 50 percent of those patients go on to

15   have permanent conduction abnormalities that require a

16   permanent pacemaker.                 The chance of that developing

17   ranges from 1 to 4 percent, depending on the site of

18   ablation.

19                    Cryoablation is very, very different.                        There

20   is no junctional rhythm.                   One can assess anterograde

21   conduction        during       the     ablation,           and   if    AV    block

22   develops,        it    resolves        very     quickly.          Indeed,         the
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1    investigators in this trial quickly obtained a high

2    degree of confidence with this technology in using it

3    very close to the AV node.

4                      Next,        please.             This        slide     shows         the

5    procedure-related acute major complications in the AV

6    nodal reentry track of cardio subjects.                               Specifically,

7    three       of        the    103     patients,         or      2.9    percent,         had

8    procedure-related acute major complications.                                  One was

9    the subject with the pulmonary embolism; another with

10   prostatitis due to a traumatic Foley placement, and

11   the third, the patient we have mentioned already, with

12   atrial           tachycardia          who      developed         thrombus         on        a

13   diagnostic catheter.

14                     There were, of course, again no permanent AV

15   blocks in this group.                    This is a clinically-excellent

16   safety profile in this patient group.                                  You can see

17   that the 95 percent confidence interval for the AMC

18   rate was .6 to 8.3 percent, and with the Bonferroni

19   correction for multiple comparisons, it ranged from .4

20   to 9.6 percent.

21                     Next,        please.            To   summarize        the     safety

22   results          in    FROSTY,         it    is    true        that    the     overall
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1    statistical endpoint was not met.                            However, as an

2    experienced           electrophysiologist,             I    can    assure        the

3    Panel that this outcome represents an excellent safety

4    profile overall, particularly for the AVNRT patients.

5                     I    should     emphasize          again    there      were      no

6    device-related AMCs.                  There were no device-related

7    SAEs, and there were no instances of permanent AV

8    block in 151 patients at risk.

9                     Next, please.           Now I would like to present

10   the      effectiveness         data.          I'll     present       the     acute

11   procedural success for all intent-to-treat subjects

12   and for the AVNRT subjects specifically.                          Then I will

13   discuss those subjects who were acute cryoablation

14   failures         who      were       treated         with     radiofrequency

15   ablation.            Finally, I will discuss long-term clinical

16   success.

17                    With regard to acute procedural success in

18   the     intent-to-treat           subjects,         there     were     164     such

19   subjects with AVNRT, including the one misdiagnosed

20   who had atrial tachycardia, AVRT, or AF.                           One hundred

21   and thirty-six subjects had acute procedural success,

22   yielding         a    point    estimate        of    83     percent     with      95
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1    percent confidence intervals ranging from 76 to 88

2    percent.          The primary effectiveness endpoint, a 95

3    percent lower confidence greater than or equal to 85

4    percent, was, therefore, not met.

5                     Acute   procedural          success,         however,          was

6    significantly         different      among      the      three      diagnostic

7    groups.          This slide shows overall procedural success

8    of 83 percent in the 164 patients overall.                           Note that

9    the     acute     procedural     success       in       the   patients        with

10   AVNRT was 91 percent compared with 69 percent in the

11   AVRT patients and 67 percent in the AF subjects.

12                    Next, please.         A number of subjects were

13   also treated with RF ablation when cryoablation had

14   not been successful.            Twenty-five of 28 subjects with

15   acute procedural failure during cryoablation went on

16   to have RF ablation; two subjects did not.                                Sorry,

17   three subjects did not.               Twenty-three of these 25 of

18   the RF-treated subjects had acute clinical success.

19                    Considering       both       cryoablation             and       RF

20   ablation, acute clinical success was achieved in 161

21   of 166 patients.            This was a point estimate of 97

22   percent with confidence intervals ranging from 93 to
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1    99      percent.                Adverse         event          measures        in       the

2    cryoablation plus RF ablation patients did not differ

3    from those in the cryoablation-alone subjects.

4                      Next, please.              I would like now to discuss

5    long-term clinical success.                          There are two ways of

6    assessing long-term outcome.                           One is by life table

7    analysis, another by Kaplan-Meier survival analysis.

8                      This slide shows the life table analysis for

9    all 136 patients who had acute procedural success.                                       We

10   see that the long-term clinical success rate in this

11   group       was        91    percent       with      95        percent      confidence

12   intervals ranging from 86 to 96 percent.

13                     This        outcome         is      clinically            excellent,

14   exceeds the protocol-specified rate of 85 percent and

15   exceeds          the    subsequently-published                   FDA     RF    ablation

16   guidance of a conditional long-term clinical success

17   rate of 90 percent with a 95 percent lower confidence

18   bound of 80 percent.

19                     This slide shows the Kaplan-Meier analysis

20   with the same 136 patients, all of whom had acute

21   procedural success.                  Using this method of analysis, we

22   get essentially the same long-term, chronic success
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1    rate       of     91     percent       with      95     percent        confidence

2    intervals ranging from 86 to 96 percent.

3                     Note that there was no recurrence of the

4    targeted arrhythmia after the third month of followup.

5     This        durable       response        is     exactly        what    we      are

6    accustomed to seeing with radiofrequency ablation.

7                     This     is    the    life table analysis for the

8    AVNRT subjects and demonstrates that the long-term

9    clinical success rate was 94 percent with a corrected

10   98.3 percent confidence interval ranging between 87 to

11   100 percent.              Again, this outcome exceeds the FDA

12   generic RF ablation guidance of a conditional long-

13   term success rate of 90 percent with 95 percent lower

14   confidence bound of 80 percent.

15                    Here is the Kaplan-Meier survival analysis

16   for     the      AVNRT     patients.            This    results     in    a    very

17   similar outcome as the life table analysis with a

18   long-term         clinical         success        rate      of    94     percent,

19   corrected 98.3 percent, with a confidence interval

20   ranging from 87 to 100 percent.

21                    Next slide.           Thank you.           To summarize the

22   FROSTY effectiveness outcomes, for all 164 intent-to-
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1    treat subjects, the primary endpoint was not met with

2    an     overall           acute    procedural            success    rate       of     83

3    percent.             The       secondary         effectiveness            endpoint,

4    however, was met with a long-term clinical success

5    rate of 91 percent at six months of followup.                                For the

6    103 AVNRT subjects, acute procedural success was 91

7    percent with a long-term clinical success rate of 94

8    percent at six months of followup.

9                       Post-hoc       analyses         need      to    be     carefully

10   assessed.            The      analysis        of     the     AVNRT      group       has

11   substantial clinical and statistical validity for a

12   number of reasons.

13                      To begin with, this is a clinically-relevant

14   group.           Furthermore, the group was defined a priori in

15   the      protocol.               There     was      a     highly        significant

16   correlation          between        diagnosis        and     acute       procedural

17   success.

18                      The       univariate            relationship              between

19   diagnosis and acute procedural success was for AVNRT

20   91 percent; AVRT, 69 percent, and AF, 67 percent.                                    By

21   chi square, this was highly significant with a p-value

22   of .002.
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1                     The multivariate relationship demonstrated

2    that      diagnosis    was       a    highly-significant         factor       in

3    predicting acute procedural success.                     With a stepwise

4    logistic regression, the p was .022.

5                     Finally, there is a significant amount of

6    additional clinical information, much of it filed with

7    the PMA, that supports the FROSTY AVNRT safety and

8    effectiveness results, as we have reported here.                             For

9    these reasons, we believe that this analysis of the

10   AVNRT subjects is valid and is clinically useful.

11                    Next, please.         I would like now to discuss

12   cryomapping, which I believe is one of the most unique

13   and potentially most important features of this new

14   technology.          Cryomapping         is    defined    as     a    limited

15   cryoapplication         intended          to     cause    a      reversible

16   alteration in cardiac conduction.

17                    In the FROSTY study, cryomapping was done at

18   minus 30 degrees Centigrade for up to 80 seconds.

19   This      allowed     for    a       reversible     assessment        of     the

20   potential effects of cryoablation at a chosen target

21   site.

22                    Next, please.         I would like to show you just
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1    one example, and for the non-electrophysiologists on

2    the Panel whose eyes may glaze over, please bear with

3    me.       We see two panels here during cryomapping.                                 In

4    the     top      panel       and    in    each      panel      you   see     surface

5    electrocardiographic leads one, two, three, V1 and V6,

6    and then high-right atrial electrograms here from the

7    high-right atrium, from the ablation catheter, and

8    from the his bundle electrogram.

9                     In    the      baseline        state,        this   patient        had

10   sustained             AV      nodal         reentrant          supraventricular

11   tachycardia           of     the    typical       variety.           These    atrial

12   electrograms represent retrograde conduction to the

13   atrium over the fast AV nodal pathway.                                The impulse

14   then turns anterograde and conducts through the AV

15   node over the slow AV nodal pathway to complete the

16   reentrant         circuit.            The     cycle     length       here    is     390

17   milliseconds.

18                    During         cryomapping          one      sees    progressive

19   slowing of the tachycardia cycle length here and here,

20   and then, finally, termination of the tachycardia.

21   Note that the termination occurs in the anterograde

22   limb, the slow pathway, which is exactly where the
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1    catheter had been placed.                   When the catheter was then

2    rewarmed, this patient again had inducible, sustained

3    AVNRT.

4                     Next, please.            One hundred and thirty-five

5    intent-to-treat subjects had a total of 820 cryomap

6    attempts.         The remaining 29 intent-to-treat subjects

7    had no attempted cryomaps.

8                     On   a   per-subject            basis,       87   of     the       135

9    subjects, or 64 percent, with an attempted cryomap,

10   had one or more effective cryomaps.                          On a per-cryomap

11   basis, 164 of 820 attempts, or 20 percent of the

12   attempts,        resulted         in    effective           cryomaps.          So       a

13   majority of study subjects and about two-thirds of

14   those       in   whom     it     was     attempted          had    one    or    more

15   effective cryomaps.                Any given cryomap attempt had a

16   20 percent chance of being positive.

17                    With regard to cryomapping reversibility, of

18   the      164     effective          cryomaps,         102     were       converted

19   immediately           into     cryoablation           without        warming        to

20   assess reversibility; 62 of the effective cryomaps

21   were      warmed      after       mapping.           Forty-nine          of    these

22   reversed immediately and completely; nine reversed in
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1    one to six minutes after rewarming, and four went on

2    to cryoablation from four to twenty-one minutes after

3    cryomapping            but   before      complete           reversal      had     been

4    observed.             Ninety-four percent, 58 out of 62, of the

5    effective cryomaps definitely and rapidly reversed.

6                      A    subject       with      one     or      more      effective

7    cryomaps was significantly more likely to have acute

8    procedural success than patients with only ineffective

9    cryomaps         or     patients      in    whom      cryomapping          was      not

10   attempted at all.                 Looking at the total group, for

11   patients with effective cryomaps, the acute procedural

12   success rate was 94 percent as compared to only 67

13   percent          in    patients      with      ineffective          maps      or     76

14   percent in patients with no cryomapping attempted.

15                     Thus, considered as a diagnostic tool for

16   catheter          location,       having        one     or     more      effective

17   cryomaps predicts a group significantly more likely to

18   have      acute        procedural       success.             This     significant

19   difference is present in the AVR patients, but the

20   trend in the AVNRT patients and the AF patients was

21   not significant.

22                     I    suspect      that     the      effect        in   the      AVRT
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1    patients          represents         the     much     greater       localization

2    challenge inherent in treating accessory pathways and

3    the corresponding benefit that cryomapping offers in

4    that group.

5                      To summarize cryomapping, the FROSTY study

6    demonstrates           that       cryomapping        can     reversibly         alter

7    cardiac conduction in the majority of subjects in whom

8    it is attempted.                  Effective cryomaps are associated

9    with a higher procedural success rate, but this trend

10   did not reach statistical significance in the AVNRT

11   diagnostic group.

12                     Cryomapping         utility        has     many    interesting

13   possibilities.               Clinical applications at the moment

14   include the ability to map in order to confirm a

15   desirable          site     for    ablation,        but      also   to    identify

16   sites that are undesirable where ablation would likely

17   result in an unintended outcome.

18                     To summarize the FROSTY study with regard to

19   safety           and   effectiveness,             cryoablation           with      the

20   Freezor catheter is a safe modality in patients with

21   supraventricular tachycardia.                      There were no instances

22   of permanent AV block in 151 ablated AVNRT and AVRT
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1    subjects, despite frequent ablations near the AV node.

2     AV block can be monitored and is quickly reversible.

3     There were no device-related AMCs or serious adverse

4    events.

5                      Cryoablation with Freezor is a clinically-

6    effective treatment for AVNRT subjects, resulting in

7    an acute procedural success rate of 91 percent and a

8    long-term clinical success rate of 94 percent.

9                      Cryomapping with Freezor was observed in 64

10   percent          of    subjects      attempted.             Cryomapping        was

11   quickly reversible in almost every case, and subjects

12   with effective cryomaps had a significantly higher

13   acute procedural success rate compared to subjects

14   without an effective cryomap, 94 percent versus 67

15   percent.

16                     From FROSTY, I think we can conclude that

17   Freezor is safe for the treatment of patients with

18   supraventricular              tachycardia.                  Freezor      is          a

19   clinically-effective               treatment          for    patients         with

20   AVNRT,           and   cryomapping         with       Freezor     may      offer

21   advantages for safely confirming desirable ablation

22   sites and also avoiding undesirable ablation sites.
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1                     Thank you for your attention.                      I will now

2    turn the podium over to Mr. Desmarais.

3                     DR. DESMARAIS:           Thank you, Dr. Friedman.

4                     Here        are        my        concluding             remarks:

5    Cryoablation        for      arrhythmia         has    a    long    history        of

6    safety.          Cryoablation has been shown to be safe and

7    effective for the treatment of cardiac arrhythmias in

8    surgery over 30 years.

9                     Freezor      has      many     proven        safety       systems

10   included in the catheter and console to ensure patient

11   safety.          In over two years of worldwide commercial

12   distribution and over a thousand procedures, there is

13   no     reported     instance         of    permanent         AV    block.          In

14   studies of almost 600 cryoablated SVTs there have been

15   no instances of permanent AV block as well.

16            Freezor        cryoablation,            as        demonstrated,           an

17   excellent safety profile with no permanent AV block.

18   It    is     clinically       effective        in     AVNRT      patients,        has

19   excellent           long-term             success          and        reversible

20   cryomapping.

21                    Ladies and gentlemen, Mr. Chairman, Panel

22   members, thank you for your attention.
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1                      CHAIRMAN LASKEY:             Thank you very much, and

2    congratulations on adhering to schedule.                              It was much

3    appreciated up here.

4                      Barring       any     burning       questions           from     the

5    Panel, which I would like to hold until after lunch, I

6    would like to proceed with the FDA's presentation.

7    Does anybody have a question for the sponsor?                               If not,

8    we will just hold until after lunch.

9                      MR. CHENG:          Good morning.           I'm James Cheng,

10   and     I    am    the    Lead     FDA     Reviewer          for    the    CryoCath

11   Cryoablation System submitted under PMA P020045.

12                     The FDA review team was comprised of myself,

13   our      Medical        Officer,       Dr.     Leslie        Ewing,       who    will

14   present           the    FDA      clinical         review          summary;        our

15   Statistician,            Dr.    Lilly     Yue,     who       will    present       the

16   FDA's statistical review summary; Cindy Demian, who

17   performed the biocapability review; Elaine Mayhall,

18   who     performed         the    sterilization              review,    and       Kevin

19   Hopson,          who     performed       the      bioresearch          monitoring

20   review.

21                     The sponsor-proposed indications for use as

22   seen earlier, the basic components of cryoablation
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1    system, the Freezor catheter, the cryoconsole, and the

2    umbilicals and accessories:

3                     The Freezor catheter is a 7 French single-

4    use catheter with a 4-millimeter gold-plated metal

5    tip, 3 EGE ring electrodes, a thermocouple sensor, and

6    a flexible, maneuverable shaft.                           The catheter lumen

7    contains a refrigerant injection tube, ECG wires, a

8    leak detection wire, and a thermocouple wire.                                     The

9    catheter handle contains a deflection mechanism.

10                    The     cryoconsole              provides             refrigerant

11   delivery         and    recovery.            It     maintains           a   vacuum

12   condition inside the catheter lumen.                         It controls the

13   refrigerant        pressure       and     flow     rate      to    achieve        the

14   target temperature range.                 It contains a device safety

15   system.          It    monitors       the     integrity           of    umbilical

16   connections, and injection control is implemented in

17   dedicated hardware and has a manual override function

18   for shutting down injection.

19                    The umbilicals and accessories consist of

20   the coaxial umbilical which delivers liquid nitrous

21   oxide under pressure to the catheter and evacuates the

22   nitrous oxide gas; the electrical umbilical, which
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1    carries the catheter electrical signals to the auto

2    connection         box;    the      auto      connection      box,       which

3    connects the electrical umbilical and ECG cable to the

4    console, and the ECG, which carries the catheter ECG

5    signals to an external monitor.

6                     The basic principles of operation of the

7    system, cryogenic temperatures are generated only at

8    the catheter tip.            Pre-cooled liquid nitrous oxide is

9    injected under pressure to the tip, where the liquid

10   nitrous oxide expands to a gas.                    The face change that

11   the nitrous oxide undergoes is an endothermic reaction

12   which       generates     the    cryogenic         temperatures       at     the

13   catheter tip.

14                    Cryoablation involves achieving a catheter

15   tip target temperature of between minus 68 to minus 75

16   degrees Centigrade and maintaining that temperature

17   for up to 240 seconds.

18                    Cryomapping      involves        achieving    a    catheter

19   tip target temperature of between minus 25 to minus 30

20   degrees Centigrade and maintaining the temperature for

21   60 seconds.

22                    The FDA pre-clinical review goals were to
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1    ensure the safety and reliability of the device.                                   For

2    safety, we want to ensure that the device has been

3    appropriately            designed        and     tested,        that     potential

4    device hazards have been analyzed and mitigated, and

5    that the device safety features have been qualified

6    for use.          For reliability, we want to ensure that the

7    design and manufacture of the device provide us with

8    assurance              of        consistency             with          performance

9    specifications.

10                    Testing           of        the         catheter         included

11   biocompatibility testing of the catheter materials,

12   reliability testing of the catheter design, mechanical

13   and electrical testing of catheter performance, and

14   qualification of a sterilization process.

15                    Qualification             of      the       console      included

16   software and hardware qualification.                          For software, we

17   assess           the        sponsor's         design         and       development

18   methodology, the device software hazards analysis, and

19   the software verification and validation process.                                  For

20   hardware, we assess the design of the nitrous oxide

21   injection          and       recovery        systems,         the      temperature

22   controller performance, the device risk analysis, and
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1    the      design       and     performance          of    all     device     safety

2    features.

3                      The major hazard posed in the device design

4    is the potential for causing a gas embolism.                                      The

5    manufacturer              addressed        this      hazard      with      several

6    mitigation features.                 One mitigation features involves

7    the design and qualification of the catheter, which

8    included burst and leak testing.                             Another mitigation

9    is that the catheter lumen is kept under continuous

10   vacuum           during     the     procedure,          which     prevents        the

11   release          of   the    refrigerant          gas    into    the    patient's

12   bloodstream if there is a catheter breach.                               There is

13   also a catheter safety interlock which prevents device

14   operation until all the catheter connections have been

15   properly configured.

16                     Additional           mitigation            features      include

17   redundant blood and fluid detector systems that would

18   detect the presence of blood or fluid in various parts

19   of the catheter as a result of a catheter breach.

20                     The flow profile of recovered injectant gas

21   is     also       monitored       to    detect       any      unusual    catheter

22   performance.              The pressure relief valve helps ensure
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1    that the catheter doesn't become pressurized, and any

2    loss of vacuum will immediately disable the injection.

3     To minimize the risk of exsanguination, again, you

4    have      the     blood      and    fluid        leak       detectors     and      the

5    catheter design and qualification.

6                     Another hazard that was addressed by the

7    sponsor          was     the     risk       of       experiencing         freezing

8    temperatures along the catheter shaft, instead of only

9    at      the       tip.           Catheter            qualification          testing

10   demonstrated that a break in the injection tube inside

11   the catheter did not allow external shaft temperatures

12   to approach freezing, and the injection flow profile

13   monitoring also helps monitor for catheter failure

14   conditions.

15                    One     last      device        hazard      is    the    risk      of

16   software         controller          failure.               This    hazard         was

17   addressed by the use of a dedicated, hardware-based

18   injection         controller          with       a    manual       override        for

19   stopping         injection         delivery          and     by    the     use      of

20   hardware-based             watchdog        circuitry          to   monitor         the

21   software for failure.

22                    In conclusion, based on the documentation
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1    provided to the FDA by the sponsor, the pre-clinical

2    testing performed by the sponsor is appropriate and

3    acceptable.            Specific hazards posed by the device have

4    been      appropriately            analyzed        and       addressed      by    the

5    sponsor's         device       design       and     qualification        testing.

6    Overall testing shows that the device is reliable for

7    human use.

8                     Now     to     present       the     FDA      clinical      review

9    summary, it is Dr. Leslie Ewing.

10                    DR.    EWING:          Good      morning.        I    am    Leslie

11   Ewing, and I have no conflicts to report.                              I will be

12   presenting the results of the study, and following me

13   will      be     Dr.    Lilly       Yue,     who     will      talk    about      the

14   statistical analysis of those results.

15                    The initial purpose of the study, as you

16   have heard, was to study the safety and effectiveness

17   of this cryoablation system to treat the two types of

18   SVT AV node reentry SVT and SVT due to an accessory

19   pathway,          and      to        treat        patients        with       atrial

20   fibrillation who have rapid ventricular response.

21                    The     study       was     a    single-arm,         randomized,

22   multicenter study using OPCs, as previously described.
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1     These OPCs were based on the medical literature on RF

2    ablation and designed to be used for the entire pooled

3    study        population.            These     OPCs     have      been     used      in

4    previous ablation clinical trials reviewed by the FDA.

5                      As also was mentioned, since the beginning

6    of this clinical trial, the FDA has put out a guidance

7    document which was issued on July 1st, 2002 entitled,

8    "Cardia           Ablation          Catheters          Generic         Arrhythmia

9    Indications for Use, Guidance for Industry."                                 It can

10   be     found       at    the     web    address        as    listed.           These

11   recommendations              were      put      out     and      intended          for

12   radiofrequency ablation catheters and were based on

13   medical literature for RF catheters.

14                     This is a table from that guidance document,

15   and      I       will    point      out,      as      has    been      previously

16   mentioned,             the   chronic         success        or   freedom         from

17   recurrence was 80 percent, as is listed here.

18                     In    this     study       there     were      three      patient

19   populations included:                AV node reentry, AVRT, patients

20   with accessory pathway, SVT, and patients with atrial

21   fibrillation.

22                     The inclusion criteria is as stated here and
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1    has      been      previously           discussed,         and    the      exclusion

2    criteria have been previously discussed.

3                      The primary effectiveness endpoint for the

4    study was acute procedural success.                             For the patients

5    with the AV node reentry and accessory pathway SVT it

6    was absence of spontaneous or inducible sustained SVT

7    at the end of the procedure, and for the patients with

8    atrial           fibrillation          it     was      absence      of       AV     node

9    conduction.

10                     The lower-bound OPC for the acute procedural

11   success, as you can see here, is 85 percent.                                      For a

12   secondary effectiveness endpoint or long-term success

13   for      the      patients         with      SVT,      there     was      to      be   no

14   recurrence             of    sustained       SVT     by    the    time      of    their

15   three-month followup, and for the patients with atrial

16   fibrillation, there was to be no evidence of AV node

17   conduction at the three-month followup.

18                     For the study, the chronic success lower

19   bound was to be 85 percent with the asterisk pointed

20   out     to       the    recently-published                FDA    guidance,         which

21   would be 80 percent.

22                     The safety endpoint for the study is that
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1    the number of major complications following the use of

2    the device should have 95 percent upper bound of less

3    than 7 percent.

4                      The definition of major complications used

5    for the study is the standard for FDA, the definition

6    of major complications, and it is any adverse event

7    which occurs within the first week following the use

8    of the investigational device and is life-threatening

9    or results in permanent impairment of a body function

10   or      permanent         damage        to     a     body   structure,           or

11   necessitates significant intervention such as major

12   surgery          to    prevent    permanent         impairment     of    a    body

13   function or permanent damage to the body structure or

14   requires hospitalization or an extended hospital stay,

15   results in moderate transient impairment of a body

16   function or transient damage to a body structure, or

17   requires              intervention         such       as    medication           or

18   cardioversion to prevent permanent impairment of a

19   body function or damage to the body structure.                                   In

20   previous          ablation       studies      the     definition      has     been

21   consistently applied by the FDA in a fairly strict

22   fashion.
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1                     As has been described, the patients all had

2    screening and enrollment into the study and all had

3    diagnostic electrophysiology studies.                             Some patients

4    had      cryomapping,          and     the     determination             of     which

5    patients         were     to     have        cryomapping          was      at      the

6    investigators' discretion.

7                     Cryoablation occurred in all patients that

8    passed the diagnostic electrophysiology study, and the

9    followup occurred at seven days, one, three, and six

10   months.          The followup at seven days was by telephone

11   and also at six months was by telephone.

12                    A     hundred       and     sixty-six           patients        were

13   enrolled         and     164     patients         received         cryoablation

14   lesions.         This was at 14 study sites, 11 in the U.S.

15   and three in Canada.               The diagnosis after the EP study

16   showed that 61 percent of the patients had AV nodal

17   reentry;         31,    accessory       pathway;           7    percent,      atrial

18   fibrillation, and as was discussed, one patient was

19   diagnosed after a short cryoablation lesion to have --

20   or       cryoablation            application               to     have        atrial

21   tachycardia.

22                    Of the 166 patients enrolled, as I said, 164
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1    had     cryoablation.              There      were     157    that       had     per-

2    protocol               lesions,          per-protocol               cryoablation

3    application, and that is a full duration, 240-second

4    ablation application.                Six had less than full duration

5    lesions          and    were,      therefore,         qualified         as     acute

6    failure of the device.                  All those patients went on to

7    have radiofrequency ablation.

8                      There were, of the total of the patients who

9    received          cryoablation,              28     failures,           procedural

10   failures, and there were 136 acute successes.                                  There

11   were      122     of    that     patient          group     that    had      chronic

12   success,         and     one    of     those      patients,        as    has     been

13   described, is the one patient who had at four months

14   post ablation.

15                     So, to reiterate what has been described by

16   the sponsor, there were 91 percent of the AV node

17   reentry patients that had acute success, 69 percent of

18   the accessory pathway tachycardia patients, 67 percent

19   of the atrial fibrillation, and as the total there

20   were 83 percent.               As has been described, this did not

21   achieve          --    so   they       did    not    achieve       their       acute

22   procedural            success     or    their       primary        effectiveness
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1    endpoint.

2                      The chronic results are the patients who had

3    no recurrence of tachycardia or AV node function at

4    three months.            Also previously discussed, of the total

5    groups, 90 percent and 91 percent for AV node, for the

6    accessory pathway patients 88 percent, and 75 percent

7    of the atrial fibrillation -- so of the patients who

8    had acute procedural success, the ones that remained

9    long-term success.

10                     There were seven patients with acute major

11   complications            within      seven      days        of    the      procedure,

12   which also has been stated by the company exceeds the

13   safety endpoint of the study.                     Three of these patients

14   had the AV node reentry ablation procedure and four

15   with an accessory pathway procedure.                             The company has

16   very clearly identified and discussed these patients,

17   so I will not go into detail with these patients.

18                     Cryomapping was performed on a subset of the

19   entire patient population.                      As you have heard, this

20   mapping          was    performed       by    using         a    reversible          cryo

21   effect           on    the   conduction         system.             The        use      of

22   cryomapping was decided on a per-case basis by the
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1    investigator, and the decisionmaking process was not

2    collected as part of the study.

3                     The    criteria       for      effective      cryomaps        were

4    pre-determined per tachycardia.                        Cryomapping was not

5    part of the pre-determined endpoints of the trial in

6    terms of effectiveness and safety.

7             A hundred and thirty-five patients out of 164 had

8    cryomapping attempts.                 Of those patients, 65 percent

9    had      effective        cryomaps        and     35       percent    had      only

10   ineffective cryomaps.                 The total number of cryomaps

11   attempts         was    812    with     20    percent        of   those      being

12   effective cryomaps, but also negative cryomaps may

13   have helped the investigator determine unsuccessful

14   cryoablation with patients.

15                    In the data-collection form process for this

16   study, the investigator could mark "reversible," "not

17   reversible," and that they had gone immediately to

18   cryoablation           attempt      without        attempting        rewarming.

19   There       were       seven   AV     node      patients       who    had      "not

20   reversible" marked on their data-collection form.                                All

21   of these seven patients had successful cryoablation

22   procedures with no adverse events reported and, as has
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1    been previously stated, no patients had unintentional

2    AV block.

3                      Dr.     Yue       will       present         the    statistical

4    analysis.

5                      DR. YUE:          Good morning.             My name is Lilly

6    Yue, Statistician at FDA.                    Following Dr. Ewing, I will

7    speak       on     the   study       results       and       give    clinical       and

8    statistical conclusions.

9                      As specified in the protocol, the primary

10   effectiveness endpoint:                   acute procedure success.                  The

11   primary           safety         endpoint:               major       complication

12   occurrence.              The     secondary        effectiveness          endpoint:

13   long-term clinical success at the three-month followup

14   conditional on acute procedural success, evaluated for

15   the entire SVT patient population.

16                     Protocol indicated that the study's, like I

17   said, criterion for the acute procedure success was

18   that the lower 95 percent two-sided confidence bound

19   of    the        acute   success        rate     for     all     intent-to-treat

20   patients should be larger than 85 percent.

21                     Please note that the two-sided confidence

22   interval here is necessary when the acute success rate
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1    could be larger or smaller than 85 percent, as it was

2    agreed upon by the sponsor and the agency at the

3    design stage.           We will see this, indeed, necessary in

4    a few minutes.

5                     The intent-to-treat patients are those who

6    have a prior ablation catheter activated.                                For the

7    major        complication          occurrence,           the    study     success

8    criterion         was        the      upper       95        percent     two-sided

9    confidence bound of the major complication incidence

10   rate for all safety patients should be less than 7

11   percent.

12                    Here the 15 patients are those who have a

13   cryoablation catheter inserted.

14                    For the conditional long-term success there

15   were statistical hypotheses specified in the protocol.

16    The alternative hypothesis said the conditional long-

17   term success rate should be larger than or equal to 85

18   percent.         It is the basic statistical concept that the

19   success rate indicated in the statistical hypotheses

20   are in the population parameter, not an observed point

21   estimate.               So     the     study      success       criterion        for

22   this      endpoint       is     the     lower       95      percent     two-sided
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1    confidence bound should be larger than 85 percent for

2    all intent-to-treat patients.

3                      Let's look at the study results.                   As we can

4    see, the point estimate of the acute success rate is

5    83 percent, less than the OPC 85 percent.                         So the two-

6    sided confidence interval is, indeed, necessary, and

7    there is no way for the lower confidence bound to be

8    larger than 85 percent.

9                      The lower confidence bound is 76 percent.

10   Therefore, the study has failed to meet the OPC 85

11   percent          for   the   acute      success       for    planned     patient

12   population.

13                     Also, the upper confidence bound of major

14   complication incidence rate, 8.5 percent, exceeded the

15   OPC 7 percent.               Therefore, the study has failed to

16   meet      the      primary      safety       OPC     for     planned     patient

17   population.

18                     For the conditional long-term success, using

19   the      protocol       specified          exact       confidence      interval

20   approach,         if   we    consider        the     crude    probability        of

21   success, that is, classified the two lost-to-followup

22   patients as failures, the lower confidence bound is 83
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1    percent, less than the OPC 85 percent.

2                     If we use a more liberal method and exclude

3    the two lost-to-followup patients from the dataset,

4    the lower confidence bound is 85 percent, just on the

5    border line.

6                     The agency also suggested survival analysis,

7    either Kaplan-Meier or life table cohort analysis,

8    which should give a lower confidence bound between 83

9    percent and 85 percent, and closer to 85 percent in

10   this case.

11                    Then after looking at the data, the sponsor

12   performed two types of post-hoc subgroup analysis for

13   endpoint statistical hypotheses.                       The first one is a

14   retrospective subgroup analysis on the ablation safety

15   and effectiveness endpoints for the three individual

16   subpopulations, using the OPCs originally developed

17   for the entire patient population.

18                    The second one is the retrospective subgroup

19   analysis on the impact of effective cryomapping on

20   ablation acute success.                    However, in the protocol,

21   there       were   no    statistical          hypotheses    and    no    study

22   success          criteria      and      claims        generated    for       all
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1    cryomapping at all.

2                      According to the post-hoc subgroup analysis

3    results, the sponsor made two new claims to support

4    the     new      indications       for    use.             No. 1, the AVNRT

5    subgroup         met    the    FDA     OPCs     for        the    safety,         acute

6    procedure success, and the long-term success.                                   No. 2,

7    there was a significant association between effective

8    cryomapping         and     ablation        acute     success           to     support

9    these two new indications for use.

10                     Question:           Can      the         post-hoc          subgroup

11   analysis results be used as valid evidence for the new

12   claims?          First of all, when should we perform subgroup

13   analysis?

14                     Generally speaking, subgroup analysis is to

15   determine if there is a reportable subset for which

16   the     treatment        effect      is     either         significantly            more

17   effective          or   harmful.            So,     when         the     study        has

18   succeeded in pre-specified overall analysis, subgroup

19   analysis may be useful in suggesting hypotheses to be

20   tested in future studies or help refine labeling.                                      If

21   the data shows a significant overall treatment effect,

22   but     non-significant           treatment        effect         in      subgroups,
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1    then the device still could be approved for general

2    use.

3                     However, subgroup analysis is not intended

4    to be used to rescue a study with non-significant

5    overall treatment effect.                        So, when the study has

6    failed in pre-specified overall analysis, generally,

7    we do not perform subgroup analysis because the risk

8    of     false     positive          results        from       subgroup      analysis

9    increases.

10                    Particularly,            here     are       some    criteria        to

11   check if a subgroup analysis is appropriate:

12                    No.     1,     is     the       hypothesis         for    subgroup

13   analysis         pre-specified?                   Pre-specified           is      more

14   believable than post-hoc-specified.

15                    No.     2,      is     the      subgroup          classification

16   clinically relevant?

17                    No. 3, is there significant treatment effect

18   in     overall         analysis?            If    yes,       may     do    subgroup

19   analysis; otherwise, generally, we do not do.

20                    No. 4, is there significant interaction of

21   treatment        with      subgroup          variable?             This    question

22   generally refers to a two-arm trial, but here we just
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1    have one arm.

2                     Let's     check      if     the    subgroup        analysis        of

3    ablation         safety       and     effectiveness          for      the      three

4    individual patient subpopulations is appropriate:

5                     No.    1,     in    the     protocol,       no      statistical

6    hypothesis        was     generated         for     the     three      individual

7    subpopulations; no study success criteria and claims

8    were developed for the subpopulations.                        And the sample

9    size estimation was not based on the three individual

10   subpopulations.

11                    No. 2, yes, the three subpopulations are

12   generally referred to SVT patients.

13                    No. 3, no, there is no significant treatment

14   effect in pre-planned overall analysis.

15                    No. 4, not applicable, but, indeed, there is

16   a big difference in the performance of the device

17   between the three patient subpopulations.                            That is why

18   the OPCs developed for the entire patient population

19   cannot be directly used for subpopulations.                                   It is

20   just our second concern on the next slide.

21                    OPCS     developed          for      the    entire         patient

22   population may be wrong for all subpopulations.                                So it
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1    cannot be directly used in a subpopulation.                             In fact,

2    from medical literature, the acute success rate for

3    AVNRT patients is significantly higher than those for

4    AVRT and AF patients.                   Therefore, the acute success

5    OPC for AVNRT should be higher than 85 percent.

6                      Our    other        concern      is,      if   the    subgroup

7    analysis and the data analysis had been planned in the

8    protocol, a multiplicity adjustment for a significance

9    level, such as Bonferroni adjustment, should have been

10   performed.             Otherwise, the overall Type I error rate

11   of the study, that is, the probability of incorrectly

12   approving the device, would be inflated and could be

13   close to 15 percent.

14                     Let's back up one step and let's suppose the

15   original OPCs were appropriate for the subgroups.                                The

16   point estimate of acute success rate is 91, 69 and 67

17   percent for the three subpopulations, respectively; 91

18   percent          for    AVNRT    is    significantly         better     than      69

19   percent and 67 percent.                 You can see a huge difference

20   here.

21                     Here the 95 percent confidence interval is

22   the analysis result without multiplicity adjustment.
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1    We      also     suggested       Bonferroni-adjusted              confidence

2    intervals.          The highlighted numbers here are the lower

3    confidence bounds, but none of them match the OPC 85

4    percent in a group.

5                     Similarly,       for      the      major      complication

6    incidence rate, none of these upper confidence bounds

7    reached the OPC 7 percent, no matter the confidence

8    intervals are multiplicity-adjusted or not adjusted.

9                     For the conditional long-term success, the

10   second column in the table gives the results of crude

11   probability of success for AVNRT subgroup.                            None of

12   these       lower    confidence       bounds       reached     the     OPC     85

13   percent.            The   last     column        gives   the     result        of

14   excluding the two lost-to-followup patients from the

15   data analysis.            The lower bounds, 86 percent and 85

16   percent, they are omitted for the AVNRT subgroup.

17                    So suppose the OPCs were appropriate for the

18   subgroups.          For any patient subgroup, with or without

19   multiplicity adjustment, the study has failed to meet

20   the primary safety and effectiveness OPCs.

21                    In conclusion, none of the three subgroups

22   met the OPCs for either primary safety or primary
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1    effectiveness.

2                     Let's look at a second subgroup analysis on

3    the association of effective cryomapping and ablation

4    acute success.            Of 164 patients with cryoablations,

5    135 had cryomap attempts and 29 didn't.                             Of the 135

6    patients with cryomapping attempts, 87 had effective

7    cryomaps and 48 had ineffective cryomaps.                               So the

8    point estimate of the effective cryomapping rate is 64

9    percent.         Of 87 patients with effective cryomapping,

10   80 had reversibility so the rate is 92 percent.

11                    Now     we     have      three           patient    subgroups

12   according to cryomapping:                 effective, ineffective, and

13   no attempts.           The ablation acute success rate is 94

14   percent for effective, 65 percent for ineffective, and

15   79 percent for no attempts.

16                    The sponsor groups "ineffective" with "no

17   attempts"        and    called      it    "without         effective,"       then

18   compared "effective" with "without effective" in terms

19   of      ablation        acute       success,         and      claimed        that

20   "effective"        was    significantly           better      than    "without

21   effective" in ablation acute success.

22                    These claim was supported by a p-value less
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1    than .05 from exact test for the overall intent-to-

2    treat patient population.                        However, the significant

3    result was driven by 49 AVRT patients.                               You can see

4    the p-values in the last column.                             However, the AVRT

5    subgroup         is    not     the    one     the    sponsor        is   currently

6    claiming for.

7                     Instead,         the      AVNRT      is      the    only      group

8    indicated in the new indication for use.                                  However,

9    there is no significant difference detected in the

10   ablation         acute        success         between         "effective"          and

11   "without effective" patients for this subgroup, with a

12   p-value of 0.45 from exact test.

13                    For this post-hoc comparison, we have the

14   following concerns:

15                    No.     1,      what       is      the      meaning     of      this

16   comparison?

17                    No. 2, why grouping "ineffective" with "no

18   attempts"?

19                    No.     3,      is     the      subgroup       classification

20   "effective"           versus       "without         effective"       clinically-

21   relevant?

22                    It seems that if we try to attach the impact
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1    of     the        effective           cryomapping         on        ablation       acute

2    success, we could compare the "effective" group with

3    the "ineffective" group and use "no attempts" as a

4    control.

5                          The ablation acute success rate, 94 percent

6    for the "effective" group, is significantly better

7    than 65 percent for the "ineffective" group, but a

8    patient had only 64 percent of a chance to have a

9    successful cryomapping when he had cryo attempts.

10                         On the other hand, if we try to test the

11   impact           of    attempted       cryomapping             on   ablation       acute

12   success,              we      could     compare         "attempt"         with        "no

13   attempts."                 Here "attempt" includes "effective" and

14   "ineffective."

15                         We performed the comparison and found that

16   there was no significant difference detected in the

17   ablation              acute    success       between       "attempt"         and      "no

18   attempt" groups, with a p-value of .59 from the exact

19   test.            The point is made that the ablation acute

20   success rate is 84 percent and 79 percent for the two

21   subgroups, respectively.

22                         From these post-hoc subgroup analyses, we
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1    can     see      that    there     are      many     ways       to     generate           a

2    subgroup hypothesis after fact.                            Different post-hoc

3    hypotheses and data analyses could lead to different

4    results, either significant or non-significant.

5                     This    is     the     situation          we   always       try     to

6    avoid, in which subgroups are defined by the data and

7    the unplanned statistical hypotheses are generated by

8    study       results.          Often,      a   treatment           effect       is    so

9    suggested          and     then       confirmed            with        statistical

10   significance on that same dataset.

11                    Clearly,       the     subgroup       hypotheses          and      the

12   data       analysis        on     the       association           of     effective

13   cryomapping and ablation acute success were not pre-

14   defined.            We      are       not     sure         if     the      subgroup

15   classification "effective" versus "without effective"

16   is     clinically-relevant.                   Also,        we     do     not      have

17   information on why those 29 patients did not have

18   cryomapping attempts, purely by chance or due to some

19   patient characteristics.

20                    No. 3, there is no significant treatment

21   effect in overall analysis of ablation acute success.

22    So,       the    sponsor's         significant            subgroup        analysis
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1    result           used    as    evidence       of     device        performance           is

2    questionable.

3                       Clinical and statistical conclusions:                                The

4    device did not meet the primary effectiveness of 50

5    OPCs for either the overall study population or any

6    patient           subgroup.           No    patient       had       unintentional,

7    permanent AV node block at the end of the procedure or

8    during           followup.            There      were         a   low      number        of

9    recurrences                   after         successful                 cryoablation.

10   Cryoablation             adherence         appears       to       have      a    durable

11   effect.

12                      The    post-hoc          assessment            of      cryomapping

13   effectiveness             is       questionable.                  There          was     no

14   significant             association         detected          between           effective

15   cryomapping and ablation acute success for the AVNRT

16   subgroup.           There was no adverse event reported due to

17   cryomapping.

18                      Thank you.

19                      CHAIRMAN LASKEY:            Thank you, Lilly.

20                      At this point, for the record, we will read

21   the questions.                We are still, fortunately, a tad early

22   here for the one o'clock break.                         So are the questions
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1    from the Panel to the sponsor or to the FDA, for that

2    matter, the FDA presenters?

3                      I had one question for the sponsor.                           I was

4    very interested in some of the acute and subacute and

5    chronic changes in the subjacent coronary artery in

6    your pre-clinical studies.                         Do you have any further

7    information             on    the    pathology        or      histopathology         of

8    these        lesions?               What      is     it       that   is      acutely

9    constrictive there?                  Is it dynamic?            Is it fixed?          Is

10   it something that we need to worry about, if the

11   latter?

12                     DR. DESMARAIS:               Mr. Chairman, I will ask

13   Patrick Chauvet, our pre-clinical scientist, to answer

14   your question.

15                     MR. CHAUVET:           Thank you.           My name is Patrick

16   Chauvet.              I am a pre-clinical scientist for CryoCath,

17   a full-time employee, and I own equity.                              My trip was

18   also paid for by CryoCath.

19                     The         question        was         dealing      with         the

20   cryoablation lesions in the coronary sinus and the

21   effect           on     the    adjacent        left       circumflex       coronary

22   artery:           What were the histological changes acutely,
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1    subacutely, and chronically?

2                          In the early trials that we performed we had

3    noticed histological changes both with RF and cryo

4    that were significantly different.                            In the RF lesions,

5    the       coronary            artery      acute       constructs,            and      the

6    hypothesis there is because of heating of the collagen

7    fibers in the medial area of the coronary artery, this

8    effect is quite dramatic, and acute constriction is

9    evident;              whereas,     with      cryoablation             there     is     no

10   heating of the collagen fibers, and our hypothesis is

11   that prevents acute constriction.

12                         In the subacute and chronic cases, we have

13   noticed in both cases medial necrosis of the coronary

14   artery           in    similar     amounts.           However,         due     to     the

15   differences              in    human       processes,           the     cryoablated

16   coronary sinus and adjacent coronary artery healed

17   very well, and there was no subsequent stenosis up to

18   three months in the cryoablation regions.

19                         CHAIRMAN LASKEY:           So is the acute stenosis

20   reversible             with    nitroglycerin,            for     example?             You

21   alluded to spasm.                 It is spasm?                Did you give nitro

22   and make it go away or some other anti-spasm?
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1                     MR. CHAUVET:           Nitroglycerin was given during

2    the study.          As you saw in the presentation, stenosis

3    was still present one week after the procedures.                                     So

4    it is not just an acute phenomena.

5                     CHAIRMAN       LASKEY:          One        question      from      Dr.

6    Waldo and then Dr. Dullum.

7                     DR. WALDO:          Actually, I have a few, but I

8    will just take one then.                   I have a question about the

9    definition of efficacy of the cryomap.                             I'm not sure I

10   understand the definition because to me, if you apply

11   adequate cooling, almost anything is effective, the

12   way I look at it.              If you don't get an effect, I think

13   that       was     implicit        in     some      of       the    things        that

14   presented, if you don't get an effect, then are you

15   sure you know you're in an area that is not useful to

16   ablate?

17                    Do you also know that it is safe to ablate

18   if you want to ablate with something else?                                  In your

19   instance,          your     presentation,           it      wouldn't       be     like

20   atrial flutter where you might want to ablate and you

21   would       want    to     make     sure     you're         not    close     to     any

22   structure.
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1                       I    don't       see    why      all      the     cryoablation

2    shouldn't be considered effective if adequate cooling

3    is applied, because it is telling you something each

4    time.             I     am   not     sure      why      you    have         to    have

5    reversibility as part of it.

6                       DR. DESMARAIS:          We will ask Dr. Lehmann, our

7    medical monitor, to answer the question with regards

8    to the definition.

9                       In    terms       of     the      cryomapping            clinical

10   applicability, I would like to ask Dr. Friedman to

11   answer that question.

12                      DR. LEHMANN:           My name is John Lehmann.                I am

13   a paid consultant to CryoCath.                         I do not own equity,

14   and my expenses were paid by the company to come.

15                      Dr. Waldo, your question bedeviled us as

16   well.        There is a kind of cryomapping where you are

17   looking for an effect, in which case we ultimately

18   simply           defined     that    as,     when     you     cool     to    a    non-

19   destructive level, did you see a physiologic change or

20   not?        And there is a kind of cryomapping where you

21   wouldn't like to see an effect, or what is loosely

22   called "negative cryomapping," where you are working
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1    with it at the node and you cool and you don't see it.

2     Exactly how to determine those in study was less

3    clear to us a couple of years ago.

4                     But at the moment we use the terminology

5    "cryomapping effect" in a positive sense, in a place

6    we would like to see the change, and we do or don't

7    with a non-destructive cryomapping application, and

8    cryomapping reversibility just for those situations

9    when we do see change in physiology and with warming

10   that change goes away.

11                    DR. WALDO:      So then, with Dr. Yue presenting

12   the statistical analysis, if I understand it, when you

13   were      ineffective,      it     was     because      you    didn't        see

14   anything.         There was nothing reversed.                 But I would

15   suggest to you, why is that ineffective?                        It doesn't

16   strike me that that is ineffective.                     It might be very

17   effective.         You know you're not in a place you don't

18   want to be, for instance.                 That is the most obvious

19   example.         I don't know why that is ineffective.

20            If you look at just the statistics, that would

21   clearly affect this.

22                    DR. FRIEDMAN:      Peter Friedman.
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1                      I    think      that    is     a   very    good      point,        Dr.

2    Waldo.           As John Lehmann alluded to just a moment ago,

3    we struggled with how to gauge and how to measure

4    mapping, because it is not something that has been

5    available with any other technology and had never been

6    done before.

7                      You're right in the sense that, if you do

8    cryomapping in a site and you don't see the intended

9    effect, that's a negative cryomap, but, on the other

10   hand, it tells you that you are in a place where it is

11   actually probably safe to ablate.

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

13   ablate.

14                     DR. FRIEDMAN:               Or not the place that you

15   want to be.             So it is another way of analyzing the

16   data.            Of   course,      we     could      include      those       all     as

17   effective,            and    then        the     numbers      would         be     very

18   different.

19                     DR. WALDO:            It would certainly affect the

20   statistical            analysis          we     just     heard,         which        was

21   suggesting            that   it    was        useless,      and   I    think       that

22   statistical analysis doesn't make any sense to me in
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1    terms of how we understand it.

2                     DR. FRIEDMAN:              Yes, I think as the study

3    went on, we learned more about what the true utility

4    of this technology is.                     It is true that, if during

5    cryomapping one sees block in an accessory pathway or

6    block in the slow pathway, that indicates that it is a

7    good place to do ablation.

8                     But     we      learned          about       what      we     called

9    "negative cryomaps" or "safety cryomaps," also, that

10   if you're applying cryo energy to an area and you see

11   an unintended effect, that is an area not to ablate

12   and it is another utility for mapping that was not

13   addressed when the protocol was written.

14                    DR. WALDO:             Am I wrong in that, do you

15   think?           If you apply it to an area where nothing

16   happens, why would you continue?                             Did you find that,

17   if you don't see any effect, you're sure that that is

18   an     area      that    is      not     desirable           to   ablate?            For

19   instance,         if    you     don't      see     any       effect     on    a    slow

20   pathway,          which         would        be       critical          for        your

21   presentation, did it prove in your data that this was

22   an area clearly that you should not ablate, that you
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1    were wasting your time to ablate that?

2                       DR. FRIEDMAN:           No, and it is difficult to

3    analyze those data from the way they were collected.

4    But, for example, there were investigators who did

5    cryomapping specifically to localize the slow pathway

6    and were unable to show a reversible block in the slow

7    pathway.

8                       Now   one    could      conclude         from    that     either

9    you're           too   far   away     or    that      the    temperature           you

10   achieved during the mapping procedure was not adequate

11   to reach the slow pathway which may have been further

12   below the endocardial surface.                      So there were actually

13   instances in the study where people, after mapping and

14   being unable to find an effective, quote, "cryomap

15   area," actually went back and ablated at those areas,

16   and some of those turned out to be successful.

17                      CHAIRMAN       LASKEY:               We     do       that        in

18   interventional cardiology as well.                           So it is not an

19   uncommon precedent.

20                      Dr. Dullum, you had one question?

21                      DR. DULLUM:       I just wanted to ask a followup

22   to your question about the coronary occlusion.                                           I
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1    noticed the intravascular ozone catheter was in the

2    heart in one of your pictures with the RF ablation but

3    not on the cryo.                 Did you have it in during the

4    ablation procedures for both of them or did that just

5    happen to be that one picture that we saw?

6                     MR. CHAUVET:         Patrick Chauvet.

7                     No,    the    AFIS     catheter           was   positioned        in

8    every        single      animal      whether        it      was    for      RF     or

9    cryoablation.

10                    DR.     DULLUM:            So     during         the    ablation

11   procedure the AFIS was in there, in the animals?

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

13                    CHAIRMAN LASKEY:           Dr. Krucoff?

14                    DR. KRUCOFF:         You mentioned that you have an

15   experience in Europe.               Is the catheter in clinical use

16   outside of the United States?                         Are there any data

17   available that would support any of these discussions

18   from your U.S. activity?

19                    DR.     DESMARAIS:              Jean-Pierre            Desmarais,

20   CryoCath.

21                    F7, the presentation, the catheter is in

22   commercial        use     in    Europe,       in    various       countries        in
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1    Europe, and in Australia and other countries in the

2    world.

3                     We found with the PMA there's two separate

4    studies which are not sponsored by us which are an

5    individual initiative from the German Heart in Munich

6    and      from    the    Rotterdam         in    The       Netherlands      which

7    compared the NRT to RF, and we do have data on that.

8    We have submitted those data to FDA during the PMA.

9                     We are trying just to plug the computer and

10   present the data to you in a minute.

11                    DR. ZUCKERMAN:         Okay, I think I have to take

12   issue as to whether the agency has seen these data.                                  I

13   don't believe so.              And the Panel needs to recognize

14   that any data not contained in the PMA Panel pack have

15   not been thoroughly reviewed by the agency and need to

16   apply the appropriate caveats to such data.

17                    DR. DESMARAIS:         Thank you, Dr. Zuckerman.

18                    CHAIRMAN LASKEY:          I am sorry, are we looking

19   for summary of the European data here?

20                    DR. DESMARAIS:         In about 30 seconds.

21                    CHAIRMAN LASKEY:              Sure, and then at that

22   point I would move to adjourn for lunch.                          So we will
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1    end on that response.

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

3                     DR. WALDO:       Just a very quick followup to

4    what I was asking before:                    Have you any instances

5    where you looked for parahisian pathways?                        I mean,

6    this is one of the areas where --

7                     DR. DESMARAIS:          I would like to have Dr.

8    Nazari to answer that question.                  Excuse me, I will let

9    Dr. Chauvet to answer that question.

10                    DR. DUBUC:     Mark Dubuc.

11                    As you know, the product is commercially

12   available in Canada, and we have used that to do about

13   17 cases with parahisian.

14                    DR. WALDO:     Seventy or 17?

15                    DR. DUBUC:       Seventeen, 1-7.        Actually, we

16   were successful in 15 of these cases, and we were able

17   to make what we call a negative cryomap or safety

18   cryomap, and we had clearly a his electrogram on the

19   ablation catheter when we did that.

20                    I can say that maybe in two cases we had

21   transient AV block and we had to cancel the procedure.

22    This is why we have the 15 out of 17 were successful.
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1                     DR. WALDO:       So you also used the mapping,

2    the cryomapping technique?

3                     DR. DUBUC:     Yes.     Well, mainly, the negative

4    cryomapping.         I want to be sure not to ablate at the

5    same time that I'm doing --

6                     DR. WALDO:     Precisely.

7                     DR. DUBUC:        So another thing interesting

8    with cryo is that during the application what you

9    cannot do with RF, you can do program stimulation; you

10   can pace the atrium, pace the ventricle, to see if the

11   AV conduction is still there during the application.

12   The catheter is very, very stable.

13                    CHAIRMAN LASKEY:        Dr. Bailey had a question.

14                    DR. BAILEY:        Yes, I was wondering if you

15   have compiled data on all initially-enrolled patients

16   as far as their rhythm status at the end of the -- I

17   know there was combining the ones who were successful

18   after radiofrequency ablation.

19                    DR. DESMARAIS:       Dr. Lehmann will answer that

20   question.

21                    DR. LEHMANN:       Could I clarify that you want

22   the      overall    clinical       success       at     the   end     of     the
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1    procedure?

2                      DR.     BAILEY:                With         the     strategy          of

3    cryoablation, followed perhaps by radiofrequency.

4                      DR.    LEHMANN:            Right.            That     was     in     the

5    presentation.             There was a slide that shows that, of

6    166 enrolled subjects, 161 had the endpoint success at

7    the end of the procedure.

8                      DR. BAILEY:            And then what about at three

9    months           or     six        months?          Did        you      follow         the

10   radiofrequency cases for their status at three months?

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

12   today.

13                     CHAIRMAN          LASKEY:        Do     you       have     the     non-

14   U.S. --

15                     DR. DESMARAIS:             This is partly the non-U.S.

16    As explained earlier, that was part of the PMA that

17   FDA maybe did not have the chance to review.

18                     There       is    a    study     by    Dr.        Zrenner     at     the

19   German Heart.             At the time of filing of the PMA, that

20   was     the       data    we       had   available            showing      comparable

21   success rate fluoroscopy induration in terms of AV

22   study.
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1                     And there is a second study by the group of

2    Dr. Jordaens in Rotterdam, The Netherlands.                              In this

3    case, he was doing it at the NRT and right septal

4    pathways.         Again, the success rate is comparable at

5    this point in time, and that was what we had at the

6    time       of    filing.          Obviously,          these      studies         are

7    continuing, but we don't have formal updated data at

8    this point.

9                     Does that answer your question?

10                    DR.   KRUCOFF:           Yes.            I   guess     you      had

11   references to thousands of uses.                     Obviously, these are

12   smaller trials then.

13                    DR. DESMARAIS:         Correct.

14                    DR. KRUCOFF:          You were talking about your

15   commercial use?

16                    DR.   DESMARAIS:             Correct.           We     do     have

17   registry data.

18                    DR. LEHMANN:         We have four IDE-like studies

19   to either Canada or the U.S., which comprise roughly

20   300     subjects       with    AVNRT      and    AVRT.          Those     had     no

21   permanent block.              There's a total of 600 patients in

22   the     registry       collection,        and     then        there's     between
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1    1,000 and 2,000 commercial uses for which there are no

2    event-reporting systems of any permanent AV block.

3                     DR. KRUCOFF:      Can you just flip back to the

4    first data slide?

5                     DR. LEHMANN:      Yes.

6                     DR. KRUCOFF:      So on the cryo side, does that

7    four third-degree heart blocks only transient?                       So "no

8    block," you mean permanent --

9                     DR. LEHMANN:      No permanent AV block.

10                    DR. KRUCOFF:      Correct.

11                    CHAIRMAN LASKEY:         Okay, thank you.          On that

12   note, we're at the magic hour, and I think we'll have

13   plenty of opportunity for each panel member to ask

14   additional        material     after      lunch.        Let's    break     for

15   lunch and let's meet again at 1:55 sharp.                       Thank you.

16                    (Whereupon, the foregoing matter went off

17   the record for lunch at 12:56 p.m. and went back on

18   the record at 2:05 p.m.)

19

20

21

22
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1                     A F T E R N O O N             S E S S I O N

2                                                                        2:05 p.m.

3                     CHAIRMAN LASKEY:           I would like to begin this

4    afternoon's portion of the proceedings by having our

5    Lead Reviewer, Dr. Cynthia Tracy, present her review

6    and ask questions.

7                     I also want to make a bold, and perhaps

8    indefensible request, for Panel members to limit their

9    exegesis to no more than 10 to 15 minutes, so we can

10   get through the afternoon, if that is possible.

11                    I'm assuming we actually got through all the

12   panelists' questions before the lunch break.                            Is that

13   a fair assumption?               That is not?              Can you hold them

14   until it is on your round?                  Would that be okay?

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

16                    DR. TRACY:         I think it is appropriate that

17   this is room is very frosty for this discussion.

18                    (Laughter.)

19                    With     that      in     mind,       I    would    like       to

20   congratulate you on your presentation.                         You covered a

21   lot of data and did it very well.                           One thing that I

22   thought was remarkably well done was the pre-clinical
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1    testing.           I think this device has a lot of potential

2    safety           issues    that      have     all     been   addressed       very

3    carefully with excellent safety features built into

4    the device.

5                       It strikes me that both the strength and the

6    weakness of this device is the small, uniform lesion

7    that is created.                 I think that is why effective in

8    many instances, but ineffective -- it is effective and

9    safe      in      many    instances,        but     ineffective    in    places

10   where you might want to create a larger lesion.

11                      Just a brief question relative to that:                      Is

12   there any way that a lesion or any development that

13   might be done could increase the size of the lesion to

14   make the device more applicable for a greater number

15   of arrhythmia substrates?                     Is that something that is

16   potentially planned?                  Would a larger catheter tip be

17   useful or some other modification?

18                      DR.    DESMARAIS:           At the current time, we

19   believe that the catheter that we have is adequate for

20   the treatment of AVNRT, but in our design strategies,

21   you know, to pursue other indications, we have a lot

22   of design strategies and looking and addressing other
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1    arrhythmia.        We will surely approach FDA in due course

2    on how best to bring those products to market.

3                     DR. TRACY:       Okay.       I think the cryolesion

4    has the nice feature of not being very thrombogenic,

5    and that might have potential implication for left-

6    sided structures in the future.                         So it was just a

7    passing thought.           But I think at this point you are

8    correct that AVNRT is probably your most approachable

9    lesion with the current device setup.

10                    In terms of the device itself, you mentioned

11   that there were equipment failures in two cases.                               In

12   looking through the packet, I think one was a console

13   failure, and it looked like on the second one multiple

14   catheters were connected to the console and it was

15   failure to deliver the nitrous oxide, I think.

16                    Can you explain, if I am doing math right,

17   about a 1.2 percent device failure?                        Are you happy

18   with that?        What exactly were the problems?

19                    DR. DESMARAIS:        I believe that the catheter

20   consumption         throughout       the     study       was    about       1.14

21   catheter on average, I believe.                     The console failure

22   was a technical failure where a valve did not open and
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1    did not let refrigerant into the catheter.                            So that

2    case never took place with trial as such.

3                      In the other failure there was a catheter

4    that kinked on two occasions, and one the injection

5    tube        was     blocked,        so      we      could     not         inject.

6    Unfortunately, the site ran out of catheter, so we

7    could not complete the case with trial.

8                      DR. TRACY:      Okay.

9                      DR. DESMARAIS:         And just to answer your last

10   question,         in   general,      we    are     very     happy    with     the

11   catheter as it is, and in terms of its reliability and

12   the way it is used.

13                     DR. TRACY:       Okay.       I'm only going to touch

14   on this because I assume Dr. Bailey will be asking

15   much      more     detailed       questions        regarding        the    whole

16   statistical analysis issue, but if you had designed

17   this study for AVNRT alone, what endpoints would you

18   have had to achieve in order to prove statistically

19   that the device was safe and effective?                        Have you put

20   thought into that?

21                     DR. DESMARAIS:          I will ask Dr. Lehmann to

22   answer that.
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1                      DR. LEHMANN:          The short answer is that we

2    have not at this point attempted to design just a

3    trial for AVNRT.               In this trial we used the OPCs,

4    which,           as   Dr.   Yue       stated,       were     for       a    cooled

5    population, and those were the numbers that we used.

6                      DR. TRACY:       Okay.      I suspect this issue will

7    get much more discussion as we go around the room, but

8    I will leave it at that for the moment.

9                      A   couple     of     procedural         questions:             The

10   procedure time average was 265 minutes.                               Does that

11   include from the moment the patient is put on the

12   table until the moment they are pulled off the table?

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

14                     DR. TRACY:       Skin to skin?           Okay.      So that is

15   probably a bit long, I think.                          Is that related to

16   device issues, people having to set things up?                                Is it

17   hard to set up to deliver refrigerant?

18                     DR. FRIEDMAN:         I think there are a number of

19   factors that go into that procedure time.                            I think it

20   is true that any investigational study by its very

21   nature, because of the data collection that occurs,

22   takes longer than a routine clinical case.
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1                       Some    of     the     time     was       certainly      getting

2    familiar           with    hook-up       procedures,          the     umbilicals.

3    Mapping I think took some time.                               There was a new

4    technology, and people were interested in exploring

5    how it could be used.                     That added to the procedure

6    time.       I think all those things together would explain

7    that.

8                       I think in routine clinical practice, not in

9    the context of a clinical trial, procedure times would

10   not be dramatically different than RF.                                In fact, in

11   the data that you saw just before the lunch break,

12   where patients had been randomized RF versus cryo in

13   Europe, there was really no significant difference in

14   overall procedure duration.

15                      Maybe Dr. Dubuc from Montreal would care to

16   comment on that because he probably has the largest

17   experience and has been using it a lot since it is

18   commercially available in Canada.

19                      DR. DUBUC:        Well, I had a chance to use this

20   product because it is commercially available.                                  I did

21   in     my        institution      more      than     150      cases    with      this

22   technology.           Actually, even our group decided to do
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1    all AV nodal reentries with this technology since last

2    August.

3                     The time is comparable, and I mean the time

4    of      the      procedure    is      comparable,        and       also       the

5    fluoroscopy time.             Even the fluoroscopy time has a

6    tendency to be a little bit lower because you don't

7    have to watch or monitor the position of the catheter

8    during cryoapplication because of the adherence of the

9    catheter.

10                    DR. TRACY:     You are comfortable enough that

11   that thing is really going to stick on there, that you

12   don't wash --

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

14                    DR. TRACY:     Okay.

15                    DR. DUBUC:     No doubt.

16                    DR. TRACY:        Okay.       A procedural question

17   that relates to one of the major adverse events:                              I'm

18   assuming that that right corner infarct either was a

19   catheter         inadvertently       positioned         down     the      right

20   coronary artery during a retrograde approach or was a

21   completely unrelated event.                Do you have a comment on

22   that particular complication?
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1                      DR. DESMARAIS:               Dr. Friedman will answer

2    that.

3                      DR.    FRIEDMAN:              It's      difficult        to     know

4    precisely.          That, I think, was a case from Canada.                           My

5    understanding of that procedure was that cryoablation

6    for the left lateral accessory pathway was done via a

7    retrogradic             aortic       approach,         and      there     were       no

8    technical difficulties encountered crossing the aortic

9    valve.           That was not difficult.                      So I think it is

10   unlikely,         based        on      what    was     reported,        that      that

11   catheter went down a coronary.

12                     The     RF      catheter        ablation       procedure          was

13   actually done by a transeptal approach.                                 That also

14   turned out to be unsuccessful.                           So this was a very

15   lengthy          procedure        in     a    patient         with   pre-existing

16   coronary         disease,        and     the     occluded       vessel,      as     you

17   alluded to, was actually the opposite side of the

18   heart.

19                     DR. TRACY:           Okay, thanks.

20                     I wanted to ask a few questions about the

21   cryomapping.            The whole concept of it is a new concept

22   that we have to try to figure out exactly what it
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1    means.

2                     I   think      that     part     of      the   idea      of     doing

3    cryomapping is that it is a way of testing where you

4    are without creating permanent damage, and yet I note

5    that there's a little bit of contradictory information

6    that is being given.                   In one part of the packet it

7    mentions          that      100      percent         of     cryomapping             was

8    reversible.           Yet, we talked this morning about seven

9    not reversible cryomaps.                      Are those cryomaps, were

10   they actually cryoablations, or what's the difference

11   there?

12                    DR. DESMARAIS:           I think what I would like to

13   do is to answer that question twofold:                               first, with

14   Dr. Friedman, to really explain cryomapping and make

15   an attempt in re-explaining that, and, secondly, for

16   Dr. Lehmann to discuss exactly the reversibility in

17   terms of the data collection.

18                    Dr. Friedman?

19                    DR. FRIEDMAN:             I can answer that question

20   with       some      assurance        because        two      of    those        seven

21   patients          were     patients         that       were        done     at      our

22   institution, and I remember the details.                               Those were
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1    patient           who      actually           had          cryomapping,          not

2    cryoablation, of the slow pathway during AVNRT.

3                     In the baseline state, both patients had

4    inducible, sustained SVT, and during cryomapping we

5    showed that the slow pathway was completely blocked

6    and SVT was no longer inducible.                             With cryomapping

7    turned off, the slow pathway recovered function and

8    there were single, occasionally two, echoes, but not

9    sustained SVT.           We waited a while, and still there was

10   no     sustained        SVT,     although        the       slow   pathway        had

11   recovered.

12                    We marked that as non-reversible because it

13   did not return to baseline, although I think it was a

14   function of time.              Had we waited 20 or 30 minutes, in

15   all likelihood it would have.

16                    DR. DESMARAIS:          Dr. Lehmann?

17                    DR. LEHMANN:          Part of your question related

18   to data that doesn't seem to match, and that is really

19   the record of our good collaboration with the FDA, to

20   clarify what we felt the true situation was.                               So the

21   report in the FDA presentation was that 80 out of 87

22   cryomap          subjects      with      an     effective         cryomap        had
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1    "reversible" marked on their form and seven had the

2    "not reversible."

3                     We went back and looked at that.                          Part of

4    the issue was, what was "reversible," quote/unquote?

5    Is    it       seconds?         Is   it    minutes?           So    we    did      the

6    additional          analysis         of     actually        looking        at      the

7    cryoapplication data to see how long it was before the

8    next        application           occurred          either         with      normal

9    conduction restored or not.                      That is the data that we

10   showed.          Either way, you get a better than 90 percent

11   reversibility            assessment         in     short      notice       and      no

12   adverse events related to cryomapping.

13                    DR. TRACY:          Okay.       In terms of the clinical

14   utility of cryomapping, how useful is this?                                     There

15   was,       I     think     it    was,      84     percent      attempted           and

16   successful,         79     percent        not    attempted,        and    yet      the

17   ablation was successful.                   So it is 79 percent versus

18   84 percent.         Is that hugely different?

19                    DR. DESMARAIS:           Dr. Friedman will answer.

20                    DR.     FRIEDMAN:           Well,      I'm   a     believer        in

21   cryomapping.           I think that it is useful.                    Having used

22   this technology, in my mind, it is very useful.
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1                      I   think      there      are     differences         among     the

2    different patient groups, and that is partly why we

3    presented the data that we did.                               For AVRT, if you

4    think about patients with an accessory pathway, these

5    tend to be very discrete structures and they are not

6    the sorts of things that one can localize simply by

7    looking at catheter position fluoroscopically.                                     It

8    requires very careful mapping technique.                               It needs to

9    be very precise.

10                     In my mind, the clearly-demonstrated effect

11   of this, of cryomapping, in that group relates to the

12   fact       that,       with      cryomapping,          you're      affecting            a

13   relatively small area with the tip of that catheter.

14   You need to be very close to the accessory pathway in

15   order        to       interrupt        conduction            in   that     pathway

16   temporarily.             If      you     see    that         effect,    then    that

17   predicts effective cryoablation because you're right

18   on the spot.

19                     With AV nodal reentry, it may be different

20   because in many cases patients are undergoing AV node

21   r-entry ablation based on anatomy fluoroscopically.

22   You can position the catheter in what you think is the
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1    slow pathway position without regard to mapping --

2    this      is     typical     of   radiofrequency           ablation      --     and

3    often get a successful ablation.

4                     So the area of ablation for the AVNRT may be

5    larger and mapping precisely may be less critical,

6    but, conversely, the negative cryomap in that group I

7    think is a very important and useful thing clinically,

8    because to map during the slow pathway ablation a spot

9    and find transient AV block identifies a place that

10   you do not want to do ablation.                     So it is useful in a

11   different kind of way.

12                    DR. DESMARAIS:         I would like also to ask Dr.

13   Keane from MGH comment on that.

14                    DR. KEANE:       My name is David Keane.                 I'm an

15   investigator,          and    I   practice        at      the   Mass     General

16   Hospital         in   Boston.       I    have no equity, am not a

17   consultant, but my travel trip expenses, my flights,

18   were paid for by CryoCath.

19                    The reason I came down here today is because

20   I'm strongly motivated to see it be introduced to the

21   clinical practice that we have in Boston, and it has

22   implications just not imminent to mapping but also
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1    ablation alone.

2                     I get a call once every two to three weeks

3    from New England physicians with patients who have --

4    typically, younger patients than older patients with

5    parahisian pathways -- and I have over 10 patients

6    whom I have sort of held off over the last five years

7    on the basis that I was involved in the animal work

8    with this system and have always told them that it is

9    only a matter of time before you will see this thing

10   come through.

11                    They have been holding out for a number of

12   years with recurrent SVT, treated on medication, and a

13   lot of these are teenagers who are treated with beta

14   blocker and anti-arrhythmic drugs.                      Some of them are

15   young females who wish to become pregnant and they

16   continue to take their anti-arrhythmic drugs.                       That is

17   the real downside for them.                   I think it is a shame

18   that they have to wait, in particular, for this system

19   to come along and kind of eradicate their arrhythmia

20   on a permanent basis.

21                    For us, it is really key to see an approval

22   for parahisian pathways because they are the folks
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1    that suffer the most in that they have had enough SVT

2    to come for ablation; they have turned down.                                     They

3    have been brought all the way, almost like being a

4    horse to the water, but they haven't been allowed to

5    drink.           We have mapped these very accurately and found

6    them to be truly parahisian.

7                       There   are       a    lot     of    patients        out    there

8    waiting in the wings, not only directly on our own

9    waiting list, but also on the referring docs.                                 So the

10   answer today has been for AVNRT.                             I think the real

11   value            for    cryomapping,            actually          the     relevant

12   importance of cryomapping greatly exceeds the AVNRT

13   group for people with parahisian pathways.

14                      As   Dr.     Waldo      referred          to   it,   it     is        a

15   negative predictive value of a cryomap that has been

16   more important than a positive predictive value for

17   these people with parahisian pathways.                             The issue is

18   that you have total adhesion to the spot.                               It is the

19   same with the mahine fiber.                     If you have mahine fiber,

20   if you do a bump map, there is a good possibility that

21   by the time you go on and your tachycardia terminates,

22   again, it is like Dr. Ruskin's video this morning:                                  If
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1    the tachycardia terminates, the catheter moves, you

2    never get it back there again.

3                       With the adhesion, the ability to do a map

4    down to 30 degrees, go on at that spot, if you have

5    elimination of your target physiological endpoint, to

6    be able to go straight on from minus 30 to minus 69 or

7    minus 70 without having to rewarm is the biggest plus

8    of this system, because you are guaranteed that your

9    spot is exactly where you mapped.                         If you do it with

10   an     RF,        either   by     bump     mapping         or   even      a     low

11   temperature, 10-watt output, you are still getting

12   smudge           lesion.    With     every      other      system,     you      are

13   constantly smudging, the same way with microwave and

14   ultrasound.

15                      With this cryo, because it is a pinpoint

16   lesion, as you point out, they are very small lesions,

17   and that's why it is critical for these accessory

18   pathways that they are precisely mapped.                         Perhaps that

19   was      underappreciated           in    the      trial,       the    critical

20   importance because you get so much collateral damage

21   with an RF.            If you're not exactly on the spot but

22   close to it, you have success.                    With cryo, you have to
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1    be absolutely on the spot.                     I think that may have been

2    underappreciated when we were performing this trial.

3                       But, for me, the biggest issue about mapping

4    is      the        ability        to     map     a     parahisian       pathway,

5    particularly for these teenagers and young people who

6    have been waiting now for several years to see this

7    system come through.

8                       Thanks.

9                       DR. TRACY:          I appreciate that comment, but I

10   think       that     the     device       isn't      being     considered        for

11   parahisian          pathways        at    this       point.      I     think     our

12   discussion is just related to AVNRT.

13                      DR. DESMARAIS:            I think Dr. Lehmann has a

14   final comment on that.

15                      DR. LEHMANN:           I have just redisplayed this

16   slide from this morning's presentation that I think

17   relates to your question.

18                      First, I would like to point out that this

19   display doesn't relate to our indications for use, but

20   we    thought        it     was    a     fascinating         finding    from     the

21   study.           In the effective cryomap column, at the bottom

22   you see the 94 percent success rate for those 87
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1    subjects who had an effective cryomap.                              For the 48

2    subjects         who    had    cryomapping         attempted        but     didn't

3    think demonstrated, they had a 67 percent complete

4    procedural success.               For subjects, the 29 who had no

5    cryomapping            attempted,       it    was       76   percent.             The

6    comparison         of    the    first        to   the      second     and     third

7    columns is clearly significant.

8                     So there is this positive predictive value.

9     That is really all we were saying, that if you do

10   happen to cryomap and get an effective cryomap, your

11   certainty about ultimate success is high, and so that

12   is really the remark.

13                    DR. TRACY:        Thank you.

14                    Moving on to the cryoablation itself, it

15   strikes me that 11 of 103 patients had transient heart

16   block, and that is high for even -- I would not expect

17   that high of a level of transient heart block with RF

18   energy.          What explains that, and what explains the

19   development of a right bundle branch block when you're

20   working in a slow pathway zone?                      I can't quite figure

21   that piece out.

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

2                     DR. FRIEDMAN:            You have touched on a number

3    of important issues, and I think, Dr. Lehmann, if we

4    could have that one slide that I had asked you to

5    show, we will talk about this.

6                     With       regard       to   the     right     bundle       branch

7    block, there is a spectrum of catheter stiffness or

8    flexibility among the catheters that are available in

9    the marketplace, with EPT catheters being probably the

10   most flexible and on the other end of the spectrum

11   maybe        a    Biosense          Webster        being      less      flexible.

12   Different catheters are used to different degrees in

13   different institutions, and people are accustomed to

14   certain kinds of handling characteristics.

15                    This catheter is probably in the middle part

16   of    that       spectrum,        but    tending       toward    the       Biosense

17   Webster.             I    think    if    someone        is   used     to    an     EPT

18   catheter, which is very flexible, then all of a sudden

19   picks this catheter up, it is a little bit stiffer and

20   it takes a little time to get accustomed to.

21                    I       think    some    of the right bundle branch

22   blocks that you are seeing there are not necessarily
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1    related          to   ablation      or    mapping.          It   is    just      the

2    mechanical handling characteristic of the catheter.

3    After all, we see right bundle branch block just with

4    diagnostic his catheters on occasion.                              So I think

5    those are my comments about the right bundle branch

6    block.

7                      With     regard        to    the     high      incidence        of

8    transient AV block, I think this relates to the fact

9    again that this was an investigational procedure with

10   a new technology, and the investigators really were

11   set on giving this technology a good test.                               So, for

12   example, this is a case actually that we did at our

13   institution.             A woman with AVNRT -- I don't have a

14   laser pointer -- but a woman with AVNRT who had, I

15   don't remember the exact number, a few cryoablations,

16   and after the last of those, the sustained SVT was no

17   longer inducible.              There were still single echo beeps

18   that were inducible.

19                     Now in radiofrequency ablation, that would

20   be an endpoint.             Most people would stop at that point

21   and not go on.             But this is a new technology, and we

22   didn't know whether that was an adequate endpoint or
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1    not.       So we persisted, and we did ablations closer and

2    closer to the compact AV node.

3                     So here's an ablation actually in the high

4    to mid-portion of the septum, fairly close to the

5    compact AV node.           You see the artifact on the ablation

6    catheter         because      of   the    ice     formation      around        the

7    catheter, and you see here the surface ECG, and here's

8    an     atrial        electrogram.          That's         conducted;      that's

9    conducted.           Here's a blocked P wave.

10                    The first blocked P wave is right there, and

11   you can see within one or two seconds the ablation was

12   turned off and you see disappearance of the ice ball

13   this quickly.           Now this is a continuous strip, and you

14   can see that this transient AV block now is gone

15   within four or five seconds.

16                    So this may relate to why we saw transient

17   AV block perhaps more frequently than you would have

18   expected, because people were using this technology

19   aggressively, knowing that if AV block occurred, it

20   would disappear.

21                    I    would    conclude         by    just    drawing        your

22   attention to the Calkins data in a previous submission
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1    with a different kind of catheter, where if one looks

2    at the -- yes, and here we have the data for you.

3                     So this is the previously-submitted Calkins

4    data      that    was     reviewed          prior       to    that      catheter's

5    approval.         This shows you the incidence of any block

6    during ablation of AVNRT or AVRT.                            The incidence was

7    3.4 percent, so maybe a little bit higher than people

8    are accustomed to seeing.                  Ours was 7.2 percent.

9                     But    here's         where       the       major      difference

10   resides, and I alluded to this in my comments earlier.

11    Of this 3.4 percent, you know, nearly a third or a

12   half went on to have persistent AV block and needed a

13   pacemaker.         Here is where our difference is:                          that AV

14   block is transient.

15                    DR.    TRACY:              It     is        interesting,           the

16   electrophysiologic definition of the substrate is not

17   the traditional thing that we look at for success.                                   It

18   talks        about     the      success          being       measured       as      not

19   inducible to 15 seconds or more of SVT.                          I would never

20   stop with 15 seconds of AVNRT residual.                              Why was that

21   chosen, and how often did you see an effect on both

22   slow and fast in the cryo?
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1                     DR. FRIEDMAN:          That endpoint was chosen not

2    for its own value, but we struggled with what were the

3    appropriate inclusion criteria.                      We didn't want to do

4    ablation in people who had non-sustained arrhythmia at

5    baseline because it would be so difficult to judge the

6    effect of the intervention.

7                     So    we   arbitrarily         chose       greater     than      15

8    seconds' duration as a definition for sustained SVT at

9    baseline.        Once we established that, then the endpoint

10   of a successful ablation was anything less than that.

11    But I would argue that the success rate long term

12   attested to the fact that that was a clinically-useful

13   endpoint.

14                    DR. TRACY:          And the 94 percent long-term

15   success rate, that's of the cryo patients, not of

16   those cryo-plus-rescue?                That is cryo alone?

17                    DR. FRIEDMAN:          That's correct, that is just

18   the cryoablation alone.

19                    DR.    TRACY:           Okay.             In   patients       with

20   recurrence, at what point was that seen?                            Is that an

21   early recurrence, within a day or two, or is that --

22   it's early?
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1                      DR. FRIEDMAN:         It is usually within a day or

2    two, certainly within the first month.                         No recurrences

3    after three months.

4                      DR. TRACY:           Okay.      How many patients had

5    first re-AV block following ablation?

6                      DR. FRIEDMAN:          I think we have the slide.

7    None of them was permanent.                    I think the table that I

8    showed you there -- go back.                     So there was one, two,

9    three, four, and all of them resolved with 24 hours.

10                     DR. TRACY:        None were permanent?               And none

11   developed first re-AV block in the first month or at a

12   point later?

13                     DR. FRIEDMAN:         No, no.

14                     DR. TRACY:       Okay.       There was sort of a -- we

15   didn't           talk   about     it    in     your        presentation       this

16   morning, but the learning curve seems to be -- it

17   seems to take quite a bit of learning to get to use

18   this catheter correctly.                  It looked like there was an

19   acute       success      rate    of     85     percent      early   versus       97

20   percent late.

21                     How hard is it to learn how to use this

22   catheter and what does that mean in terms of how you
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1    would train physicians to use the system?

2                          DR. DESMARAIS:              I think I'll have a multiple

3    answer to that question.                            I'd like to start with Dr.

4    Friedman to discuss how to use the device.                                   Secondly,

5    there is a real number where we have Dr. Lehmann that

6    can answer some of that.

7                          Then, in real practice, Dr. Ruskin.                         In the

8    real practice, then we can talk, Dr. Dubuc can, who

9    has been using the catheter now for over 150 cases, as

10   he reported earlier.

11                         DR. FRIEDMAN:               As a clinician who has been

12   around longer than I care to recall, I think it is

13   fair to say that there is a learning curve with any

14   new technology, and that was true of radiofrequency

15   ablation.                  If    one       goes      back     and    looks   at     acute

16   procedural success in some of the older trials, you

17   know, 85 percent was acceptable.                                 Now we use an OPC of

18   92     or        93    percent.                So,     seemingly,       there     is     an

19   evolution in the field as people do more and more and

20   get more comfortable, but that is true of also the

21   cryoablation catheter.

22                         It        is      difficult           to      demonstrate        that
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1    statistically within the confines of a small study.

2    So     we        actually       didn't      demonstrate             statistically                 a

3    learning curve.              Maybe Dr. Lehmann can comment on that

4    further.

5                       DR.    LEHMANN:            I   think        it       is    worth       just

6    keeping it very simple.                    There was a very minor trend.

7     There were a couple of difficulties.

8                       One      is         there        were            a        number          of

9    subinvestigators, and when you take 166 or 164 cases

10   and      divide          them     amongst         13    sites           with       multiple

11   subinvestigators, it is just impossible to do any --

12   you don't get enough case accrual.                             That was really a

13   major issue.               When we did it on a per-site basis,

14   there was nothing significant.

15                      DR. DESMARAIS:            And Dr. Dubuc?

16                      DR. DUBUC:            As I said before, we did more

17   than 150 cases in our institution.                              I did myself 100

18   cases of these.                 When we switched to -- we decided to

19   go     for        cryo    for      all     our     AV     node          reentry         cases

20   afterwards, I mean since last August; my colleagues

21   started doing it, but they knew about the technology;

22   they knew about the result of the studies we performed
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1    in Canada previously.             And they quickly got it.                 Right

2    after three or four cases, they were able to do these

3    things by themselves.

4                     You have to realize that actually the thing

5    you learn from the technology is that you don't expect

6    the same response from the energy source.                             Like when

7    you do RF ablation, you expect irradiated junctional

8    rhythm during the ablate.               You don't have that.

9                     The catheter adheres to the under-cardial

10   surface.          So it is different.                    You don't have to

11   monitor on the fluoroscopy.                  This is what you have to

12   learn.

13                    More than my colleagues, also the personnel

14   working in the lab, they know what to expect and they

15   make      the    connection      quickly,        and      we   know    what     to

16   expect from the technology.                   So it comes very, very

17   quickly, if you have somebody -- not everybody has to

18   go through the same learning curve, I would say, you

19   know, like I did.            My colleagues near me, they did it

20   very quickly.

21                    In   closing,        your       question        about         the

22   complexity of the system itself, you have a catheter;
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1    you have, compared to RF, you have two connections

2    instead of one, and you have an on-and-off button.                             So

3    from a complexity standpoint, it is not very complex.

4                     DR. TRACY:     Okay, thanks.            Just to return to

5    some of the labeling issues, I don't know if you want

6    to look at your labeling section, but I think that,

7    based on what you have presented today, I agree these

8    are the appropriate indications that you should be

9    seeking approval for.

10                    Under   the    precautions,            just   a   couple      of

11   statements:         The one, two, three, four, fifth bullet

12   down, "Consider periprocedural coagulation therapy for

13   patients undergoing left-sided and transeptal catheter

14   procedure and for selected patients undergoing right-

15   sided procedure."              That doesn't quite fit with the

16   indication, but I understand why that might be there.

17                    DR. DESMARAIS:          Well, obviously, when we

18   wrote the indication originally, we understood that

19   indications and instructions for use is something that

20   has to be worked on at a later date, obviously.

21                    DR. TRACY:       Okay.        And down further, the

22   third-from-the-bottom precaution:                   If patients need to
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1    be defibrillated during the procedure, disconnect the

2    catheter's             electrical         connection              part         to     do

3    defibrillation.            Why?

4                     DR. DESMARAIS:           I would have Marwan Abboud

5    to    answer      that     question.           He    is         our   Director        of

6    Engineering.

7                     DR. TRACY:        Okay

8                     MR.    ABBOUD:           Ladies      and        gentlemen,          Mr.

9    Chairman         and     Panel       members,        I      am        Director        of

10   Engineering.

11                    The different relation issue is mainly --

12                    DR. TRACY:          Excuse me.             Could you please

13   tell what your conflict of interest is?

14                    DR. DESMARAIS:           Marwan Abboud is an employee

15   of CryoCath.

16                    DR. TRACY:        Okay.

17                    MR.    ABBOUD:         Director           of    Engineering          at

18   CryoCath.

19                    DR.    TRACY:         Okay.         I'm        sorry      I    didn't

20   understand.

21                    MR.    ABBOUD:         The     defibrillator              issue      is

22   mainly to protect the console.                      As any equipment, when
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1    you      defibrillate,             since       we     have         a     thermocouple

2    measurement,                in    order      to     prevent        destroying           the

3    temperature            measurement          circuit,          we   recommended           to

4    disconnect the catheter.

5                       DR. TRACY:          Okay.      That's fine.               All right,

6    that's basically all the questions I have at this

7    point,           but   I    sort       of   reserve       the          issue     of     the

8    statistical questions, might come back to that.                                       I am

9    hoping others will do that, too.

10                      CHAIRMAN        LASKEY:            Great.             Thank        you,

11   Cynthia.

12                      While         Dr.    Tracy       had        the       luxury         and

13   prerogative of spending 15 minutes, you can appreciate

14   the number of people up here who need their moment in

15   the sun.           So I would like to ask the Panel members to

16   share their thoughts and direct their questions to the

17   sponsor and the principal investigators in less than

18   five      minutes,          five       minutes      or    less,         if     they     can

19   summarize the key issues that they have before us.

20   That way, everyone can have a fair shake.

21                      MS. WOOD:           Actually, at this time it would

22   be     general         questions         for      either       the      FDA      or     the
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1    sponsor.         We would ask the sponsor to vacate the table

2    at this time, please.

3                     CHAIRMAN LASKEY:           I would like to begin the

4    Panel's questions and comments with Dr. Gilliam.

5                     DR.   GILLIAM:           I    have       a   few   questions

6    related.         I think Cindy touched on several, but I am

7    looking at your labeling.                      You do say, "The foot

8    switch is available only in Europe."                           Is that the

9    plan?        I am just wondering, why was that set up that

10   way, your foot switch for your console?

11                    DR. DESMARAIS:          Obviously, every device has

12   design evolution.              When we designed this trial, we

13   designed it with the current product that we had.                               At

14   that time there was no foot switch that existed with

15   the design of the console that we have, but the design

16   evolution        in    Europe     is    moving       faster.        So    it    is

17   available there.            But, in due course, when it is time

18   to file amendments to the current product, we will do

19   so within the boundaries of the FDA regulations.

20                    DR. GILLIAM:          Another thing, looking at the

21   first panel of your labeling, I guess that is on the

22   first page on the righthand side, the third point
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1    down:            "Do   not    connect       CryoCath         to   radiofrequency

2    generations             as       it       may        result        in       patient

3    electrocution."              It seems pretty drastic.

4                      Is there a real possibility of that?                                   I

5    guess I would direct that to your engineering.

6                      DR. DESMARAIS:            I will ask now our Director

7    of Engineering to answer that.

8                      MR. ABBOUD:          I think, as any RF, you, even

9    for the eruption rater, they do recommend not to put a

10   diagnostic catheter.                  Since our catheter printout on

11   the connection are different from regular RF catheter,

12   we recommend not to do it at this time.                            Thus, we are

13   using different thermocouple.                        Since we have a cold

14   temperature, we use a different thermocouple.

15                     DR. GILLIAM:          I'm not opposed to not hooking

16   up to an RF.            It was just quite drastic when you saw

17   electrocution.               Have you all had some experience with

18   that perhaps?           You don't have to answer.

19                     (Laughter.)

20                     While you are there, I do have one question.

21                     MR. ABBOUD:         Yes.

22                     DR. GILLIAM:          Your panel that you viewed the
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1    temperature that is right on the console, is that

2    exportable to any type of monitor that an operator

3    could see if they are not directly looking at the

4    console?

5                          DR. DESMARAIS:          At the current time, it is

6    not exportable.                 It is not designed to be in such a

7    way.         However, again, in Europe we are looking to

8    introducing that concept.                      Whenever it is ready for us

9    to introduce in the USA, we will do so again, within

10   the boundaries of the FDA regulations.

11                         DR.   GILLIAM:          This      may      be   one   of     your

12   investigators could answer this.                               Looking at your AV

13   node reentry population, is it typical that you would

14   be doing the slow pathway ablation while the patient

15   would be in tachycardia insofar as you will not have

16   the junctional rhythm that we typically see with RF?

17   How would you, other than looking at a negative map,

18   cryomap, how would you know you have achieved some

19   degree           of    success       with      slow     pathway       modification

20   during an ablation run?

21                         DR. FRIEDMAN:          There are a number of ways

22   that one can do that.                     The example I showed you this
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1    morning was cryomapping, just to illustrate how the

2    tachycardia would terminate, and in the anterograde

3    slope pathway direction.

4                      During       ablation,          most        typically,          the

5    ablation         is    actually       during      a   sinus       rhythm.         The

6    advantage to that is that the patient's in sinus; you

7    can monitor the PR interval.                     Indeed, you can even do

8    atrial pacing or programmed atrial stimulation during

9    the ablation application.

10                     That catheter tip is fixed to the myocardium

11   and will not move, and that allows you to monitor

12   during sinus rhythm or during atrial pacing, while the

13   ablation          is     going       on,      when      the       slow     pathway

14   disappears.

15                     DR. GILLIAM:           As far as the shipping and

16   storage          of    the   catheters,         are     there      any     special

17   precautions of this catheter, given it is sort of a

18   multi-lumen            catheter?         I   notice         the   kinking      is       a

19   concern,         obviously,        for     reasons,         but   how    does     the

20   catheter come in storage?

21                     DR. DESMARAIS:             The catheter is packaged

22   into a tray system.               It is packaged flat and it is not
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1    coiled           on    itself,      and     the     storage      conditions         for

2    catheters             and   console       is    standard       of    any   ablation

3    catheter out there.

4                          DR. GILLIAM:          Those are all the questions

5    that I have right now.

6                          CHAIRMAN LASKEY:          Thank you, sir.            Thank you

7    twice.           Mitch?

8                          DR. KRUCOFF:         I also will try to be brief.

9    I guess I am most interested in the use of the OPC-

10   based trial design.                      Obviously, that is consistent

11   with the precedence in this area of industry.

12                         But I think it has been remarkable to me, in

13   listening to your presentation, the difference between

14   the fascinating findings from this study, which is to

15   me     the       investigator's            view     of    what      happens     in        a

16   patient and how it works, versus what you have welded

17   yourself to with an OPC-based trial design that I

18   think Dr. Yue did a very eloquent job of illuminating.

19    It is really a population kind of statistic.

20                         So the observed behavior of the catheter in

21   individual patients, the PI sort of view, and how it

22   will behave in the population, and whether or not you
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1    qualify          based   on     boundaries         for       your   endpoints       as

2    successful or not are two very different worlds.

3                      I guess what I would like to hear is, why do

4    you think you failed to show the boundary outcomes?

5                      DR. FRIEDMAN:           I think there are a couple of

6    points to mention in answering that question.                                    When

7    the protocol was being designed, we were faced with a

8    choice of either using an OPC, an historically-derived

9    OPC, or doing a randomized comparison between cryo and

10   RF.      The randomized comparison would not have allowed

11   us to look at cryomapping because there is no way to

12   map with radiofrequency.                   So we were, basically, stuck

13   with the OPC comparator for the purpose of this trial.

14                     I would point out that that OPC is derived

15   from      results        recently,         and     RF    is     a   very     mature

16   technology.          It has been around for nearly 20 years

17   now.        This is a very young technology.                           So we are

18   comparing ourselves to a very high bar.

19                     Beyond that, I think that the technology was

20   demonstrated to be clinically effective in the group

21   for which an indication is being sought:                               Ninety-one

22   percent in the AVNRT patients is a clinically-valuable
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1    result.

2                      The reasons why the OPC weren't met I think

3    relate to the fact that some of the ablations were in

4    AVRT, left-sided accessory pathways.                          This technology

5    is very different than radiofrequency.                              I think you

6    saw the acute effectiveness results were less dramatic

7    in the AVRT group than the AV nodal reentry group.

8                      I    think     you      have      to      think     about        the

9    biophysics of ablation and the differences between

10   these       two       technologies       to    understand       that.            With

11   radiofrequency ablation of the left free-wall pathway,

12   typically done along the mitral valve annulus, this is

13   a high blood-flow area.                 That high blood-flow actually

14   serves to cool the radiofrequency tip, and in a way it

15   is almost akin to a saline-irrigated RF ablation.

16                     From Dr. Dubuc's animal studies, we know

17   that radiofrequency ablation causes a larger area of

18   damage on the endocardial surface.                           That relates to

19   the fact that the catheter is moving.                         It is not stuck

20   to a certain point.                 It paints back and forth across

21   the endocardial.                So that one doesn't need to be

22   exactly          on    the     accessory         pathway      to      achieve            a
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1    successful ablation.

2                       It     is    very      different           for    cryoablation.

3    Cryoablation adheres to the point and does not move

4    from      that      point.          That     high      blood-flow          along      the

5    mitral           valve    actually       acts     as     a    heat     source       that

6    minimizes the efficiency of the cryoablation.                                  I think

7    that relates to why there may be a difference in

8    effectiveness             in     that      group,       which        affected         the

9    overall results.

10                      But,    conversely,            I    would        look   at     it        a

11   different           way,       because       in       high-flow       areas       where

12   cryoablation may not have an advantage, in contrast to

13   low-flow areas, it may have a very real advantage, and

14   specifically              in     post-receptal            accessory          pathways

15   within           the     coronary         sinus,        for     example,          where

16   radiofrequency often can't be done because of high

17   impedance and low-energy delivery, and in the slow

18   pathway position, which is not as high a blood-flow

19   area.        It results, I think, in the fact that in that

20   circumstance it is highly effective.

21                      DR. KRUCOFF:          Well, I mean, I hear you, but

22   I'm honestly not sure to which side of my question
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1    this -- you know, again, to me, what I hear is an

2    enormous           amount        of     conceptual            and     intellectual

3    fascination in why and where this technology really

4    might be an advance beyond RF.

5                       But how much of that is reflected in this

6    clinical trial or can be deduced, or even in the 91

7    percent in AVNRT, is the actual observation?                                      It is

8    the boundaries around that that become even relevant

9    to talk about with an OPC.                         As was described, it is

10   not the boundaries around the whole population.                                       It

11   would be the boundaries around the RF population and

12   AVNRT.           Again, at least my understanding of the data,

13   unless I missed something, is that even the boundaries

14   around           the    91     percent      for     AVNRT      do     not     compare

15   favorably to the RF historical boundaries that you

16   would pre-define if you had prospectively pre-defined

17   for that population.

18                      So, I mean, I get that there are a lot of

19   theoretical             both    safety       and    effectiveness           possible

20   subpopulations that this instrument might be terrific

21   for.      On the other hand, I also get that, like so many

22   things           that   we     do,    it    is     possible         that    the    more
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1    damaging milia that RF creates may have areas where it

2    is actually more effective.

3                       The fact that I saw two different sets of

4    numbers, but whether it is 23 out of 25 or 25 out of

5    27 of the cryo failures that were successfully done

6    with RF, I don't need an explanation of that.                                 To me,

7    it just says that one is more histologically pleasing

8    to look at than the other.                          It ultimately begs the

9    question           of   when       you     start       applying        this    to        a

10   population of human beings, where is the data that

11   gives you confidence that this is a safe and effective

12   approach?

13                      And with an OPC set of boundaries that, even

14   in the group who you are asking for an indication, if

15   you drill down retrospectively to your point control

16   population, you still don't make the boundaries for

17   the AVNRT.

18                      So I am just missing a link as to, if you

19   bought           into   this     trial      design      from     the    beginning,

20   which obviously you must have at some level, how do

21   you come to see the data supporting the fascination?

22   The fascination is self-evident?                              The data that this
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1    is safe and effective compared to a well-established,

2    as you say, mature technology is, I think, what the

3    patient or user side question is.

4                     I am really interested in why you think,

5    both      in     the   safety      and    in    the        effectiveness,        you

6    failed to make your boundaries?

7                     DR. LEHMANN:         I will just briefly comment on

8    the design.            As you do know, sponsors don't have a

9    free hand in choosing a clinical study design.                               It is

10   negotiation with the agency.

11                    We either had the choice of a --

12                    DR. KRUCOFF:            Well, you could have done a

13   randomized trial.

14                    DR. LEHMANN:            Yes, we could have done a

15   randomized trial, but there are a number of problems

16   with        that,      including          standardizing           RF      therapy

17   procedures and equipment, which is actually rather

18   hard to do -- it will cause a large study -- and the

19   difficulty with cryomapping.

20                    As    to   the     implications            of   what   we     have

21   demonstrated, I think Dr. Friedman will just have a

22   few remarks.
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1                     DR. FRIEDMAN:         I will try to answer your

2    question.         I understand what you are wrestling with,

3    and it is a difficult issue.                 I will try to answer it

4    by putting it in clinical perspective.

5                     I think it is very helpful to step back and

6    try to look at things from the perspective of the

7    patient.         If I'm a 20-year-old patient with AV nodal

8    reentry that is interfering with my lifestyle and a

9    physician gave me two choices:                   One choice, I can have

10   radiofrequency ablation with a 94 percent chance of

11   acute success; however, there is a 1 to 2 percent

12   chance that I am going to wind up with a permanent

13   pacemaker.         Or I could have a cryoablation with a 91

14   percent acute procedural success rate and no chance --

15   no chance -- for a pacemaker.                    It is very clear in my

16   mind what I would choose, and I would venture to say

17   that most individuals faced with that decision would

18   make the same decision that I have just made.

19                    CHAIRMAN   LASKEY:          I    must   say     I   need      to

20   object to that last statement.                    It is not zero.             The

21   confidence intervals of zero events observed in 150

22   patients go out on my back-of-the-envelope, amateur
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1    stat. program here to 2 percent.                          It's not zero.               I

2    think you do need to be rather intellectually honest

3    to some of these questions.

4                     I   think      we     are      on        the    threshold        of

5    perseverating as well.                 So I'm not sure we are going

6    to get to what you really need to know.

7                     DR. KRUCOFF:          I think a question is on the

8    table, and I think, you know, again, I am just going

9    to move on because I only have a couple of other brief

10   questions.

11                    In your European experience, are you aware

12   of any instances where RF ablation has failed and

13   cryoablation has succeeded?

14                    DR. DESMARAIS:           Well, in fact, every time

15   that       there     has     been      ablation           in    AVNRT     and     do

16   defibrillation         near      the     aveno       where      the     physician

17   either pulled back, because of fear of I think an AV

18   block and subsequently tried trial, there is a lot of

19   data that concurs that we have successful cryoablation

20   after RF.

21                    DR. KRUCOFF:          Okay.      Thank you.            So what I

22   am hearing is, in situations that the operator sort of
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1    judged to be too risky to actually fire RF energy --

2                     DR. DESMARAIS:            Or has fired RF and failed

3    in that, as well I think there's a current trial in

4    the U.S.         Again, this was filed initially by the PMA.

5     The data we have, we know that these are patients

6    that      failed       RF,    that      the    study        conducted    by     Dr.

7    Chapman right now, which is a small subset study, but

8    we don't have any data to present on that.

9                     DR. KRUCOFF:          Okay, and are you aware of any

10   experience with cryo patients that were not durable,

11   that came back, that were redone with cryoablation?

12   Can you go back and freeze the same site twice.                                  Do

13   you have any experience with that?

14                    DR. DESMARAIS:            Yes, and I think Dr. Dubuc

15   can answer that.             He has done some of those patients.

16                    DR. DUBUC:         I think I have two parts of this

17   question, if we have patients who have failed RF and

18   they went to cryo or if they had two sessions of cryo?

19                    DR. KRUCOFF:          Yes.

20                    DR.    DUBUC:          Okay.         Well,     yes,    with     no

21   problem.         No problem at all.

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

2                      DR. DUBUC:         Nothing will happen because the

3    process is already in evolution.                                 Actually, I could

4    say that, even if you stand there, and why we picked

5    that time of four minutes is because we know that

6    after three minutes you reach a plateau that the ice

7    ball inside the tissue will not grow anymore.                                    It will

8    stop      there,        and     that     has     been        proven        by     cardia

9    ultrasound, because you can see the ice ball with

10   ultrasound, with intracardiac ultrasound.                                   Actually,

11   we     can       monitor      that.          Actually,            the     correlation

12   coefficient between the measurement done by echo and

13   the histology was .95.

14                     DR.    KRUCOFF:             Okay,          I     have     no     other

15   questions.

16                     CHAIRMAN LASKEY:               Thank you, Mitch.                     Dr.

17   Page?

18                     DR. PAGE:          Thank you.          I will try to keep

19   this as short as possible.

20                     The first question is -- actually, the first

21   two questions have to do with the footprint of this

22   device.           Peter,       maybe     you     could           answer    this,       Dr.
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1    Friedman.

2                     In        terms       of      looking        for       biological

3    plausibility for why you found what was, I guess, an

4    unexpected result, that AVNRT was successful and AVRT

5    was       not,        as      I     wrestled         with      the      biological

6    plausibility           of      that     finding,        as    opposed      to     just

7    chance, which is what we always have to be concerned

8    about with a post-hoc analysis.                         Would you say it has

9    to do with the footprint of this device being smaller

10   and being adherent at the time of ablation lesion?

11                    DR.       FRIEDMAN:            I    think     those       are      the

12   answers, as I alluded to earlier, yes.

13                    DR. PAGE:            Okay, fair enough.             Do you have

14   an idea, how long is it before you get adherence of

15   this catheter at the ablation site?

16                    DR. FRIEDMAN:              It occurs within a matter of

17   10 or 15 seconds.                   It depends a little bit on how

18   stable the catheter is to begin with and what kind of

19   contact one has with the tissue.

20                    But by the time the artifact on the catheter

21   that I showed you there indicating freezing appears,

22   that catheter is stuck.
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1                     DR. PAGE:       And, likewise, would you say that

2    it detaches at about the same interval that we saw on

3    that      electrogram?            So     a   few     seconds,    but     pretty

4    promptly?

5                     DR. FRIEDMAN:           Within three or four seconds.

6                     DR. PAGE:          Within three or four seconds,

7    good.

8                     And   as    someone         who   performs     ablation,            I

9    recognize the advantage of having an adherent catheter

10   at the spot you are burning or freezing in this case,

11   because,         especially         if       you    are     burning      during

12   tachycardia --

13                    DR. FRIEDMAN:           Yes.

14                    DR. PAGE:       -- then it will stay put when the

15   geometry and the motion of the heart changes as you

16   break the tachycardia.

17                    Let me flip that around.                  I have spent the

18   last 10 years doing ablations in Texas, and every once

19   in a while a patient would get up off the table in the

20   middle of a burn or grab or move a leg.                         What data do

21   we have in terms of, if a catheter is pulled when

22   adherent to the tissue -- you understand my question?
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1                     DR. FRIEDMAN:          I do.

2                     DR.   PAGE:        We've all been through this,

3    being in a busy lab, and suddenly a patient moves, and

4    your catheter might move with him.                        With the standard

5    RF catheter, it may perforate or it may more likely

6    pull away from where you are burning.

7                     But if you are attached and someone took a

8    tug at that catheter, what happens to the tissue?

9                     DR. FRIEDMAN:           Well, there are some animal

10   studies that we could cite, but I would follow up just

11   by saying that, if the patient moved, injection can be

12   halted within a matter of seconds.

13                    DR.   PAGE:        I    understand        that,      but     this

14   happens so fast, and we have already agreed that it

15   sticks for a couple of seconds.                     This happens in less

16   than half a second, as we all -- anybody who has been

17   in an EP lab recognizes sometimes the patient will

18   suddenly come up off the table.

19                    DR. FRIEDMAN:          Yes.

20                    DR.   PAGE:        So     if    that     does    occur       with

21   adherence, what happens to the underlying tissue?

22                    DR. DUBUC:        I mean, if the range of motion
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1    you are talking about is rather small, I mean I don't

2    think that the patient would start running from the

3    table.

4                     DR. PAGE:     No, but imagine -- let me put it

5    clearly because it happens.

6                     DR. DUBUC:     Yes, I know.

7                     DR. PAGE:     Imagine someone in the middle of

8    the burn tugs it forcefully.                 I mean, what comes with

9    the tip?

10                    DR. DUBUC:       Okay.        If the patient moves,

11   nothing will --

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

13                    DR. DUBUC:      Okay.       If somebody tugs really

14   just a little --

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

16   tug.

17                    DR. DUBUC:      Well, you can do damage to the

18   tissue underlying the --

19                    DR. PAGE:    The underlying tissue?

20                    DR. DUBUC:     Yes.

21                    DR. PAGE:    Okay.      And my only caution being,

22   you know, we have had physician experts talking about
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1    looking forward -- I should just mention, first of

2    all, that at the AV node slow pathway area, this

3    probably would not be a major catastrophe.                           If someone

4    is taking this to other places -- we have talked about

5    parahisian.            What    if     we    wanted        to   outflow      track

6    ablations, something like this, where the tissue is

7    thin, atrial tachycardias where the tissue is thin, do

8    we have any data on what would happen then?

9                     DR. DUBUC:       Well, something wrong can happen

10   because, you know, we made animal studies on that or

11   on purpose we pulled --

12                    DR. PAGE:      Sure.

13                    DR. DUBUC:         -- you know, strongly on the

14   catheter.         Actually, if you pull a lot, you can bring

15   part      of     the   heart     inside       the    IVC       and   even     have

16   avulsion of the tissue.                     Really, if you have two

17   people on the -- we did that testing.

18                    DR. PAGE:       Sure.       It doesn't happen often,

19   but it does happen rarely.

20                    DR. DUBUC:       Yes.

21                    DR. PAGE:      Okay, thank you.

22                    One question I had, and I just have one
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1    other question after this:                      We seem to agree that

2    there       were      no   catheter-related               complications,        but

3    there were a number of complications that I think

4    related to procedure time and DVT, atrial clots, and

5    bladder infection related to a Foley that you don't

6    need for an hour-and-a-half procedure, but you might

7    need for a 260 average minute procedure, the average

8    number of burns is 7.5, and those were four-minute

9    burns?           Is that right?

10                      DR. FRIEDMAN:       Four-minute freezes, yes.

11                      DR. PAGE:       Thank you.

12                      (Laughter.)

13                      I am so old-fashioned.

14                      So four-minute ablations, if you will.                        So

15   that is about 30 minutes of actual ablating time.                                So

16   this      is,       indeed,    a     longer     procedure,        related        to

17   whether it is the experimental condition or not, it is

18   a    longer        procedure.         I   think      the      length     of     the

19   procedure           related     to     the     experimental          protocol,

20   indeed, was responsible for increased complications.

21                      I would mention that the European data you

22   showed us, which I never had a chance to see before
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1    today, was reassuring in terms of number of lesions as

2    well as duration of the procedure.                         So I could presume

3    that those wouldn't be ongoing complications, and the

4    procedure time would, indeed, shorten.

5                      My   last     question        was,       in    terms        of       the

6    comment on parahisian pacing, which, as I mentioned,

7    concerns          me   because      we    are     talking        about        a    very

8    limited          indication     here,       and    with         approval,          I   am

9    already hearing that people are looking forward to

10   using off-label use of the device and potentially in

11   tissues where we have already discussed could be a

12   problem if the catheter weren't handled properly.

13                     But if I saw the data properly, when you

14   have a failed cryomap, that still translated to a 67

15   burn success at that site?

16                     DR. KRUCOFF:        Ablation.

17                     DR. PAGE:      Ablation.         The slide, it was like

18   90     percent         ablation      when       you    have       a      successful

19   cryomap,         but    even    a   failed        cryomap,        you      ended       up

20   getting successful ablation 67 percent of the time.

21   So my only caution is, with these 20-year-olds that

22   are waiting to have their parahisian pathways ablated,
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1    a negative test pulse, cryomap, will not necessarily

2    translate to failure to ablate the his bundle.                                Am I

3    interpreting the data correctly?

4                     DR.    LEHMANN:          I    would      make     one      minor

5    correction.            The figures that you are quoting that

6    were recently up there were on a per-patient basis.

7    The distinction between a subject with one or more

8    effective cryomaps versus subjects who were attempted

9    but had not effective cryomaps, versus the group that

10   was never attempted.

11                    So that isn't on a --

12                    DR. PAGE:        So on a per-burn basis, it is

13   lower than that?

14                    DR. LEHMANN:            Well, the overall is -- we

15   would have to go back and look.                     I don't have that on

16   the tip of my tongue.

17                    DR.    PAGE:        I    think      you're      right,       it's

18   significantly lower.

19                    DR. LEHMANN:        Yes.

20                    DR. PAGE:         My only caution being that I

21   don't know what comfort I have that the test pulse,

22   indeed, will not result in true ablation of the normal
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1    conduction system.

2                     And my last question is, the reversibility

3    of the heart block that you have seen, that wasn't

4    just       with    cryomapping;        that      was    also     during        an

5    attempted         ablation,    is    that     right?      And       then      you

6    turned off in time and, indeed, conduction returned?

7                     DR. LEHMANN:       There are two aspects to this.

8     One is the straight cryomapping where we had 162

9    effective cryomaps, of which only around 64 of them,

10   62 of them were warmed for reassessment.                              That is

11   where we got the 90-plus percent reversibility of an

12   individual intended cryomap effect.

13                    Then we had 11 adverse events, these device-

14   related transient AV block, of which one was related

15   to cryomapping and led to a death.                      It was intended.

16   It wasn't the therapy, they contend.                    They were trying

17   to go after one of the slow pathways, and that subject

18   had unintended AV block that lasted 20 seconds.                                So

19   that was an adverse event.

20                    DR. PAGE:       But in terms of when you are

21   therapeutically ablating, those do also, if you see

22   heart block, they tend to get better?
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1                     DR. LEHMANN:             Those, we had the 14 instances

2    in 11 subjects all reverted.

3                     DR. PAGE:           And that is reassuring.                          Thank

4    you very much.

5                     CHAIRMAN LASKEY:                Nobody in this room is

6    more sensitized to the off-label use of the material

7    that we're discussing.                     So could we please restrict

8    our comments to the material at hand and not encourage

9    off-label use?           But thank you very much.

10                    Dr. Aziz?

11                    DR. AZIZ:         I, too, enjoyed the presentation,

12   and       I      must        say      I      learned             a     little           more

13   electrophysiology today.

14                    Let     me      just      address           a       few      questions.

15   Looking          at    the     number       of     patients            who       actually

16   developed either arterial or a venous clot, I guess

17   part of that may be related to the time that the

18   catheters were in place, and it seems that the times

19   with experience do decrease.

20                    Do    you     put     these      patients            on      any     anti-

21   platelet agents or anything that you suggest that that

22   should be done?
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1                     DR.   FRIEDMAN:            In     the        study   protocol,

2    decisions about anticoagulation during and after the

3    procedure were left to the investigator based on the

4    practice in that laboratory and, as you might imagine,

5    varied widely from one institution to another.

6                     For example, the one case of a pulmonary

7    embolism that I mentioned as an AMC was a woman who

8    actually had a fairly short procedure and did not get

9    heparin during her procedure, but she went home and

10   spent two days in bed and developed a deep venous

11   thrombitis that embolized, undoubtedly related to the

12   catheter         insertion     site,      but    in       a   sedentary,       bed-

13   ridden person.

14                    These other procedures that I showed you,

15   one of them I mentioned specifically was a very, very

16   long procedure where no heparin had been given for

17   some eight hours.

18                    So our own practice at our institution is

19   that patients get anti-coagulation during right- and

20   left-sided ablations, and they all get sent home on

21   aspirin, but I think that that is going to vary from

22   investigator to investigator.
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1                      DR.       AZIZ:          And       you     have      seen        the

2    histological slides of the difference in damage done

3    with cryoablation versus RF.                       In clinical usage, did

4    you see that translate into better or less CPK leakage

5    with cryoablation versus RF, or you didn't think about

6    that?

7                      DR. LEHMANN:           We did see some CPK rise and

8    we didn't compare it to any RF experience, but there

9    is some CPK rise with --

10                     DR. AZIZ:           In somebody who had a prior,

11   let's say, tricuspid valve repair or a tricuspid valve

12   replacement,              could    you    still      use     this    technology,

13   depending on, obviously, the type of --

14                     DR. LEHMANN:           These subjects were excluded

15   from this trial.

16                     DR. AZIZ:         I guess, when it does come out,

17   could you see it being used in somebody who has had

18   prior tricuspid valve surgical procedures done?

19                     DR. FRIEDMAN:             That's a problem even with

20   radiofrequency ablation.                    I don't know the answer to

21   that.            As   I    think     about       the    biophysics        of     this

22   technology, nothing occurs to me right away that would
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1    make me think that it would be contraindicated.                             If

2    there is a sewing ring in the tricuspid valve and you

3    are trying to ablate beneath that, I am not sure how

4    effectively the cryo energy would be transmitted.                           It

5    might not be that effective, but I don't think there

6    would be any particular safety concern.

7                     DR. AZIZ:    Let me just go over -- there were

8    one or two patients.            On page 85, Subject 0917, could

9    you just have a look at that?                 This was actually a 76-

10   year-old male who had the procedure performed.                           Echo

11   post-procedure showed that his EF had increased and he

12   had quite significant mitral regurgitation, and that

13   the left atrial size had actually also increased.                          The

14   dimensions had increased by 9 millimeters.

15                    DR. LEHMANN:      Which document?

16                    DR. AZIZ:    Page 85, Subject 0917.

17                    CHAIRMAN    LASKEY:         In    the   general     packet

18   itself, the patient descriptions.

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

20                    DR. AZIZ:    The patient was 0917.

21                    DR. FRIEDMAN:         I'm reading here from the

22   report.          I don't know this patient, but let me just
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1    read the details of what we know.

2                      DR. AZIZ:       Okay.

3                      DR. FRIEDMAN:          An 89-year-old female had a

4    baseline         echo     which     showed       aortic       stenosis,             mild

5    tricuspid, and mitral regurgitation and inject --

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

7                      DR. FRIEDMAN:           Okay.       Seventy-six-year-old

8    male,       baseline      echo     showed       thickened          aortic         valve

9    leaflets, mild MR, mild TR, and an injection fracture

10   of 63 percent, underwent successful AV node ablation

11   for      rate      control     and     permanent           pacemaker           without

12   adverse          event.        Post-procedure              echo        demonstrated

13   dilated          left   atrium;       the     pacemaker           in      the     right

14   ventricle.

15                     I think it is difficult to compare those two

16   echoes for a couple of reasons.                      No. 1, baseline, the

17   patient had a very rapid ventricular response and,

18   presumably, a normal QRS because of rapid conduction

19   through the AV conduction system.

20                     Post-ablation, clearly, had a much slower

21   heart rate, which by itself would increase cardiac

22   dimensions by any measure, and, in addition, had a
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1    right       ventricular       pacemaker,         because        there           was   no

2    intrinsic AV conduction.                Pacemaker implantation alone

3    in someone with AV block could lead to ventricular

4    dilation and even some degree of mitral regurgitation.

5                     My guess is that that is related to the

6    pacemaker implant and the presence of AV block post-

7    procedure         as    compared        to     pre-,        not       a     function

8    specifically of cryoablation.

9                     DR. AZIZ:      Thanks.

10                    DR.   WALDO:           I    just         had     a       few    short

11   questions.        The histology that you showed us, the iced

12   lesions looked like ventricle.                      Am I correct?                  Have

13   you done that at atrium?                     Is there any more of the

14   same, because --

15                    DR. DUBUC:       For the purpose of presentation,

16   we showed mainly ventricle lesions.                        Those lesions are

17   all ventricular, the lesions you saw this morning in

18   the presentation, but we did the same in the atrium.

19   Naturally, all these lesions were transmural.

20                    DR. WALDO:          That was my point; they are

21   transmural?

22                    DR. DUBUC:       Yes.
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1                     DR. WALDO:           And no other problems?                    Okay.

2    How do you decide on 4 millimeters being necessary

3    duration of the application of freezing?                            For minutes?

4     I'm sorry.

5                     DR. DUBUC:         The four minutes, yes.                Well, we

6    --     and       this    work      is    already         published,         but     we

7    demonstrated with the ultrasound we can monitor the

8    ice ball growth within the tissue, and we can monitor

9    the size and it is growing for about three minutes,

10   and then you reach a plateau after three minutes.

11                    So we decided that four minutes was okay.

12   This, as I said previously, the size of the ice ball

13   correlated          very      well      with       the      coefficient,           the

14   correlation            coefficient         of    .95,       when     we     compare

15   histology to the size we found by ultrasound.

16                    DR.     WALDO:         Okay,      two      other    very       brief

17   questions:              Peter,      when     you     answered        an     earlier

18   question,          you     didn't       address        the     issue       of      the

19   relatively surprising to me poor success rate for his

20   cryoablation.

21                    DR. FRIEDMAN:           Yes, that does stand out, Dr.

22   Waldo, though I am not sure why.                             The numbers are
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1    small, and those confidence intervals are fairly wide.

2     I think it is hard to make any definite conclusions.

3                       DR. WALDO:          Okay, now just a little heresy

4    from       me:           I     don't       know,     I        think    this        is       a

5    philosophical                point     I     would        like        to        make    in

6    considering this.                   I think the statistics here have

7    been very well presented.                       I am not a statistician.

8    We are going to hear a lot of more, and I think if you

9    just took a statistic, there are some real questions,

10   and Mitch addressed some of them.

11                      But,       for    me,   that      is   why     it       is    heresy,

12   because I hope -- I have been a scientist in my time,

13   and I think data are very important, but I look at

14   this, do look at this in part as a clinician.                                    I think

15   one of the things I look upon this as another option.

16    There           are    not    a     lot   of     secrets        about      AV     nodal

17   ablation.              We know the mechanism.                  We know how to go

18   about it.              There are not a lot of secrets about hisp

19   ablation, even about getting accessory AV connections.

20                      I just see that there are times when one

21   would want to have an alternative technique.                                    And what

22   becomes           important         there       is    safety.              And     if       I
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1    understand the data, I think we have seen that it is

2    remarkably safe.

3                     I think efficacy is always important, but I

4    haven't seen a terrible efficacy really.                       I have seen

5    quite a good efficacy, maybe not as good as some of us

6    would like to see, especially statistically or if you

7    look at ITT and a lot of other things.                     I understand

8    that thing.

9                     But I think that we shouldn't lose sight of

10   the fact that this provides the clinician with an

11   alternative         therapy      that      may     be   very     important

12   sometimes, and it is safe.               I would just like to leave

13   it at that.

14                    CHAIRMAN LASKEY:         Not heretical at all, Dr.

15   Waldo.

16                    Dr. Bailey?

17                    DR. BAILEY:       Well, I feel like everyone's

18   waiting for my remarks here.

19                    (Laughter.)

20                    As a statistician, I guess I belong to the

21   group that we don't allow second chances; we don't

22   allow rescue procedures for analysis.                   If you miss it
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1    on your first shot, we don't bail you out, although I

2    think the sponsors were well motivated to try because

3    it certainly looks like a very interesting device.

4                     However, as a patient or as a consumer, I am

5    certainly interested in rescue procedures.                               I guess

6    most of my remarks tend to be on the philosophical.

7                     I agree, if you accept the design of the

8    study, the OPC pretty much ropes you in and you don't

9    even need to think about it.                    I agree, I thought both

10   the      sponsor      and      the      FDA     made       excellent,        clear

11   presentations          of      the      data,      with      obviously         some

12   differences in interpretation.

13                    Of course, the subgroups, you know, we don't

14   let you look at subgroups, but, of course, you have to

15   look at subgroups.             You have to; they are interesting.

16                    I   guess,      what     does      it     mean   to    have      an

17   overall OPC if, indeed, the efficacy is intimately

18   linked to the composition of the study population?

19   Now I don't know how much of the variability would

20   have been known ahead of time, but I understand in the

21   radiofrequency literature there's also variability of

22   efficacy of ablating these three different entities.
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1                     So I guess from a philosophical point of

2    view, how do you come up with an overall OPC when you

3    have heterogeneity that may influence what the result

4    is in any given population?

5                     There was a little bit of vagueness in the

6    way the protocol was written, but I think, to be hard-

7    nosed, you have to accept that the overall results are

8    what count.          However, this thing about the rescue

9    procedures, I mean, as a consumer, you know, if I am

10   being offered a procedure that has much better safety

11   in some sense, but I agree with the comment that

12   that's not necessarily been shown, then I might be

13   willing to have a lower efficacy, initial efficacy

14   rate, if I can also, then, get the RF procedure as a

15   backup.

16                    I guess it has sort of surprised me that we

17   weren't looking at the overall success rate of the

18   strategy.         Now the RF procedure, is it done in the

19   same catheterization or do you have to come back later

20   for it?

21                    DR. FRIEDMAN:        It was done at the time of

22   the same procedure.
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1                     DR. BAILEY:        I presume it adds quite a bit

2    of time though to the overall procedure.

3                     DR. FRIEDMAN:          It depended on the patient.

4    Some patients who failed cryo also failed RF.                                They,

5    obviously, tended to be longer procedures.                          Some had a

6    successful        RF    very      quickly,        and      it   was    a     short

7    procedure.

8                     DR.    BAILEY:          I     had        thought     that      the

9    complications weren't related, but, as I understand,

10   they could be related to the length, overall length,

11   of the procedure.              So it would be important to know

12   whether the complication rate was, indeed, related to

13   the     length     of    the     procedure        and,      indeed,        to   the

14   performance of the back-up procedure or two procedures

15   rather than just one.

16                    But, subject to that, I would think that,

17   from the point of view of seeing where this fits in or

18   if it fits in, it is not really fair to compare the

19   initial efficacy to the efficacy of radiofrequency

20   ablation, unless you are proposing this procedure as a

21   substitute for it without the opportunity to perform

22   RF ablation.
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1                      But if you are proposing a strategy, then

2    now that may imply that we need a higher limit than 85

3    percent,          but   I   think     that,        as   a   consumer,     not        a

4    statistician but a consumer who happens to have a

5    Ph.D. in statistics, that is what I would be looking

6    at, is, you know, what's the efficacy, given that I am

7    going       to     be   able    to    have     a    rescue    procedure,        if

8    necessary?          Not rescue, a back-up procedure.

9                      That is why I would have been interested in

10   -- well, we were given that initial success rate, and

11   it    was        well   over   90    percent.            I would have been

12   interested in the success rate at three months, and so

13   forth.

14                     In terms of the safety issue, it is also

15   amazing how different, again, the OPC is from the way

16   the data seem to be that are most relevant, in that

17   although -- again, that was probably from naivety -- I

18   didn't realize that it is possible that it may be

19   somewhat           actually      difficult          to      determine      which

20   complications are related to the procedure versus just

21   the device.

22                     But the one thing that stands out is that,
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1    in order to achieve your OPC, you had to have four

2    events -- I'm sorry -- you needed to have a rate such

3    that         you     were       expecting           four      events,           four

4    complications,         five       was      the     limit,     and      then       you

5    actually observed seven.

6                     I   guess     what     is     striking       is    how     little

7    tolerance there is between those numbers.                            So I think

8    this gets at the point that this is a very small study

9    on which to base safety, given the vagaries of what

10   causes these complications, and the extent to which

11   they are dependent on the devices is unknown.                              That is

12   why either large numbers or a comparison group or

13   something.

14                    In terms of the randomized trial, I didn't

15   follow the argument why the cryomapping prevents you

16   from doing a randomization.                   You can still look at the

17   efficacy and safety of the strategy of cryoablation.

18   You could even randomize the use of cryomapping or

19   not, if you wanted to, versus radiofrequency without

20   the alternative of -- of course, on the cryoablation

21   side,        you     would       have      the      opportunity           to      use

22   radiofrequency,         if      necessary.             Then   you       would      be
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1    comparing efficacy immediately at three months and, of

2    course, complications.

3                     But I didn't follow the -- I heard you say

4    that the cryomapping made it impossible, but I didn't

5    follow the logic of that.

6                     And I agree with all the comments that have

7    been said, that the cryomapping really, in order to

8    understand it, you really have to compare the groups

9    that get cryomapping versus groups that don't, if you

10   are     trying     to    look     at    the efficacy of it from a

11   strategy point of view, and probably even in this

12   study, even doing that analysis is very fraught with

13   the usual observational biases.

14                    So those are my questions.

15                    CHAIRMAN LASKEY:           If they were questions, do

16   you want comments or questions or more thoughts?

17                    DR.    BAILEY:         They are comments that are

18   questions.

19                    CHAIRMAN LASKEY:           Oh, I see.

20                    DR. BAILEY:         We should give the sponsors an

21   opportunity to respond then, starting with --

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

2                      DR. LEHMANN:           Well, it could be possible to

3    do that.           I rose to just respond to a few of the

4    numbers, if I could address those.

5                      Just to the overall strategy of cryo and

6    then RF, if cryo failed, resulted in a rate of 97

7    percent for every study subject, and in each instance

8    RF was undertaken in the same procedure.

9                      Any    measure         of    adverse       events       was      not

10   correlated with either the number of cryoapplications,

11   the number of cryomaps, the number of cryoablations,

12   nor procedure duration.

13                     In descending order of certainty, we have

14   151 IDE subjects in this trial with no AV block.                                 In a

15   prior       IDE    trial       of    a   9     French       device,      otherwise

16   essentially            identical      to      this   one     in    its    mode      of

17   action,          and     two        trials      done        in    Canada        under

18   essentially the identical protocol, using the same

19   monitoring group and submitted to the TPT, and filed

20   with the FDA in the PMA.

21                     So    we     have      almost        300       very-carefully-

22   observed patients followed for many months, and the
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1    number AV block in that population was zero.                         Zero out

2    of 300 is, back of the envelope, is about 1 percent

3    upper limit.

4                     Now with lesser degree of certainty, there's

5    another          300   AV      node      reentrant         tachycardia,        AV

6    reentrant tachycardia subjects in a European registry,

7    where they do get more attention than normal.                             It is

8    not carefully monitored in a classic sense, and that

9    is about 600 no AV block.                    Then, of course, there is

10   the commercial experience, which, as we all know, has

11   its issues on reporting.                 So those are some numbers in

12   relationship to some of the remarks you make.

13                    CHAIRMAN LASKEY:           Thank you.       Dr. White?

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

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

16                    (Laughter.)

17                    DR. WHITE:          I would like to echo, without

18   repeating the words, what Dr. Krucoff said.                           I think

19   we hold very similar opinions about understanding the

20   magic or the theoretic nice pieces of this procedure,

21   but wondering why the device didn't actually perform.

22                    Could I just ask a specific question about
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1    the IFU, about the instructions for use?                                  Could you

2    clarify for me whether it is possible for this device

3    to be connected to an RF generator?

4                     DR. DESMARAIS:         The answer is no.

5                     DR. WHITE:        Then why did you take the time

6    to write it in here?

7                     DR. DESMARAIS:          I think, you know, you want

8    to address from when we do a risk hazard analysis,

9    which is a technique used in the industry when you

10   look at all the potential hazards.                          By design we've

11   mitigated        that,    but     it's     always         there      and     a     good

12   practice to put all kinds of warnings and precautions

13   to address the risk analysis that you conduct.

14                    DR. WHITE:       Is the criteria for LV ejection

15   fraction being greater than 35 percent, I think, in

16   your       protocol,       is     that       necessary              for    clinical

17   practice?

18                    DR. DESMARAIS:         I will ask Dr. Friedman.

19                    DR.      FRIEDMAN:                 As          a         practicing

20   electrophysiologist,              I    wouldn't           see       that      as     an

21   exclusion.        I think for the purposes of the trial, the

22   intent was to identify healthy patients who were less
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1    likely to have co-morbid conditions.

2                     DR.   WHITE:         How     do    you      feel       about     IVC

3    filters and working through them?

4                     DR. DESMARAIS:         Dr. Friedman?

5                     DR. WHITE:       Is that a problem or no problem

6    for this device?

7                     DR.     FRIEDMAN:            With         other        catheters,

8    radiofrequency           catheters,         we     traverse        IVC     filters

9    without difficulty.                The average dimension in this

10   catheter is really 7 French, the same size.                               I don't

11   foresee a problem.

12                    DR.     WHITE:            And      for      aortic           valves

13   retrograde, do you mean mechanical valves or do you

14   mean a pig valve as well?

15                    DR. FRIEDMAN:          No, we don't think we would

16   advocate         traversing      retrograde         a     mechanical          aortic

17   valve.           Those     patients         would         have     to    be     done

18   transeptally.          But for a porcine prosthetic valve or a

19   native valve, this catheter could be used retrograde.

20                    DR.   WHITE:         Because       the     contraindication

21   simply says any aortic valve replacement, you may want

22   to be more specific about that.
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1                     In the demographics, in slide No. 46 that

2    you showed, it struck me that you had excess of women

3    in the trial.            Is it that women have more of these

4    arrhythmias than men?

5                     DR. FRIEDMAN:          That's a very good question

6    actually, but that mirrors clinical practice.                                 Women

7    present with AVNRT and AVRT more commonly than men.                                     I

8    don't know whether it is a genetic difference or there

9    is     a    difference       in    diagnosis.              Maybe      men     don't

10   complain of palpitation or are less troubled by the

11   palpitation.           There could be a host of explanations,

12   but --

13                    DR.   WHITE:          But     you        would     agree       that

14   percentage would be representative of the clinical

15   practice.

16                    DR.     FRIEDMAN:                I       think        that        is

17   representative of clinical practice.

18                    DR.   WHITE:        And the minorities were not

19   represented in an adequate fashion here.                             I mean, is

20   there a reason why American Indians, Blacks, Hispanics

21   were not represented in percentages that are reflected

22   in our population?
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1                      DR. FRIEDMAN:           I don't have an explanation

2    for that, but I would point out that overall it was a

3    fairly small trial, and you might not expect to see it

4    reflected in those small numbers.

5                      DR. WHITE:        We have heard today, I think, a

6    lot     of       reasons    to    think      that,      because     the     device

7    attaches          and      because      the      device      has     a     smaller

8    footprint, that there may be some theoretical safety

9    benefits, but I am not sure I am convinced that the

10   device has been proven to be safer because it has not

11   been directly compared.

12                     As I think Dr. Page mentioned, I think some

13   of the complications which are not catheter-related

14   certainly appear to be procedure-related.                           And I think

15   that if, as you are comparing the patient who is going

16   to have one or the other of these procedures, those

17   complications need to be taken into account.

18                     The   other       issue       is    that    I    am      not     an

19   electrophysiologist, so I am hearing so much about AV

20   block and how terrible this is with RF, but in the

21   paper that you provided us in the Panel pack, the

22   Calkins paper that looked at the thousand patients
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1    with radiofrequency ablation, the incidence of heart

2    block was only 1 percent in that population.

3                          So I guess I am not being struck with -- I

4    am not convinced that in 151 patients that you have

5    actually convinced me that AV block will happen in

6    less than 1 percent of your patients.

7                          DR. FRIEDMAN:          I think there are a couple of

8    points           to    mention       there.          First      of   all,    if     one

9    actually              does     a    careful        literature        search,        the

10   incidence ranges from 1 percent even to as high as 14

11   percent in some series actually reported from fairly

12   busy laboratories with experienced investigators.                                    So

13   1 percent is probably the lower bound, if you will.

14   It is the best that you would expect.

15                         The other point I would mention is that it

16   does not include patients who were referred for AVNRT

17   ablation, who may get one or two ablation attempts,

18   and then because of proximity to the compact AV node,

19   the procedure is stopped.                       I have seen patients, like

20   every       one        of     us    who     does      these     procedures        have

21   patients like that.                    They don't develop AV block, but

22   they      also         don't       have    a    successful       procedure,         and
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1    they're not reflected in those data.

2                     DR. WHITE:       The other thing I would like to

3    ask you about is in slide 64 and 66, which were the

4    Kaplan-Meier curves for long-term success.                          It appears

5    that the patients drop out of your Kaplan-Meier curve,

6    and it is not clear to me why you haven't retained the

7    patients in the Kaplan-Meier curve.

8                     You've got at six months, for the long-term

9    success of all subjects, 77 patients being measured in

10   the Kaplan-Meier curve, whereas your flow sheet at six

11   months you've got, I believe, 119 patients who were

12   available.        It is slide 64.

13                    DR. FRIEDMAN:          Well, I will see if we can

14   find the slide.           Sixty-four.

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

16   it.

17                    DR. FRIEDMAN:          Right.        So just bring that

18   one up.

19                    DR. WHITE:        You see at six months you have

20   77 patients when in your flow sheet here you have

21   accounted for 119.

22                    DR.   LEHMANN:          First      of    all,    here's        the
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1    three-month point, starting here, and the effect is

2    stable.          This six-month telephone followup, here is a

3    dispersion, because there was a window of following

4    the subjects.                The software, of course, takes the

5    exact number as of the exact point.                            When you do a

6    live      table,       you    take     the    inferred      endpoints.           So

7    you've got all of these subjects with the nominal six

8    months, but in this subject attrition line it stops

9    dead right there, losing -- so that is why you do both

10   of the assessments.

11                    But really with this curve you can see that

12   there has been absolutely no change, and all of the

13   six-month follows are represented, although they don't

14   come to that number.

15                    Have I addressed the question?                 No?

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

17                    (Laughter.)

18                    I mean, how many patients got measured at

19   six months?

20                    DR.     LEHMANN:              A     hundred     and      twenty

21   something.

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

2                       DR.    LEHMANN:          Because if the phone call

3    occurred at six months and one day, then it doesn't

4    show up in that six-month number in the Kaplan-Meier;

5    in the survival analysis it measures every day as a

6    distinct           event.       In     the     life     table   analysis        it

7    measures the increment, the normal increment.

8                       DR. WHITE:        All right.

9                       DR. BAILEY:         So, technically, it shows the

10   status of that patient.

11                      DR. WHITE:         That is not the way I do my

12   Kaplan-Meier             curves.        I    don't     understand     them,          I

13   guess.           Are you telling me that's right?

14                      CHAIRMAN LASKEY:          Dr. Bailey?

15                      DR. BAILEY:        No, in a way, I think you might

16   want to consider interval censoring there.                               If you

17   assume that you don't get recurrence that goes away,

18   if    you        just    assume      that    the     later   time    point      is

19   representative of the earlier time point, you could

20   sort of back it --

21                      DR. WHITE:          I guess I would like to be

22   assured that all of the patients have been followed
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1    and that their events are being accounted for.                                    So

2    when      I      see    40   percent      of     the    patients     not     being

3    accounted for, I am concerned that you are not seeing

4    them.

5                      DR. LEHMANN:         No, I forget the exact number,

6    but      over      95    percent       of      the     subjects    with      acute

7    procedural success were followed.

8                      DR. WHITE:        Right.       Well, no, they are here

9    in your flow sheet.

10                     DR. LEHMANN:         Yes.

11                     DR. WHITE:          And they are identified here.

12   So I am just wondering why they are not showing up.

13                     DR. LEHMANN:            Well, go back to the live

14   table.           Go up to the live table.               I think if you look

15   at the life table, here you see we start with 136, and

16   these are the subjects that are lost.                          So by month six

17   we have lost three out of 136 from analysis.                              There's

18   122 who remain successful --

19                     DR. WHITE:        So does it strike you as strange

20   that your graph doesn't show 122 at six months?

21                     DR.    LEHMANN:           It       doesn't    strike     me     as

22   strange at all.              That is just the way it works in the
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1    two different analyses.

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

3    dumb.

4                     CHAIRMAN LASKEY:              No, Chris, you're just

5    rebelling         against        how      computers         constrain         our

6    thinking.

7                     (Laughter.)

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

9                     DR. WHITE:       Yes.

10                    CHAIRMAN LASKEY:          George?

11                    DR. VETROVEC:          Very briefly, was there any

12   evidence that procedure time got shorter by the number

13   of procedures done?                In other words, in the second

14   half of the study, is the average procedure length

15   less?

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

17                    DR.   VETROVEC:             And     then    in    terms       of

18   training, the observation was made that, "I learned to

19   do a hundred of them and then I could teach the other

20   fellows in four or five procedures."                        What is it that

21   you have to teach them that is unique about this,

22   because this is going to be important, if you come
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1    down to, what do you specify as a training issue?

2    What is it that's different?

3                     Even if you couldn't document a learning

4    curve, there was something, it sounds like, you had to

5    train the other personnel in doing.                        What was it?

6                     DR. DESMARAIS:           I will let Dr. Dubuc answer

7    that, specifically what has to be done for training of

8    the person.

9                     DR. DUBUC:        I think you can call it training

10   or teaching.            People doing this procedure with this

11   new technology, they have to acknowledge that it is

12   different from RF, and that is the only point here.

13                    The thing is, like I said previously, when

14   you do AV nodal reentry ablation and you are going

15   into a slow pathway area, you expect the technology to

16   produce,         when     you     are      successful,        to     do    rapid

17   junctional rhythm.              This you don't have with cryo.                  So

18   this is different.               So the operator has to know more

19   than that; their catheter will stick to the wall,

20   adheres to the endocardial surface.                          So during that

21   time you can do pacing or program stimulation, which

22   you      cannot    do      with     radiofrequency.             So    this      is
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1    different.

2                      And, third, you have the attachments.                        So

3    you cannot move the catheter during the position, and

4    the catheter is very, very stable.                            It will stay

5    there, not like RF, when you have this slippage from

6    the area.

7                      So those are the three main reasons, and the

8    people doing the procedures, they have to acknowledge

9    that it is different from RF from the beginning.                               So

10   it takes time because you change the way you ablate

11   and you make your procedure.

12                     DR. VETROVEC:          I don't disagree with you,

13   but it just is an issue in terms of, how has this been

14   disseminated into the practicing population?

15                     DR. DESMARAIS:         In that respect, I will put

16   up just a few slides.              I don't even need that.

17                     But we believe that through instruction for

18   use, operator manual, and we believe that there is a

19   need for didactic training, as Dr. Dubuc just alluded.

20                     We    will       utilize          skilled       physicians

21   experienced with Freezor to train and initiate at new

22   sites.           We have learned that from our experience in
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1    Europe,          and    we    will     provide        ongoing    support       with

2    clinical support specialists, which we are doing in

3    Europe as well.              We are convinced that this is a need.

4                      DR.    VETROVEC:              Are     you     talking      about

5    physicians proctoring this or are you talking about --

6                      DR. DESMARAIS:           Yes, yes.

7                      DR. VETROVEC:             And how many procedures do

8    you anticipate as necessary?

9                      DR. DESMARAIS:            That is very difficult.               It

10   depends on the site in terms of the volume, the number

11   of physicians.               So it is a very difficult to estimate

12   at this point in time.

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

14                     DR. DULLUM:          You said that in the ice ball

15   you saw after three minutes stayed stable, so that is

16   why you chose four minutes.                           In surgery there is

17   usually a dry field in this aspect that a little bit

18   was talked about, that there is going to be warm blood

19   going by.          So that was monitored, and you still know

20   that at three minutes with warm blood that it stays

21   the same?

22                     DR.    DUBUC:         Well,      we    know   in   a    beating
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1    heart,           which     could         be     different          from     surgery

2    sometimes, in a beating heart we know that it is very

3    stable           after   two     minutes.           Even      if   you    keep     the

4    catheter there for six, seven, or eight minutes, there

5    will be no change.                 But if you go in the preparation,

6    like a fine muscle preparation, you will see that the

7    ice ball will still grow after three minutes.                                      The

8    longer you will keep the catheter there, the bigger

9    will get the lesion, which does not happen, actually,

10   in a beating heart.

11                      DR. DULLUM:           So you basically have a cool

12   sink.

13                      So did I understand that it took an average

14   of seven-and-a-half cryoablation procedure times with

15   your catheter?            Is that the same with RF?

16

17                      DR. DUBUC:           I would say it is about the

18   same, yes.           It is the same range.

19                      DR. DULLUM:          So are you going to recommend

20   that in clinical practice then, when do you know when

21   to stop?           Do you say, okay, after seven-and-a-half or

22   do you just keep going until you get tired or the
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1    patient gets tired?

2                     DR. DUBUC:        I think it is like our effort

3    goes with the clinical judgment.                               I mean, you are

4    doing the procedure and sometimes you know that on the

5    average it will take, four, five, six lesions, but

6    sometimes it takes more.                I mean, even with RF, I have

7    seen cases you do 30, 40 applications.                                So that can

8    happen also with cryo, I imagine.                          I mean, that goes

9    with the clinical judgment.

10                    DR. DULLUM:        And my last question:                     Are you

11   going to recommend that if you go with cryo and you

12   don't ablate, then you switch to RF, or vice versa?                                        I

13   think, as someone said, there was an RF that was not

14   successful and then you used cryo.

15                    DR.   DUBUC:          I   think          we    had      no    safety

16   problems with that in this clinical trial, doing RF

17   after cryo.

18                    DR. DULLUM:       And vice versa?

19                    DR. DUBUC:         Well, we did not -- just to

20   correct, there were no subjects in the study who got

21   RF first.         Everyone, out of 166, 164 had cryo first.

22   Some failed; some succeeded, and some of the failures
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1    were      RF.           Two    of     the     subjects         did       not     have         a

2    cryoapplication; they had RF alone without any cryo

3    following.

4                       We    did     look       at    the     complications,                any

5    measure of adverse events in the group of cryo and

6    followed with RF, and there was no difference between

7    those two groups.

8                       Furthermore,          in      terms        of   the      number       of

9    cryoapplications, either mapping or ablation, they had

10   no relationship with measures of adverse events as

11   well.            So that bears a little bit on some of your

12   questions.

13                      CHAIRMAN LASKEY:              Thank you.          Mark?

14                      DR. HAIGNEY:          Okay, I will be brief.

15                      I am still confused about your indication.

16   You      are      asking       for     an     indication           for      parahisian

17   pathways?          You're not?           Just AV node?

18                      DR.   DESMARAIS:              As   presented           today,        the

19   indications for it --

20                      DR. HAIGNEY:          AV node --

21                      DR. DESMARAIS:           Correct, AVRT indication.

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

2                      DR. DESMARAIS:         Correct.

3                      DR. HAIGNEY:         Okay.     On page 62 of the final

4    report, there is something that really confused me.

5    It said, under adverse events, it says, "Thirty-one of

6    42 Canadian subjects and eight of 124 United States

7    subjects were reported with these AEs."                           Is that what

8    I think it is saying?

9                      DR.    LEHMANN:        We believe that the three

10   Canadian         sites     had    a    very    different         view    of    what

11   constituted an adverse event.                    No, we don't feel there

12   was any -- other than sequelae that would indicate

13   they had had a much different means of accessing the

14   circulation, and I know it was quite consistent across

15   the Canadian sites.                   So we think it is a reporting

16   anomaly.

17                     DR.     HAIGNEY:         Well,      it    is    a     reporting

18   anomaly          with    somebody.          Whether        it    is     with     the

19   Canadians or the Americans, they're not going to say.

20                     Finally, I have one more weird comment to

21   make.              Have     you        considered          as     a      possible

22   contraindication patients with known cryoglobulinemia
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1    anemia?          It just occurred to me over breakfast, and it

2    seems to me that that would probably be -- if you had

3    a patient who had known cryoglobulinemia, that it is

4    probably not the technique you would want to use.                         So

5    I would suggest putting that in as a contraindication.

6                       On the whole, I think the device represents

7    an important contribution potentially to the progress

8    of EP.           It's a niche device, and it doesn't replace RF

9    ablation.           So I am not as bothered by the fact that

10   you didn't make your OPCs.                  I agree that there are no

11   clear device-associated complications.                    So given the

12   fact that this is not replacing RF ablation, I think

13   I'm inclined to be a little more lenient than perhaps

14   Dr. Krucoff.          I usually am.

15                      (Laughter.)

16                      CHAIRMAN LASKEY:            You're not supposed to

17   spill the beans until after the break.

18                      (Laughter.)

19                      We're about to take a short break, following

20   which we will reconvene and do the voting.                   However, I

21   would like to raise one point here in my prerogative.

22                      I think in the future -- and I think it is
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1    unfortunate in this trial, but in the future when we

2    have these sorts of interventional trials requiring

3    prolonged fluoroscopy, we should have some measure of

4    dose.            I think all of the agencies around, there's

5    none that I can think of that should be more aware of

6    patient dose.            Procedures that have up to whatever the

7    estimate is, many, many minutes of fluoro time, that

8    is    not        a    surrogate    for     dose.        I think we should

9    require that of the studies down the road, because we

10   are going to see more and more prolonged laboratory

11   time.            So let's build that into the protocol.                       It

12   might even be a measure of safety as well.

13                        Thank you.     So let's take a 10-minute break.

14    Let's reconvene.              Then we will go over the questions

15   to the Panel and the Panel's preferences.

16                        Thank you again, Panelists, for sticking to

17   the schedule.

18                        (Whereupon, the foregoing matter went off

19   the record at 3:48 p.m. and went back on the record at

20   4:05 p.m.)

21                        CHAIRMAN LASKEY:        Good, thank you.

22                        At this point I would like to proceed with
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1    reviewing the questions put to the Panel, if we can

2    have them up.

3                      As we go through these, I will do my best to

4    summarize points of agreement and disagreement amongst

5    the Panel members.

6                      "The results of this clinical trial were

7    compared          to    objective        performance          criteria,        OPCs,

8    established             for    the      study      for       both    safety        and

9    effectiveness.                The    OPCs     were     determined        from      the

10   radiofrequency ablation medical literature."

11                     The first question to the Panel with respect

12   to safety:             "The safety endpoint was the occurrence of

13   major complications, as defined in the study protocol.

14    The        FDA        interprets         the        definition        of      major

15   complications to include all adverse events requiring

16   treatment         which       occurred       within      seven      days    of     the

17   procedure.             The upper 95 percent confidence bound for

18   the major complication rate was 8.5 percent.

19                     "This       exceeded         the      safety      OPC,       which

20   specified an upper 95 percent confidence bound of less

21   than 7 percent.               Please comment on the following:

22                     "a.     Please discuss whether the results of
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1    the clinical study provide a reasonable assurance of

2    device safety for the intended patient population."

3                      To paraphrase Dr. Bailey, I think that you

4    certainly were roped into these constraints by the

5    OPCs in that there is not a lot of wiggle room in a

6    small study.              One patient either way could have made

7    the difference, and, unfortunately, it didn't work in

8    your favor.

9                      "b.      Please discuss the applicability of a

10   safety           OPC     for    cryoablation           which        was    based      on

11   reported           clinical         experience          with        radiofrequency

12   ablation."

13                     I think that the Panel alluded to this in

14   some of their comments.                   That is basically all we have

15   to fall back on as a benchmark.                         It may or may not be

16   appropriate, but that serves as a benchmark and it is

17   a not unreasonable benchmark.

18                     Question 2, with respect to effectiveness of

19   ablation:              "The device did not meet the effectiveness

20   OPC     for       the     overall       study      population         or    for      any

21   patient subgroup.                   The lower 95 percent confidence

22   bound        for        acute      success        for         the   entire       study
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1    population was 76 percent.                   The OPC for acute success

2    specified a lower 95 percent confidence bound greater

3    than 85 percent.

4                     "a.     Please discuss whether the results of

5    the clinical study provide a reasonable assurance of

6    effectiveness in (a) the overall patient population or

7    (b) in any individual patient subgroup."

8                     I think that both statisticians have spoken

9    cogently to this point.                Again, you are constrained by

10   your boundaries.              One patient either way could have

11   made the difference.                  Again, it's an awfully small

12   study to allow for that kind of non-leeway.

13                    With     respect       to     the     individual     patient

14   subgroups, I think that the Panel has done a good job,

15   as well as the FDA statistician, at pointing out the

16   foibles of doing post-hoc subgroup analysis.                               It's

17   really treacherous, and you really live or die by the

18   limitations of this technique.

19                    "b.    If the clinical trial does not provide

20   enough evidence of effectiveness, please discuss what

21   would be needed."

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

2                      DR. ZUCKERMAN:          Could we, for Question 2,

3    which really gets to the heart of the matter, could we

4    hear from several other Panel members?                          Is there a

5    consensus on this summary as you presented it?

6                      CHAIRMAN LASKEY:           Let's go back to a and b

7    with -- both parts, a and b?

8                      DR. ZUCKERMAN:        Yes.

9                      CHAIRMAN LASKEY:           Okay, well, feel free to

10   chime in, Panelists, if I didn't quote you correctly.

11    Cindy?

12                     DR. TRACY:      I would like to jump in, because

13   this is sort of the crux of the struggle with this

14   thing:           What would it take -- can you construct a

15   study that would look at AVNRT or do the data that we

16   have      --     how   close    are     we    to    defining    safety        and

17   effectiveness in AVNRT?

18                     I have whole issues with the safety, given

19   the way there is such a variance in reporting between

20   the Canadian side, just the variance in reporting in

21   this study.

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

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

3    really 2b?

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

5                     (Laughter.)

6                     CHAIRMAN LASKEY:           Please discuss what would

7    be needed, because we have before us a negative trial.

8                     DR. TRACY:        Dr. Bailey was struggling with

9    this.       Maybe he can struggle some more for me.

10                    DR.   BAILEY:         Well, yes, as a true/false

11   question, the answer is false, but if it's an open-

12   ended question, I mean the data do seem to support

13   efficacy, but only if you look at the strategy of

14   cryoablation with the possibility of RF as a backup.

15   That's to say nothing of the safety, but in terms of

16   efficacy, you get 161 successes out of a 166, which

17   seems pretty reasonable.

18                    DR. WHITE:        Well, but the problem, though,

19   Ken, is that's not what we were being asked to judge

20   because you have no comparer.

21                    DR. BAILEY:       Right, but that's why I say, if

22   it is a true/false question, the answer is false.
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1                     DR. WHITE:         The question is, what Cynthia is

2    asking is, what would it take to make us say that they

3    have satisfied efficacy?                  Is it because there were so

4    few patients that the margins were so narrow and the

5    lower bounds were not met?                        If there were another

6    hundred patients enrolled, would the bounds narrow?

7                     DR. BAILEY:           No, no, I think the OPC as

8    stated doomed them to the result because that was not

9    a quirk of sample size.                   You can't get that high an

10   efficacy with this technique.                        But in terms of the

11   overall clinical application, it's pretty high.

12                    DR. KRUCOFF:          I think that is a really key

13   point.           I think we have actually heard it stated

14   several times, but it seems like when this trial was

15   first        designed,       that      the      catheter       behavior          and

16   performance was expected to be the same as an RF

17   catheter.           Yet,       it   sounds       more      like    the     actual

18   experience that's evolved out of the trial is that the

19   catheter performance may be a little inferior to an RF

20   catheter.

21                    When it is, you can bail out with an RF

22   catheter,         but    the     other      safety         elements     and      the
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1    potential to pre-map and to protect more vulnerable

2    areas, that's what gets actually into an area where

3    you're suggesting a trial design that would look at a

4    potentially              slightly      inferior          efficacy        from       the

5    device, but at least an equivalent behavior in an

6    intention          to     treat,     which      includes       the    RF     backup,

7    where overall the safety would be better.                             I don't see

8    that it would be very complicated to design that kind

9    of a trial.

10                     The trouble is that that's not how that OPC

11   was     designed.            That's,       unfortunately,         I     guess       the

12   question that we're going to be asked today in 2a, and

13   then in the 2, bottom "b," I think it would be pretty

14   straightforward, based on this experience, to see a

15   design           where    you      would      do    an       intention-to-treat

16   analysis          for     efficacy        and      really      concentrate           on

17   safety, and whether these are catheter or dwell time

18   or radiation time safety issues or not.

19                     DR. WHITE:         But without a comparison group,

20   I have a hard time understanding the safety --

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

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

2                      DR. GILLIAM:           I don't think you can see the

3    safety in 150 patients, but I also don't think it

4    would change if they had 650 patients or a thousand

5    patients, because the comparison that we really are

6    talking about is looking at, for instance, use of

7    radiofrequency               in    an    AV   nodal      reentry        group      and

8    skilled operators today.                       I mean your heart block

9    risk, if you will, is something less than 1 percent.

10   I mean it is.

11                     If    we    start      looking       at    the    comp.       we're

12   seeing,          no    one    is    saying     that      there     is    something

13   intrinsically not safe with this catheter.                               I mean we

14   are getting complications because they only had 150

15   patients, and if we probably take 150 patients from

16   any of the procedures, we may have like complications.

17    These are procedure-related but not catheter-related.

18    It may very well have been RF cases we were looking

19   at to get the same type of complications.

20                     I    think       the   reality       is    that       this    is       a

21   procedure that potentially may be less likelihood of

22   creating complete heart block in an AV node reentry
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1    population, and, ultimately, the overall efficacy of

2    this one alone may not be as good, but taken with the

3    option of using RF, it may provide an additional tool.

4                     That's saying a clinical trial -- I'm not

5    sure what we're going to compare it with.                            I think it

6    would be very difficult to provide such a study.                                      I

7    don't see how it could be done easily.

8                     DR. WHITE:       Well, I don't understand why you

9    say      that     because     there      is        a    standard          clinical

10   procedure now to treat these patients.                           So you take

11   the     experimental      procedure,         you       compare       it    to   the

12   standard clinical procedure, you get a comparison.

13                    DR. GILLIAM:        If we were going to replace

14   the procedure, I would agree with you.                           But I don't

15   think that anyone would suggest that cryoablation is

16   intent to replace radiofrequency ablation.                                I think

17   that      that's    where     I    think      it       would    be    difficult

18   because it may very well be that you can go in and

19   just look at RF, you know, first or second.

20                    You may go in with cryo first, and if you

21   find an easy point, you map and you get it right away,

22   then fine, you may just go with it.                            If you need a
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1    bigger lesion, if you will, or you just use RF, I just

2    don't think that you are going to be able to compare

3    one to the other because they're not going to be used

4    the same.

5                      I don't think you're going to replace RF

6    with cryo.              It's a smaller, more discrete lesion.

7    That means that you're likely to have less efficacy, I

8    mean all things being even.                       But, on the other hand,

9    potentially that one or two people that surprise the

10   heck out of you, that when you step on the pedal, they

11   all of a sudden develop heart block, and you jump off

12   the pedal real quick, you know, if you're lucky, as we

13   most of the time, frankly, are -- I mean that we don't

14   get permanent heart block.

15                     But    every      now     and     then     you   look      at    it

16   happen,          and    you   say,     "Oh,      my God, I wish it was

17   reversible."             Maybe this is reversible.                 You know, I

18   don't think they've proved that, but I don't think

19   they've proved that it is any more dangerous.

20                     CHAIRMAN LASKEY:            But, again, we're not here

21   to talk about replacement.                        We have heard the word

22   "supplement" and "adjunct to."                           Whether that lends
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1    itself           to    non-inferiority             versus        class    RCT      is,        I

2    guess,           what       Dr.    Zuckerman         needs       to   know     here      in

3    Question 2b.

4                          DR. VETROVEC:            But let me ask you, if the

5    goal, based on what you say, is to look at this as

6    something to prevent it, then it will become your

7    first choice.                 Otherwise, you're going to have heart

8    block the whole time.

9                          So now you're suddenly substituting this as

10   a first choice, and RF is becoming second choice, and

11   do you know that that's a fair trade?                                    That's what

12   you're suggesting, if you're going to use a hundred

13   times to prevent one or two heart blocks.

14                         DR. TRACY:         Do we have data that -- is there

15   a way to look at this data for non-inferiority?

16                         CHAIRMAN LASKEY:            Which data?

17                         DR. TRACY:         The effectiveness data.

18                         CHAIRMAN LASKEY:               The way I look at this

19   trial, this was a non-inferiority trial.                                   That's the

20   study design to me.

21                         DR.    KRUCOFF:           Well,      it    didn't       make      its

22   boundaries on --
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1                     CHAIRMAN LASKEY:          No, exactly, but --

2                     DR.   KRUCOFF:            It     is      a    negative       non-

3    inferiority on a safety compared to an historical.                               So

4    a classic non-inferiority, this is not a randomized

5    dataset.

6                     DR. TRACY:       Effectiveness, not inferiority.

7                     DR. GILLIAM:          But if we're looking at heart

8    block, let's just look at just heart block.                             Then, in

9    effect, this study doesn't --

10                    CHAIRMAN LASKEY:          We need numbers.             We don't

11   have      numbers      here.        There's       no      precision      of     the

12   estimate,        and    maybe      I    guess,      Dr.       Page,    you    said

13   something during the break about adding some precision

14   to the number.            We know it's not zero.                      Nothing is

15   zero.        But could it conceivably be on the same order

16   of magnitude as RF and is it, therefore, as safe from

17   that standpoint?

18                    DR. PAGE:      Yes, I would just like to comment

19   that, first of all, I think in all fairness, as Rosie

20   Gilliam said, in good hands the risk of heart block,

21   and I would say there are a number of good EPs in this

22   room, and please speak up if your heart block is over
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1    1   percent,          but   most     of    us are less than that, I

2    believe.

3                     That being said, I believe that the cryo is

4    probably as low or lower in terms of heart block.                                       I

5    see this as another arrow in the quiver, if you will,

6    as being supplemental.

7                     In    addition,          one    thing      that    has     to     be

8    mentioned is we've focused on the specific indication

9    for AV nodal reentry, but, in addition, to have this

10   other tool in terms of cryomapping is going to be

11   valuable in a number of circumstances.

12                    If    I    understand          the indication as it is

13   written, we are not limited to the device being used

14   in the AV node reentry for the cryomapping, is that

15   correct?

16                    DR. ZUCKERMAN:            No.    Dr. Page, your comments

17   are     well-founded,          but     I   think      you're       getting      into

18   Question 3.           Perhaps if we could go back to Question 2

19   and take it in an ordered fashion, it will help us

20   decide what the trial showed and what can be done with

21   this device.

22                    I would like, Dr. Laskey, first of all, to
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1    know, for Question 2a, the overall patient population.

2     Is there a Panel consensus as to whether there's

3    reasonable assurance of effectiveness?

4                     DR.    PAGE:            Just       so     I'm    clear,         is

5    effectiveness          only      in    successful          ablation,      having

6    nothing          to    do       with        the       second      indication,

7    effectiveness as a mapping tool?

8                     DR. ZUCKERMAN:          That's correct.          Right.        For

9    acute procedure success; we would all agree that they

10   didn't meet it for the overall patient population.

11                    CHAIRMAN LASKEY:            I think we all agree with

12   that.

13                    DR. ZUCKERMAN:          Good.      Okay.

14                    CHAIRMAN LASKEY:             It would be hard to say

15   otherwise, yes.

16                    DR. ZUCKERMAN:            Now Question 2b asks -- a

17   subgroup analysis was done.                       You've heard multiple

18   comments as to whether or not the subgroup analysis is

19   valid for AVNRT.            It's important for the agency to get

20   a consensus, if there is one, or just a response from

21   the Panel as to the validity of the result, of the

22   effectiveness results for the AVNRT population.
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1                     DR. BAILEY:          I thought your statistician

2    made the excellent point that the OPC was for the

3    overall mixed population, and we don't know what would

4    have been specified, had it been this one subgroup

5    that was recruited.

6                     CHAIRMAN LASKEY:           As a non-expert in this

7    area, though, it did look as though the AVNRT group is

8    the group most likely to do well of the three groups

9    anyway.          So, therefore, the bar would be even higher.

10    So that we would expect this procedure to do better

11   in that group which tends to do better.

12                    So I think that you need to sit down with

13   the applicant and go over the applicability of OPCs.

14   There must be data in the literature on the success

15   rate of AVNRT only rather than all-comers, and that

16   may be helpful, although retrospective still.

17                    DR. ZUCKERMAN:        Okay, that's one way to look

18   at it, but the electrophysiologists here in the Panel

19   have offered the suggestion that these two devices,

20   cryoablation plus RF ablation, could be used in a

21   treatment strategy approach because of a comfort level

22   associated with cryoablation.
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1                     So another approach which is similar, Dr.

2    Laskey, to what we do with guide wires to cross-total

3    occlusions is, if we do believe the first device has

4    some intrinsic merit, might be safer, we may accept a

5    lower success rate with a first device, and then if it

6    doesn't work, you go to your next device.

7                     So    I'm    not     sure      I   have       heard      from     the

8    electrophysiologists that for the subpopulation called

9    AVNRT we necessarily need a higher bar, given the

10   risk/benefit profile.                   Can the electrophysiologists

11   comment?

12                    CHAIRMAN LASKEY:              You don't need a higher

13   bar.

14                    DR.    TRACY:              I'll       speak        now     as      an

15   electrophysiologist, and I would be happy with this

16   level       of   success,        knowing       that         there   are     certain

17   patients with very narrow -- there are some people

18   with very narrow anatomic windows between the slow and

19   fast pathway, that this would be a very nice thing,

20   very stable catheters used.

21                    There would be certain circumstances where I

22   would use this as a first line, and I would be very
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1    comfortable knowing that I had a backup of RF, and in

2    my lab the chance of heart block is less than one-half

3    of 1 percent.             So it's not high, but in those patients

4    that have the funky windows, those are the ones that,

5    if they are going to get into trouble, those would be

6    the     ones       that     would     have     the     problems    with      heart

7    block.           So there's a group of people where this device

8    would have a distinct advantage to use.

9                       So if it is a 91 percent success rate with

10   this device, that's not that far off from reported

11   data on other AVNRT studies, although our success rate

12   is 98 percent.              If I took this catheter and put it in

13   a heart, what my success rate would be -- presumably,

14   it would be better after the tenth case than on the

15   first two or three.

16                      To me, it's in shooting range of what would

17   be acceptable for any device.

18                      DR. WHITE:         But the problem I have is that

19   there is one option to approve this device for -- what

20   is it called when there is a very narrow indication

21   for this, like we use for the atrial septal closure

22   devices?
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1                     MR.    MORTON:          Those       are        HDEs,    and      the

2    population is way --

3                     DR. WHITE:          Right.        Well, you're talking

4    about a very small population that you would choose

5    this device for.           So it would be a very narrow window.

6     But when this device fails, the OPC, the lower bound,

7    then I don't understand how we can say that we're in

8    the neighborhood and we ought to let that go.

9                     I don't see the purpose of the OPC if you're

10   going to ignore the OPC's lower bound.                            I mean, once

11   it is set, once it is agreed and we proceed with that,

12   then I find it a specious argument to work around the

13   number, if the device fails the lower bound.

14                    MR.   MORTON:         I think that's the hardest

15   thing       about      this,    is    that,       obviously,            there's         a

16   patient population who it seems to be a real consensus

17   would benefit from doing cryos first, but if, as a

18   plumber,         I'm   understanding          what        I'm    hearing,       that

19   patient population isn't identifiable upfront.

20                    DR. TRACY:       It is.      In short order it is.

21                    MR. MORTON:         It is?        So when you get into

22   the lab, you can see when the window's --
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1                     DR.   TRACY:        It    is.        Once   you    have      the

2    catheters        in    place     and      you've     done    your    baseline

3    study, then you know who you would pull which catheter

4    out for.         And if you had both available in your lab,

5    you would have a very clear distinction which catheter

6    would be appropriate to use.

7                     In terms of the OPC, I think that the OPC is

8    not appropriate.

9                     DR. GILLIAM:          I agree.           I think that the

10   question isn't -- I think the OPC is a high standard,

11   which is good.

12                    DR. WHITE:       A high standard?

13                    DR. GILLIAM:        I think it's very high.

14                    DR. WHITE:       For AVR?         I mean, I don't think

15   you can -- that's not true.                  I don't know how you came

16   to that conclusion.

17                    DR. WALDO:          You know, I think if you're

18   introducing a brand-new concept -- ablation is not a

19   new concept.           I mean if you're introducing a brand-new

20   concept, if you're doing a mated one, or maybe if

21   suddenly         you're       taking        a     new      technology         and

22   introducing it to a new treatment mode, you have to be
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1    extremely -- well, you should be rigorous always, but

2    this is something very different.                     This is ablation.

3                     We have several tools for ablation.                        There

4    is not just one RF ablation technique.                       There are many

5    RF ablation techniques, from the size of the catheter

6    to cool tip, to, you know, saline irrigation.                               There

7    are all kinds of ways to do these sorts of things, but

8    the concept is clear.               This is a concept of ablation.

9     It's another way to do ablation.

10                    I think we can even get some information

11   from      Dr.    Dubuc,      because       what      if   your      laboratory

12   switched to only --

13                    DR.   WHITE:         Well,      I   don't    think       that's

14   relevant.

15                    DR. WALDO:        I'm going to suggest an answer

16   then.       If you don't think it is relevant, I'm going to

17   think that they decided in their group -- I'm guessing

18   because I haven't talked about it, but they decided in

19   their group that it was worth doing the cryo technique

20   because they found it very, very effective and they

21   found it safe.

22                    DR. WHITE:         I disagree.           He's conflicted.
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1    He's a paid consultant for that company.

2                     DR. KRUCOFF:      I think we've got to recognize

3    that there's a difference between what these numbers

4    are from the study and what these numbers potentially

5    mean when they are applied to a population.                              Kent,

6    please correct me if this wrong, but I think that's

7    really what boundaries are about.

8                     The OPC historical control creates a non-

9    randomized clinical trial venue.                        What that means is

10   that the 91 percent doesn't mean -- I mean it's 91

11   percent for this 130 patients; when you get to 136,000

12   patients, the boundary is what you may see.                          You may

13   see that's 97 percent or the upper boundary or you may

14   see that it's 83 percent or the lower boundary, and

15   that 83 percent, if that's what happens in 136,000

16   patients          compared      to      your        98      percent        with

17   radiofrequency ablation, that is my understanding of

18   what an historical boundary branded number is telling

19   us for application of population.

20                    That's, to me, what is so difficult and what

21   we seem to be wrestling with.                           Ninety-one percent

22   sounds really good, and certainly if it's safer and
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1    there's a population who would benefit from it, you

2    know, that's where the consumer side of a Kent Bailey

3    steps up and says, "Maybe that's what I would like to

4    have used."         But 91 percent is what happens in this

5    130-ish patients.           The boundaries tell us what might

6    happen at 136,000 patients, and that's why if the

7    trial design pays attention to the boundaries rather

8    than to the number -- and somewhere we've got to

9    figure out how to digest that into whether this is

10   just another neat arrow for the quiver or whether what

11   this trial may be telling us by failing its boundaries

12   both in safety and efficacy is that, when you really

13   get out there and start using this thing, compared to

14   what       you're    already       getting        with    radiofrequency

15   ablation in your lab, there's going to be a bigger gap

16   than the 91 percent kind of number indicates.                             That

17   seems to me to be what we are wrestling with.

18                    So we've come full circle.              We basically all

19   agree that they failed to meet all their pre-specified

20   endpoints, and we're not being terribly helpful here

21   to the agency or to the vendor.                    But I would have to

22   say, if we did 136,000 or million, the confidence
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1    limits would shrink.                  They wouldn't stay that way.

2    They would be awfully tight.                       Is that right?              They

3    wouldn't stay where they are?

4                     DR. BAILEY:        The learning curve.

5                     CHAIRMAN LASKEY:             But to get back to what

6    your needs are, you know, the Panel is torn.                              We have

7    a body of scientific evidence before us which meets

8    the     null     hypothesis,        which      has     not   been      rejected.

9    Yet, as clinicians we have a gut feeling that this

10   probably is safe.             If you take out the prosthetist and

11   you take out a few other weird things that can happen,

12   it probably is safe and it probably is effective.

13                    But you're asking us, and we need to qualify

14   that      again    and     again      and     again,       that   we    vote      as

15   clinicians and not as methodologists or statisticians.

16    If you want a positive study, it needs to redone in

17   some manner with a larger sample.

18                    Does that reflect --

19                    DR. ZUCKERMAN:             That's helpful as a start

20   because it helps us through 2a.                      We have a difference

21   of    opinion      as    to    what     the data show in terms of

22   effectiveness right now.
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1                       So then we go to 2b.               Given this difference

2    of opinion, is there any consensus on what would be

3    required in terms of replication of results or new

4    dataset that could help everyone here concerned?

5                       DR. WALDO:        Well, you're not going to get a

6    trial of a thousand patients.                      I mean you know that.

7                       DR. ZUCKERMAN:            No, but I don't think the

8    agency would require a trial of a thousand patients

9    for RF ablation.                I think we have to go through the

10   usual panoply.

11                      One is you always start with a randomized

12   trial.           There's a difference of opinion there.                    But at

13   the other end of the spectrum, do we need another

14   registry experience where we can replicate a number

15   that was developed in a post-hoc analysis to make

16   everyone           feel     that      we've       reached     a     bar    that's

17   acceptable?           I mean there's always a wide range of

18   designs when we're talking about device trials.

19                      CHAIRMAN      LASKEY:          And I, for one, would

20   suggest that.              I think that if post-hoc analysis is

21   all       about       hypothesis-generating,                 then     certainly

22   registry of AVNRT only, which is what the indication
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1    here -- it looks like that's the indication they're

2    going for.          If that's the indication, then a registry

3    of some reasonable number of patients, less than a

4    thousand but greater than a hundred, would answer the

5    question as to the safety and efficacy track record.

6                      I think that we're sort of jumping the gun

7    here.

8                      DR. TRACY:         What registry are we talking

9    about?

10                     CHAIRMAN LASKEY:             A registry such as has

11   been suggested to add to the qualifications of a vote,

12   for example.

13                     DR. TRACY:       You're talking about a registry

14   that this catheter would be entered -- or patients

15   would        be    entered       into      who     had       their   ablations

16   performed with a cryocatheter versus a registry that

17   we would pull out of the shelf in the library and say,

18   let's compare this data to a bunch of AVNRTs?

19                     CHAIRMAN LASKEY:          Prospective.

20                     DR.    TRACY:             We're          talking    about           a

21   prospective though.

22                     DR. ZUCKERMAN:            I would just take a step
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1    back.       I'm looking at the screen, and we've dealt with

2    Question 2a, which suggests that there's a difference

3    of opinion as to effectiveness.                   So then we go to 2b,

4    which is, how much more might be necessary to go to

5    the goal line?

6                     I think it's important for folks on this

7    Panel to understand that it doesn't imply that needs

8    to be a randomized trial.               It doesn't imply that needs

9    to be a single-arm registry.                   We're just looking for

10   ideas here for those who feel uncomfortable with the

11   present dataset, realistic ideas.

12                    DR. KRUCOFF:        I think one thing that has

13   been said a couple of times is that the size of the

14   current dataset plus or minus one or two patients

15   flirts source.         One way to consider going forward, it

16   would seem to me, would be to focus on your indication

17   population and sit down with a calculator and see how

18   many patients enrolled in the identical protocol, but

19   with just that one indication, treated in the same

20   way, could be potentially appended to take away some

21   of the flirtation with the boundaries and really find

22   out whether you're at or better than the boundary or
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1    whether you're not.

2                     DR.      WALDO:          Can      I       ask     a      point        of

3    information?           In terms of safety, we heard that the

4    events, when they adjudicated all the cases, that none

5    of these things were device-related.                              Isn't that my

6    understanding?

7                     Now I understand that there are procedure-

8    related problems in all things, and the real issue,

9    then, if I understand it correctly, is that, is the

10   device indirectly the cause of some of the problems?

11   That's what you're struggling with, is that right?

12                    Because I read through.                   I pulled it out a

13   couple of times, and I read through all the things.                                         I

14   don't       know    how    to    answer       that     because           I'm     not        a

15   statistician, but as a clinician I thought a lot of

16   those things, the countings we see anyway, most people

17   don't look that hard.

18                    I recently sat on an events committee where

19   we     found       some    things       that      were       newly-recognized

20   because they were looking very hard.                             When we started

21   looking at other patients who were not in this kind of

22   study, they found the same thing these other patients
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1    had, a very, very good laboratory.

2                     So I don't know, I would not like to -- I

3    mean, what I hear a couple of things, and I think our

4    Chairman has stated them very well earlier -- I really

5    think there is a comfort level for me, and I'll speak

6    only for myself, about the safety of this device.                                    I

7    think it has a utility.

8                     Then the question is, do we want to just

9    disregard that at this point because it is a small

10   study and there are -- I don't know if I'm using the

11   right term -- secondary concerns because it's not the

12   device per se that has been associated with the safety

13   concerns; it's the procedure, and we don't know if the

14   procedure of the use of the device or if there is

15   something unique about the device and the procedure.

16   My suspicion is that it isn't, but I don't know that I

17   can say.

18                    I don't know if I have made myself clear,

19   but I think we're focusing on numbers, and we're not

20   focusing on what I think is the substance of something

21   that we in electrophysiology deal with a whole lot,

22   and     that's     ablation.         I    think         the   ablation,        the
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1    results of ablation are clear.

2                     For me, a 91 percent and 97 percent and 96

3    percent, it's still an option for a physician and

4    there are times you want to use it.                         That's why I made

5    that remark earlier.               I think that it's an option that

6    I    think       is   legitimate,        and     I   think      the      data      are

7    sufficient to me to suggest that there's an adequate

8    efficacy, and the safety problems that I see here are

9    not      the     kind     problems        --    I    haven't         seen      life-

10   threatening           things.         I've     seen        things      --     you've

11   proselytized          the    most      obvious,        but    someone         had        a

12   problem with a sheath in a diagnostic catheter.                                          I

13   mean those things happen from time to time.                             There are

14   a bunch of other things like that.

15                    So I think the forest and the trees thing

16   here is what I'm talking about.                            I think seeing the

17   forest, I think this is something useful.                            If you look

18   at all the trees, then you haven't got a sense of what

19   the forest is about here.                 That's what I see.

20                    DR. WHITE:        I guess my problem is that they

21   failed on every single boundary.                            They failed every

22   one.       It wasn't like two were good and one was bad,
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1    and shouldn't we overlook that?                         I mean, we're talking

2    about rescuing the --

3                       DR. WALDO:          But you're focusing on efficacy.

4     I mean, I don't think 91 percent and 97 percent is to

5    be     ignored,           but      we're       not     talking         about      life-

6    threatening              rhythms.              We're      not        talking      about

7    something terrible.

8                       I think Dr. Bailey really had a very -- he

9    saw it immediately, and he called it as a consumer,

10   but I think really the approach, if you take the

11   approach if you want to start with cryo, and if it

12   doesn't work, go on to RF, you've got an enormously

13   good success rate.                   I think that is how we think as

14   clinicians.           That's how they did it in the study.

15                      You have to ask yourself then, why do OPC

16   trials at all if you're not going to accept the data?

17                      DR.    WHITE:           I   haven't         thought      about      it

18   forever, but just off the top of my head, I mean if

19   you're breaking new ground, if you bringing in a whole

20   new direction of therapy, if you're introducing your

21   first            implantable          defibrillator             or     your       first

22   bimitricular pacer, talking in my own area of devices,
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1    I think you're breaking new ground.                              But we're not

2    really           breaking    new    ground       in    terms      of     ablation.

3    We're playing with the technology of ablation; that's

4    all.      That's how I see it.

5                       CHAIRMAN LASKEY:            Well, but this is not a

6    510(k) either.              This is a new --

7                       DR. WALDO:       Well, it's not 510(k).

8                       CHAIRMAN       LASKEY:        This       is   a     new    energy

9    source.

10                      DR. WALDO:       I mean, the safety issues to me

11   are not safety issues that are out of my cage; put it

12   that way.

13                      CHAIRMAN LASKEY:          No, I would agree with you

14   that these are procedure-related complications, but

15   these are the chances you take when you do a study.

16   You roll the dice and that's it.                            If you win, great,

17   but in this case they didn't.

18                      But   they're      procedure-related              and     they're

19   often hard to disassociate from any device.                                  It's in

20   the hands of the operator, and there's seven or so

21   variables           that     go    into      procedural          complications.

22   Nevertheless, I tend to agree with you that I think we
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1    do see the forest through the trees, but the trees are

2    awfully big.

3                     DR.   TRACY:          Does     anybody     have     a    rough

4    estimate         of    what     it    would       take    to   achieve         an

5    effectiveness endpoint?                Is it five patients or is it

6    5,000 patients?

7                     DR. PAGE:        If I may just ask, I think it

8    troubles the heck out of me that an OPC trial was done

9    and it failed, but in retrospect I don't think it was

10   the right trial.            I think it was too small, and given

11   what I believe the safety is of this device, then I

12   think the bar was set too high in terms of efficacy.

13                    Then we're looking back at the safety issue.

14    When we dissect out the safety issue, which I think

15   is fair in this case, because one or two going the

16   other       direction     changes       the     whole     result,    when      we

17   dissect out the safety, then it doesn't look like it

18   is the catheter that's responsible for it.

19                    So I feel like I'm totally schizophrenic

20   here because, as a statistician, if I were one, I

21   would not accept what I just said, but as a clinician

22   I think we would be wasting our time to do another
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1    pre-approval           trial    because       I      don't    know     if       this

2    Committee could even figure out what our endpoint was,

3    then much less go through all the time of running a

4    trial.

5                     I think a registry afterwards of this type

6    of patient would be very valuable, the first thousand

7    cases, and really look at it.

8                     DR. ZUCKERMAN:           Right, but the problem is

9    you need the data before approval to label a device

10   for     a    certain     indication.            So    to     respond       to   Dr.

11   Tracy's question, though, I think we need to remember

12   that with the approximate number of AVNRT patients

13   that were in this trial, the lower bound was about 82

14   percent.         So if you were going to do a subsequent

15   trial, where you could accept a lower OPC, for some of

16   the reasons alluded to, you're in the same ball park,

17   not as exactly, as to what was studied, what was

18   retrospectively determined to AVNRT patients, around a

19   hundred or so.

20                    MR.    MORTON:         Dr.       Laskey,     just     a    quick

21   comment:         I know that we're all looking at the same

22   screen, but one thing that I would emphasize that the
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1    agency and the sponsor have come before the Panel to

2    ask     is,      is   there    proof      of    reasonable       safety        and

3    effectiveness?           And that is exactly what I'm hearing

4    you wrestle with.

5                      DR. GILLIAM:         My concern is, just looking at

6    the OPC, I mean I'm not so certain that if we were to

7    do this study with 5,000 patients and it didn't meet

8    the OPC, does it mean that we should not approve the

9    device?          I guess at the end of the day we have to take

10   a vote.

11                     As Dr. Waldo said, I sort of feel that, if

12   you were to say, "Is this device as effective as RF

13   for      ablation,"       then     I    would      probably      say     RF     is

14   probably a little bit better.                     I mean, it's a bigger

15   lesion maybe, and maybe that's why it's better or

16   maybe quicker, whatever.

17                     But is this an effective treatment?                   I would

18   have to say, yes, it's effective.                         Maybe it's not as

19   good as RF, but it's different.                           It's not the same

20   thing.

21                     So I think using the OPC standards we have

22   for RF may not fully be applicable to this type of
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1    therapy.          I mean it's an ablation, but it's different.

2     I mean, maybe the efficacy is not as good, but it

3    doesn't mean that it is still not effective.                            I think

4    that's the distinction that I make.

5                      DR. HAIGNEY:        Would it be possible to have a

6    registry that would be aiming at safety?                        I think it's

7    quite possible that this isn't as good as RF, but RF

8    is darn good and it has been developed over 10-11

9    years.           If it turned out, after looking at a thousand

10   patients, it had an 85 percent success rate, I would

11   say fine, that doesn't bother me because there are

12   certain patients who I want to use it in.

13                     It would bother me, however, if we did a

14   registry and we started getting more heart blocks.

15   Then I would say, well, wait a minute, maybe this

16   isn't the thing I want to try in the area of the AV

17   node.        In a registry, couldn't we design a registry

18   that was a couple hundred patients with the express

19   purpose of being sensitive to detecting AV node block

20   and other -- the sort of device-related complications

21   that we're all --

22                     DR.   WHITE:          If     we     haven't    seen      heart
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1    blocking in over 600 patients I heard, how are you

2    going to find it?             This is going to be very hard to

3    find.

4                     DR. WALDO:     Well, that's terrific.          I don't

5    want to find it.

6                     DR. WHITE:     No, no, no, but I mean for pre-

7    approval.        We already have 600 --

8                     DR. WALDO:     You've only had 150 patients to

9    look at.         You've had 150 European experience.

10                    DR. WHITE:      Well, I would love to see that

11   data.       I would love to see it, but it wasn't presented

12   to us.           So I have 150 patients with a 1 percent

13   incidence.

14                    DR. WALDO:      If the prevalence is zero, the

15   confidence is because the numbers are small, is what

16   we're talking about.

17                    DR. WHITE:      But it would only take one or

18   two patients.         The next two patients have heart block,

19   and all of a sudden --

20                    DR. WALDO:       AVNRT has fewer patients than

21   that, but I think we have to decide what the agenda of

22   the Panel is.          If, ultimately, there's a regulatory
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1    process that's asking a question about an indication

2    based on data, then that's one conversation.

3                     I think you could probably put this catheter

4    in the hands of any of the EP people sitting here, and

5    in about five or ten cases they would know 99 percent

6    of what we have been talking about today, but that's

7    not data.

8                     I think ultimately we have to decide whether

9    there       is   information     here      sufficient      to   support           a

10   regulatory approval and/or indication or not, and if

11   not, then what would provide that, I think is what I

12   interpret to be the part of this question to allude

13   to.

14                    DR. WHITE:     I may be confused, but what I'm

15   hearing from the EP group here is that this may not be

16   as good as RF, but it has a niche.                      But, on the other

17   hand, what the sponsor, I think, asked the FDA was,

18   how could we have this approved that it's at least

19   equivalent to using the guidelines of RF ablation?

20                    We didn't quite hit that, and that is the

21   problem we are struggling with.                         I have sat on a

22   number of these panels, and I'm always startled by the
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1    fact that somehow the studies really never have the

2    power to answer the question you would really like.                                   I

3    think       when    you   go     back      and look at these in the

4    future, you hope that people will do the studies that

5    are going to answers the questions you want or design

6    the question, design the trial to answer the question.

7                     Maybe    it    should       have been designed as a

8    niche device trial in some way rather than the way it

9    is being presented, but somehow the position of the

10   product needs to fit the study that's done, and an

11   adequate         study    ought       to    be     done    to    answer       that

12   question.

13                    DR. KRUCOFF:         Well, the OPC questions are on

14   the safety side that the boundary established tells us

15   that the use of this catheter is not going to do more

16   harm than radiofrequency.

17                    And on the effectiveness side, the other

18   boundary basically tells us that this catheter is at

19   least       as     good   as,     within       a   range,       the   point      of

20   comparison.           The      reality      is     I   think     what    we     are

21   hearing is that clinicians who do these procedures

22   would be happy to have this instrument in their lab,
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1    even if it was not as good as.                   The trouble is that's

2    not what this trial addresses.

3                     Either we have an approval process based on

4    the trial or we have an approval process based on

5    what, unfortunately, may or may not be some degree of

6    bias, having looked at the data as to where you think,

7    in fact, the right trial design might have been, if

8    you were to go backwards.              It's a little head spin.

9                     CHAIRMAN LASKEY:        Does it help the agency at

10   all for the Panel to at least say with some unanimity,

11   I think, that the OPC criteria, these criteria chosen

12   are      not     applicable,      and,      therefore,      need     to     be

13   evaluated in that context?

14                    That gives us the room in which to make a

15   clinically-driven decision rather than the one that

16   we're       agonizing   over,      which      is    our   clinical     horse

17   sense says one thing, but our methodologic rigor says

18   another.         But if we were all willing to discount or to

19   freely acknowledge the known limitations of the OPC

20   criteria as to another device, to this device, that

21   would make us all feel better in terms of our final

22   recommendations.
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1                     DR. WHITE:      I'm not sure I feel guilty about

2    this.         I mean, I'm not the one who choose to do the

3    OPC trial.

4                     CHAIRMAN LASKEY:           No, but having done it,

5    you know, we're trying to be fair here to everyone,

6    and      it      is   fair,     I    think,        to    acknowledge        the

7    limitations of somewhat arbitrary criteria that act as

8    a benchmark, which is a moving target, and perhaps if

9    done in 2003, and not in 1990, would be different.

10                    DR. BAILEY:        But I think the considerations

11   that make people think that it has a niche are the

12   heart block issue and things like that.                      It seems it

13   might theoretically have a better safety profile, but

14   we don't have data --

15                    CHAIRMAN LASKEY:           There are no numbers to

16   support that.

17                    DR. BAILEY:        We don't have enough precision

18   on the thing that gives it the niche that it needs.

19   It has to be better at something.

20                    CHAIRMAN LASKEY:           You keep putting us back

21   in the hole.          We need to get out of the hole.

22                    DR. ZUCKERMAN:           Oh, but that's fair.                    I
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1    think it's fair to summarize there's a difference of

2    opinion          on     Question        2a     and         b   regarding        the

3    effectiveness           shown     presently.           We'll     get    into     it

4    later with the Panel voting, but I'm not sure there's

5    more to say about this question more.

6                     CHAIRMAN LASKEY:            Thank you.        Agreed.

7                     (Laughter.)

8                     There are so many ways to rephrase it.

9                     Question 3, effectiveness in the cryomapping

10   area:            "The     submission          describes         the     use      of

11   cryomapping technology and effectiveness evaluation.

12   Please discuss whether the study results show that the

13   cryomapping technology is effective for use in the

14   intended patient population."

15                    First      of      all,        the        intended      patient

16   population is now AVNRT.                  So to answer that question,

17   we need to delimit the Panel's response to AVNRT, not

18   to AVRT or AF, is that correct?

19                    DR. HAIGNEY:         No, I don't think so.

20                    CHAIRMAN LASKEY:            No?

21                    DR. HAIGNEY:           I believe the indication is

22   for     cryomapping         around      the     AV    node     for     accessory
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1    pathways, as well as AV node reentry.                        Isn't that

2    correct?

3                     DR. WALDO:      No, it says, essentially, says

4    for AV-conducting tissues.               That would include --

5                     DR. ZUCKERMAN:          Dr. Haigney, do you have

6    Section 3 of the label?

7                     DR. HAIGNEY:      Yes.      It says, "Cryomapping of

8    conducting tissue near the AV node."

9                     CHAIRMAN LASKEY:           You're correct.         That's

10   absolutely correct.           That's my misread, uh-hum.

11                    DR. TRACY:      I think that is, in fact, what

12   that      says,    but   when    it    was     asked    earlier    of     the

13   sponsor, maybe that would need to be clarified, but

14   their answer was pertaining to the AV node.                    You could

15   say, well, that is anterioseptal pathways conducting

16   tissue near the AV node.                So that it's not -- if you

17   want to limit this specifically to AV nodes, you have

18   AV nodes or peri-AV nodal tissue, something to more

19   specifically state that.

20                    MR. MORTON:      I have a question.           Shouldn't

21   we be looking at the slides that were presented today

22   by the sponsor and the agency, rather than what was in
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1    the labeling, because this labeling was presented or

2    actually was what was used to start the study, as I

3    understand?         Is that not correct, when we're talking

4    about the indications for use?

5                     CHAIRMAN LASKEY:            I suppose that's a good

6    point, Mike.           We need to make sure we're on the same

7    page.

8                     DR. TRACY:        It's actually on page 4 of the

9    sponsor's         --     the      identification            of    a      variant

10   conducting tissue responsible for SVT using reversible

11   electrophysiologic             cryomapping        of      conducting      tissue

12   near the AV node.              It doesn't really narrow it down

13   any further.           In fact, it broadens it if you consider

14   aberrant conduction to mean accessory pathway.

15                    DR. HUGHES:          To me, that means that you

16   could use it to cryomap accessory pathways where you

17   think there's danger of causing AV block, but not

18   ablate those accessory pathways with the cryoablation

19   catheter.         Just a little bit odd.                  I guess you would

20   pull the catheter out at that point.

21                    CHAIRMAN LASKEY:             Well, that's right.                     I

22   mean that's the problem with the semantics here, and
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1    it does need to be reworded.                  You can't reword it on

2    the fly?         Can we reword it on the fly, because as it

3    is it's not --

4                     DR. GILLIAM:      Did they show that cryomapping

5    was successful at any point for anything?

6                     CHAIRMAN LASKEY:          No, the results were the

7    same with and without.

8                     DR. GILLIAM:       My question, really to be on

9    the other hand, I think I'm kind of liberal with the

10   first area.         As a clinician, I want to go that way.

11   But the second area, I think I might be the guy with

12   the dagger to put into it because I think at that

13   point -- I mean, I haven't seen anything in any of the

14   study, in any subgroup, in any way that suggests that

15   cryomapping has been effective in any way.

16                    DR. HAIGNEY:      Didn't they show that they had

17   a higher percentage of successful burn for efficacy in

18   the sites with positive cryomaps?                       Is that correct,

19   the 95 compared to 67, which they had positive or

20   negative in the seventies if they didn't do a cryomap?

21                    DR. TRACY:      I think the problem was it was

22   more effective than a negative cryomap, but it was
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1    particularly more effective than if you had not done a

2    map.       But if you had done a map in the places where

3    you had not done a map, you might have had further

4    data in one direction or another.

5                      So it was only a piece of the data that was

6    collected,          and     it     was     not     mandatory        to     collect

7    cryomapping.             So it makes it a little hard to say too

8    much definitive about it.

9                      DR. WALDO:          But having more rigorous and

10   selective -- I mean savvy, it would have been really

11   nice to focus specifically on the patient groups of

12   interest, but I think we all know why we would love to

13   have this, if it really works, which theoretically it

14   ought to.

15                     CHAIRMAN       LASKEY:            But     just     to     remind

16   everybody, it was P equals NS.                       I think it was .59 or

17   something from the chi square result, that was just

18   not even close, the efficacy with and without mapping.

19    So they chose to do the analysis and it was way off.

20                     All right, can we move on?

21                     This study did not show it's effective, at

22   least        if     we     talk       about       the       intended       patient
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1    population, which was the chi square that they gave

2    us.

3                     No. 4 -- oh, sorry.              I will read on.          With

4    respect to the training and learning curve, "Acute

5    success rate varied per institution in this study,"

6    albeit the numbers were also variable.                      "Acute success

7    rate      per    institution        ranged       between    zero    and      100

8    percent.

9                     "a.   Please discuss the concept of the site-

10   based and physician-based learning curves."                          Can you

11   go back to A?                  Thank you.

12                    DR. WHITE:       You know, in our world there are

13   roll-ins, and that's how we take care of learning

14   curves with plumbing devices, is we decide how many

15   you need to get comfortable with this, and then you

16   have roll-ins and then you start your pivotal trial.

17   So I think that's the way that you handle a learning

18   curve with any new device, which we all agree is

19   there.

20                    The only question is, how many roll-ins do

21   you need to feel comfortable?                   Three?     Five?    Seven?

22                    DR. WALDO:       But maybe to demonstrate this, I
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1    thought          that     they       admitted         that    they      didn't

2    demonstrate any learning curve.                        The numbers are so

3    small.

4                     DR. WHITE:        But I think it was because they

5    had     multiple        operators       at    the    sites,   and    so     they

6    didn't have numbers -- it kept changing over time,

7    too.

8                     DR. WALDO:          But I don't think there's any

9    question among us that a new device requires some

10   training and some comfortability, and that you don't

11   want to hit the deck with the first time that it ever

12   touches your hand, impacting the safety and efficacy

13   pivotal trial, and that's the purpose of a roll-in.

14   So you get to try it and it doesn't count you if you

15   have a problem until you get comfortable.

16                    CHAIRMAN LASKEY:             So the Panel agrees with

17   the concept of physician-based learning curves.                             What

18   the number is is up for grabs.                      I think we all espouse

19   that.

20                    "b.     All new devices inherently involve a

21   learning curve in their evaluation.                          Please discuss

22   whether the concept of a learning curve, either per
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1    site      or     per    physician,        may     be       considered    in     the

2    evaluation of device safety and effectiveness."

3                     Yes,    it    may    be considered.              Some trials

4    actually do allow for that in terms of looking at

5    roll-in patients and not counting them in a randomized

6    but still analyzing them in the same way.                             So I think

7    we all would agree that they may be considered in the

8    evaluation, and, in fact, should be.                         Roll-in patients

9    should be followed in every detail the same way as the

10   rest of the trial.

11                    "c.     Please discuss whether and/or what type

12   of    physician         training      should      be       required     for   this

13   device if approved."

14                    Here I think there was lots of discussion.

15   So, Cindy, do you want to lead off whatever consensus

16   you took away from the recommendations for training?

17                    DR. TRACY:          I think there has to be some

18   physician training.              I don't know whether that has to

19   be a visitor come to your lab and show you how to use

20   the equipment versus you go and observe the use of the

21   equipment someplace else.

22                    I     think   it    would      be     preferable       to    have
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1    somebody come and train onsite.                        I'm not sure it needs

2    to     be        a   physician.           It    could         be   a     well-trained

3    clinical field engineer or something like that.                                     But I

4    think        there         should       be     some     specific            individual

5    physician training as well as training of the staff in

6    the laboratory on how to use the device correctly.

7                         I   think    I    would hesitate to mandate the

8    specific             number      of    cases     that     would        have       to     be

9    performed with an observer in the lab with you.                                               I

10   think it would depend on the individual expertise of

11   the person learning.

12                        CHAIRMAN LASKEY:          It sounds reasonable.

13                        DR. PAGE:         Will you forgive my addressing

14   Question No. 3 one more time, and just to point out,

15   because I think what we just agreed on wasn't what I

16   remembered               and   isn't     supported        by       the      FDA     slide

17   series?

18                        If I can just draw your attention to slide

19   No. 70, which shows a p-value of .0001 in terms of the

20   analysis of cryomap.                     The overall group -- so the

21   prospectively-defined, overall, no subanalysis group

22   is .001.
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1                     The next slide, 71, points out that it's

2    driven by the AVRT patients, but, in fact, that's

3    where I see the mapping as being useful.                              Actually,

4    that's where the proposed indication is.                             The second

5    proposed indication reads, to my interpretation, and

6    maybe       it   needs     to    be    clarified,         but   reads      to    my

7    interpretation           exactly       the    issue       of    mapping       AVRT

8    around the AV node.

9                     So   it    seems      to     me    that,       at    least      my

10   impression was, we dismissed the idea of cryomapping

11   showing any efficacy, and it seems to me we have both

12   an indication of efficacy on slide 70 and a request

13   for indication for that exact purpose on slide four.

14                    CHAIRMAN       LASKEY:          The      request      for      the

15   indication calls for the identification of tissue.

16                    DR. PAGE:       Right, for mapping.

17                    CHAIRMAN LASKEY:            Period, right.

18                    DR. PAGE:       But, as I interpret that, aren't

19   they talking about parahisian conduction in and around

20   the AV node?

21                    CHAIRMAN LASKEY:            They didn't specify.

22                    DR. TRACY:           It's not specified, and it's
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1    inconceivable that somebody would put in a catheter,

2    map an anterioseptal accessory pathway successfully,

3    pull that catheter out, and put another catheter in

4    and try to get it in the same place.                         I mean it's a

5    can of worms that you open there.

6                     DR. PAGE:      Well, I didn't open it.

7                     (Laughter.)

8                     But   that's      the     request        that     they      have.

9    Indeed, the data are the data.

10                    CHAIRMAN LASKEY:            Lilly, could you help me

11   out here?         What was the results of your analysis in

12   the 2-by-2 table of the outcomes by mapping or no

13   mapping?

14                    DR. YUE:       Okay.     Now please remember we have

15   three       subgroups:          effective,         ineffective,           and     no

16   attempts.         The sponsor combined effective -- sorry,

17   the sponsor combined "ineffective" with "no attempts,"

18   correlated        without       cryomapping,         then    compared           this

19   without          effective         cryomapping            with        effective

20   cryomapping.

21                    Okay,    now    here      the    overall        p-value,        the

22   p-value for the overall analysis is less than .0001,
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1    but you'll see it is driven by 49 AVRT patients.                               This

2    subgroup is not the group that the sponsor is, it is

3    occurring to me, claiming for.                          Instead, the AVNRT

4    group is the only group they are claiming for.                                    We

5    have a concern about this grouping.

6                      DR. GILLIAM:            I think you're asking what

7    ablation --

8                      DR.    YUE:        What      is    the    meaning       of     the

9    comparison?             Why are they grouping "ineffective" with

10   "no      attempts"?             Is     the      subgroup      classification

11   "effective"            versus    "without        effective"       biologically

12   plausible?

13                     It seems if we try to test the impact of

14   effective cryomatching ablation with success, we could

15   compare          the    effective       group       with    the    ineffective

16   group, then use "no attempts" as a control.

17                     Now from here, we can see the acute success

18   rate is 94 percent for effective group.                             It is much

19   better than 50-65 percent for the ineffective group,

20   but the chance of having an effective cryomatching is

21   only 64 percent.             On the other side, if we try to test

22   the impact of our attempt cryomatching on ablation
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1    with      success,      we   could       compare         attempts    with      no

2    attempts.         Attempts include effective and ineffective

3    here.

4                     We   performed      this     study.        Then we found

5    there's no significant difference in ablation acute

6    success between attempt and no attempts.

7                     Now here the p-value is .59 here.

8                     DR. BAILEY:      The point is, if you were doing

9    a randomized trial, it would be use of cryomapping or

10   not using cryomapping.              You can't just take the people

11   that are positive and say, because their success rate

12   is high, that shows that cryomapping is a good thing

13   to do.

14                    DR. WALDO:       You know, this is the problem.

15   We understand the statistic very clearly, and there's

16   no challenge to that.              But the specific thing that we

17   are talking about is very unique.                    What you are trying

18   to do is avoid the his bundle, and I'm not sure they

19   presented that specific data.

20                    We are not talking about ablating -- this is

21   very, very unique, and you can't apply it the same as

22   looking at pathway on the left side with a his bundle.
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1     This       is   a     very     unique      application         where     we     have

2    nothing at the moment to help us, and, fortunately, it

3    is not the most common type of Wolf Parkinson-wide or

4    accessory AV connection problem, but it's very, very

5    real.

6                     The hope is, and maybe we heard some of it

7    anecdotal, unfortunately, here, but the hope is that

8    you can use this cryomapping technique to find the

9    sweet spot and avoid the his bundle and help the

10   patient effectively and safely.                        That is as simple as

11   that.

12                    That's not going to come out of anything we

13   say about the statistics here because it is just not

14   going to.        It's not there.

15                    DR.     TRACY:           It's      also      not    necessarily

16   something that needs regulating.                             This is something

17   that people over time can find out:                          If I attempt, I'm

18   successful, I ablate; what is my success at ablation

19   at that spot?

20                    So I think this is something that you can do

21   with this catheter that is unique.                            You can't do it

22   with anything else, but it doesn't seem to be the make
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1    or break whether this catheter is useful or not.

2                      DR. KRUCOFF:         I think this is also a good

3    illustration of the difference between the data we

4    actually have to discuss and the questions that go

5    through your mind.                 In fact, I think the sponsors

6    during their presentation came up with a discussion

7    that actually the inability to show any effect may be

8    a   great        way   to   show     that it's safe to ablate in

9    certain patients, but while it's a great concept, you

10   know, this trial doesn't give us the basis to address

11   it with data.          I mean it's a great concept.

12                     CHAIRMAN LASKEY:           Frankly, all bets are off

13   with the cryomapping because there was an arbitrary

14   selection criteria that we were not privy to as to who

15   were mapped and who were not.                     It is really difficult

16   to take any lessons home from that.                        I just wish it

17   weren't here, but it's the second bullet in their IFU.

18    So sorry.

19                     Labeling:      "Labeling for a new device should

20   indicate which patients are appropriate for treatment,

21   should           identify     potential         device-related       adverse

22   events, and should explain how the device should be
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1    used to optimize its risk/benefit profile.                                  If you

2    recommend         device       approval,          please       address            the

3    following:

4                     "a.     Please discuss whether the proposed

5    warnings,         precautions,          and      contraindications                are

6    acceptable, based on the study results."

7                     Let's be clear about one thing:                       We're now

8    back to the AVNRT group, is that right, Panel members?

9     Right.

10                    Are     the       warnings,              precautions,            and

11   contraindications            acceptable,          based       on     the      study

12   results?

13                    DR. GILLIAM:          I'm going to go back to my

14   electrocution          question       still.          I    still      have      real

15   issues with that, and maybe I'm not electrocuting a

16   dead horse.        But it is not clear to me how this device

17   can electrocute a patient if it were hooked to an RF

18   generator.         I think if it is possible, then maybe a

19   little sterner warning needs to be connected, because

20   I can't see how you can avoid or prevent me from

21   hooking this device to an RF generator.

22                    DR. TRACY:       I don't think it fits.
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1                     DR. WHITE:        I asked them specifically that.

2                     DR. GILLIAM:         You said they can't do it, but

3    if you're going to be able to record, I assume at some

4    point you record an electrogram from the end of this

5    catheter some way.               That means it's got to plug into

6    your recording machinery you have.                          So at some point

7    there's a pin that gets to my, if you will, Pruca or

8    whatever system you have.

9                     So that would suggest to me that I could

10   plug it into an RF generator, because all I need is

11   one pin.         If that is a significant risk, it may need

12   to be a little bit higher.

13                    I mean I've never seen anything like this in

14   anything         we've     done     other      than        plugging    the      pin

15   directly         into    the    shield,       when     we    went     to   hooded

16   pins --

17                    DR. TRACY:         Well, but I'm not sure, Rosie.

18   You might, then, carry it to the extreme of saying:

19   Don't plug this into the wall because that could be

20   dangerous.

21                    I think the connectors are simply not meant

22   -- they don't fit into an RF generator.
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1                     DR. GILLIAM:          Okay.        I think that's how we

2    ended up with the hooded pins, by the way, so people

3    didn't plug them into the wall.                     But I'm maybe getting

4    a little bit overboard here.                        I just find it very

5    curious.          I    have     never      seen      that    specific        thing

6    written out in any way.

7                     CHAIRMAN LASKEY:           Well, it's certainly a red

8    flag, but can we settle this one more time from the

9    engineer?         Can you explain the physical basis for the

10   inability to make this hazardous connection?

11                    MR. ABBOUD:         Actually, technically, you can

12   connect anything to an RF generator, right?                              You can

13   take any wire and connect it to the RF generator.

14                    The catheter has a tip, a metal tip, and has

15   a wire on it.             And like you said, you can take that

16   wire      and    put     an    adapter        and     put    it    on     the     RF

17   generator,        but     no    electrocution          can   happen.            That

18   catheter is not designed to deliver enough energy, and

19   there is no reference electrode first to connect it.

20   That means someone has to take that catheter, that

21   second end wire, make all the adaptation and put it to

22   the right pin to an RF generator and make it work,
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1    right?

2                      CHAIRMAN LASKEY:             Okay.        All right, and we

3    do have a big warning with a box around it, is that

4    right, in the IFU?

5                      Let me just go back to identify potential

6    device-related adverse events.                      I think Dr. Waldo, in

7    the lead, explained it is very difficult to pinpoint

8    specific device-related AEs when they are procedure-

9    related.           So I might suggest modifying that language

10   to get us off the hook.                       We can't look at device-

11   related AEs unless it's heart block, and that didn't

12   occur.

13                     So other than Rosie's concern --

14                     DR. ZUCKERMAN:            Okay, Dr. Laskey, maybe I

15   can     take       you    and    the     Panel      through     the    labeling

16   because we do need some comment on the big ticket

17   items.           I'm looking at the label which is in Section

18   3, "Indications for Use," Mr. Morton, which is the

19   same as on our slide.

20                     This is the key point.                    The first bullet

21   regarding cryoablation, is that still acceptable to

22   the Panel, and the second bullet should be removed?
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1                     CHAIRMAN LASKEY:          What page are you on?

2                     DR. ZUCKERMAN:          I'm in Section 3, "Labeling

3    of the Panel Pack," and page 2 starts with, "Device

4    description" and then "Indications for Use."

5                     The    "Indications          for         Use"   somehow         got

6    deleted from Question 5, but is our major question

7    here:       Is the device appropriately labeled?

8                     DR. TRACY:        I think it would save a lot of

9    angst simply to remove that second bullet.

10                    DR. ZUCKERMAN:           Okay.       Part "b" would be:

11   "Is        the     Panel        satisfied           with         the      current

12   contraindications?            Should some be removed?                  Are there

13   others that are important?"

14                    DR. TRACY:        Didn't we decide that we could

15   put it through a bioprosthetic aortic valve, so that

16   that slight change in the wording in the retrograde --

17   but then again, why are you going retrograde for the

18   AV node?         I suppose you could, if you were ablating it

19   on the left side.

20                    I mean, it's there.             It's not pertaining to

21   this population, but --

22                    DR. VETROVEC:         If I'm correct, if one reads
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1    the package insert for a porcine bioprosthetic valve,

2    it says it should not be crossed by a catheter, not to

3    say that we haven't, most of us in this room, done

4    that, but --

5                     MR. MORTON:     I think the valve manufacturers

6    would definitely not want you crossing anything across

7    prosthetic valves.

8                     DR. GILLIAM:      Do we have guidance from other

9    like RF catheters and their ablation systems?                                The

10   contraindications, are these substantively different

11   from that in any way?            I guess I'm asking FDA.

12                    DR. EWING:     The indications for all the non-

13   generic-indicated          RF      catheters            include   accessory

14   pathway and adrophobe.

15                    DR. GILLIAM:        I was thinking more of the

16   contraindication, not the indications.                        I mean, the

17   indications I will grant here a specific arrhythmia,

18   but are there any specific contraindications to RF

19   systems?

20                    DR. DESMARAIS:       I can answer that.            We based

21   the contraindication of this indication for use based

22   on prior RF ablation safety and effectiveness data
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1    that we lifted from the FDA website, and this is the

2    model we used to create this impression for use and

3    this labeling.

4                       DR. WALDO:          By eliminating your angst, we

5    eliminated the one potential advantage of this because

6    we haven't had data, and we've made our peace with

7    that, is that what we're saying, unhappily, but that's

8    the way it is?               Is that we're saying?

9                       DR. TRACY:        Yes, that's what that means.

10                      DR. PAGE:        Does everybody agree with that?

11   I    personally          think     that      having      this    as    a   mapping

12   device           for    cryomapping          is     a    potentially        useful

13   indication.

14                      DR. HAIGNEY:         I agree with that.             I think it

15   does require us to have certain amount of faith in our

16   fellow           man   that    they     will      map    and    then    pull     the

17   catheter out, but I don't think -- I think it depends

18   on whether you have a Hobbesian view of man or not.

19                      CHAIRMAN LASKEY:           Again, we're straying from

20   the data.              I think it always helps to go back to

21   homeplate,             and    I    think       we       all    understand        its

22   attractiveness, but we're straying from the data to
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1    support that.          We all know that you're going to do it

2    anyway.

3                     DR.   WALDO:           That's       an    easy    thing       to

4    recommend, a recommendation on how to focus them on

5    identifying a bunch of patients like this --

6                     CHAIRMAN LASKEY:          Yes.

7                     DR.   WALDO:        --    and     giving    us    the    data.

8    That's the one easy thing I think of all the things we

9    talked about so far.

10                    CHAIRMAN LASKEY:          Well, we'll get to that.

11                    Brian, do you want to lead us through the

12   wilderness some more?

13                    DR. ZUCKERMAN:         Okay, now we're dealing with

14   warnings.        Dr. Gilliam has expressed an opinion on one

15   warning.         Are there any other warnings that are of

16   concern here for the precaution section?

17                    DR.     HAIGNEY:                The       cryoglobulinemia

18   contraindication I think should be included.

19                    CHAIRMAN     LASKEY:          I    think    we're     all     in

20   agreement about what not to do.                           There's confusion

21   about what to do, but I think Part a is pretty easy

22   here for the labeling.               Do you agree?          Yes?
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1                       Do we feel the IFU described how the device

2    should be used?               From a technical standpoint, I think

3    so, yes.           Agree?     Good.

4                       Are we awake?

5                       No.   6,    from      a   post-marketing          standpoint:

6    "If you recommend approval, please discuss whether a

7    post-market study should be performed to address any

8    issues that are unresolved, but not essential to the

9    pre-market approval of the device."

10                      DR.   KRUCOFF:            Were     one    to   approve          the

11   device, then one might append a post-market look at

12   the value of mapping, for instance, if it's built into

13   the same device.              That might be --

14                      DR.   WALDO:          Specifically,        the      parahisian

15   mapping.

16                      CHAIRMAN LASKEY:             One might, agreed.               What

17   else one might recommend?

18                      DR. VETROVEC:          Can you look for things that

19   aren't           necessarily      indicated?            If   we   talked       about

20   removing one of the indications, then that wouldn't be

21   a legitimate question to ask someone to do.

22                      DR.   ZUCKERMAN:             I    think    Dr.      Vetrovec's
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1    viewpoint is correct.                    The parahisian question is an

2    important one, but that could be studied in a new IDE

3    study with the intent to get that on the label.                                   We're

4    really           talking     about       some    issues       for      the   intended

5    indication which are not show-stoppers for making a

6    decision          today,      but     would      be    nice       subsequently         to

7    study because there would be utility for having that

8    additional data.

9                       DR. TRACY:            This is a dreadful suggestion

10   because it just goes full circle to where we were

11   earlier in terms of our registry on effectiveness.

12                      DR.     AZIZ:          What        about       monitoring           the

13   instance of heart block that people have spoken about?

14                      CHAIRMAN LASKEY:             Sorry?

15                      DR. AZIZ:         The instance of heart block that

16   people have spoken about?

17                      CHAIRMAN       LASKEY:          Yes,       I   couldn't        agree

18   more.            I am very enthusiastic about -- I would go

19   further than one might.                      I would strongly suggest a

20   prospectively-designed registry, designed for a safety

21   outcome analysis.                I think the efficacy is believed by

22   most,        but     safety         is    the      issue,         if    this      is        a
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1    complementary or an alternative technique.

2                      DR.    ZUCKERMAN:              I     think,     again,        in

3    understanding the nature and intent of post-market

4    surveillance for a problem like complete heart block,

5    which       has    an    extremely        low     incidence,      while      that

6    information might be interesting to clinicians, it

7    would really require several thousand patients perhaps

8    to make a definitive determination.                         That's not the

9    intent usually of post-market surveillance.

10                     What we are asking here is for the intended

11   use indication under study, are there some additional

12   points where we still feel very uncomfortable, not

13   where we still want to dot an "i" rather than get an

14   A-plus-plus on a paper?

15                     DR. GILLIAM:           I think the utilization of

16   cryomapping         even      in    the     AVNRT      patients     could       be

17   effectively shown.              I mean, you could show, when you

18   achieve an effective cryomap in a specific place, I

19   mean in the study here it suggests that it wasn't

20   particularly useful, but I think the data are really

21   suspect because we don't know how those patients were

22   selected or, you know, in any way.                         I think that is
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1    something          post-market       could      be    handled    within        the

2    study population.

3                      DR. BAILEY:       I don't see how you could learn

4    about the efficacy unless you design a study to look

5    at it.           I mean, post-marketing, some people will get

6    cryomapping and some won't, but how do you know, what

7    does that show?

8                      DR. GILLIAM:         I mean specifically design a

9    study to look at that.

10                     DR. BAILEY:       But that's not post-marketing.

11                     DR.   ZUCKERMAN:           Right.        Again, that's a

12   traditional IDE study for a new indication on the

13   label.           Perhaps to put this in perspective and allow

14   the Panel to better appreciate what we're getting at

15   here, if this was a traditional RF ablation catheter,

16   there       wouldn't       be    any     post-market        study     required

17   because, as several people have pointed out, this is a

18   tried-and-true technology.

19                     Is there something unusual here that has

20   been indicated in the dataset about a safety issue

21   that would make you really want post-market data?

22                     CHAIRMAN LASKEY:           The consensus seems to be
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1    no, but --

2                     DR. VETROVEC:           Heart block seems to be the

3    obvious.

4                     CHAIRMAN LASKEY:             Heart block seems to be

5    the obvious one, yes.

6                     DR. BAILEY:         Yes, I think heart block would

7    be --

8                     CHAIRMAN LASKEY:             With due respect to the

9    precision        of   the      estimate,        I    would    think     that         a

10   thousand cases could be done across the country in a

11   reasonable period of time.

12                    DR. BAILEY:         And if the incidence is zero,

13   the estimate will be quite precise?

14                    CHAIRMAN LASKEY:           Yes.

15                    DR. KRUCOFF:         The other part of this is the

16   premise of approval based on current data, because

17   while        device-related           safety        looks     pretty       good,

18   procedure-related safety, if a significant percentage

19   of these procedures end up being bailout RF ablations,

20   you're going to have catheters in the blood -- I mean

21   the      safety,      the     potential         safety       issues    from          a

22   procedural point of view, if this was approved for
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1    use, might well be worth tracking in the post-market,

2    but that begs the question of whether you see the

3    safety issues as sufficient to approve the device in

4    the first place.

5                     So the way this question is stated, it's a

6    little hard to --

7                     DR. TRACY:       Does it make any sense to look

8    at how the catheter is used, how many times it is a

9    bailout for RF versus how many times RF is used to

10   bail out from a cryo?             Is that something that would be

11   -- I know it would be interesting.                       Is it something

12   that's worthwhile?

13                    CHAIRMAN LASKEY:           Or easy to do.         I mean,

14   recording that kind of stuff is just one more thing to

15   record.          Generally, the surveillance studies are just

16   do it and we'll look at the outcomes, but this is yet

17   another iteration.              So it's one more thing to do.

18   It's       getting     closer       to     a    study    than    just       an

19   observational kind of thing.                     I would think it's a

20   good idea, but it just requires one more thing to do

21   and puts the sponsor on the hook for paying for that

22   information.
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1                      DR. KRUCOFF:          I think what we are wrestling

2    are ideas for actually it would just be better studies

3    to do.           Maybe pertinent to the agency's interest, I

4    haven't heard anyone suggest that there's anything

5    about the lesion in animals or the behavior of the

6    catheter, or whatever, that ought to spook us in some

7    way that would make you want to keep watching longer.

8                      I would suggest that the real question here

9    is approval, not sort of unique post-market kind of

10   issues.

11                     CHAIRMAN LASKEY:             So as we get ever closer

12   -- at this point I would like to ask the sponsor -- at

13   this point I would like to ask the agency and then the

14   sponsor          if   they     have     any     additional   comments        or

15   questions before the vote.                   So the agency first?

16                     DR. ZUCKERMAN:           The agency doesn't have any

17   additional comments.

18                     CHAIRMAN LASKEY:             Again, on behalf of the

19   Panel members, I thank the various contributors who

20   have helped us out significantly.

21                     Any final comments from the sponsor?

22                     DR. DESMARAIS:          Yes.
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1                      CHAIRMAN LASKEY:        Brief?

2                      DR. DESMARAIS:       Very brief.

3                      CHAIRMAN LASKEY:        Thank you.

4                      DR. DESMARAIS:       We really appreciate and are

5    fortunate to be here and to present our technology to

6    the Panel.          We are very grateful to the Panel and FDA

7    for their thoughtful comments.

8                      We believe that the risk/benefit profile for

9    this product for this profile is favorable and that

10   the technology will play an important role in the

11   patient care.

12                     Once again, on behalf of CryoCath, I would

13   like to thank the Chairman, Panel members, and ladies

14   and gentlemen for letting us present our technology.

15   Thank you.

16                     CHAIRMAN LASKEY:        Thank you, sir.

17                     Before we proceed with the motion, I would

18   like to ask our industry and consumer representatives

19   if they have any final thoughts, beginning with Mr.

20   Morton.

21                     MR. MORTON:     Just to thank the sponsor for a

22   clear       and    good   presentation          of       data   and    clinical
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1    utility of the device, and thank the Panel.                    This is

2    exactly the sort of decision that the agency needs

3    Panel input on, new technology and the outcomes not

4    being crystal-clear.           So thanks very much.

5                     CHAIRMAN LASKEY:        Mr. Hughes?

6                     DR. HUGHES:       Thank you Dr. Laskey.           Let's

7    see, I know it's late in the day and I would like to

8    be brief, should be brief.                  If it wasn't for spring

9    break, I would have done a three-hour lecture at my

10   institution.

11                    I think that, first of all, I appreciate the

12   presentation by the manufacturer and the FDA, as well

13   as the comments and discussion by my colleagues.                             I

14   think that there were a couple of points that I really

15   would like to highlight some that have come around.

16                    That is one with regards to learning curves

17   and being able to translate whatever level of success

18   the device has to other physicians, other surgeons,

19   and certainly a concern when it comes to the consumer.

20    The consumer I think of as being the patient, as

21   opposed to his or her learned agent; that is, the

22   surgeon or physician.
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1                       I also appreciate the comments of Dr. White

2    having to do with labeling and mechanical valves; that

3    is,      making         sure     that       the    labeling      does      not      say

4    specifically or does not indicate that it might be

5    okay       to      traverse        mechanical          valves,       as    well      as

6    representativeness                     of      any        studies,         minority

7    representation,             gender          representation,          things       like

8    that.

9                       I    think     overall,         though,      this      particular

10   device           does    need     in        some   form       more   study,       more

11   statistical             study     to    assure        its     efficacy      for     the

12   patient.            This particular kind of study or set of

13   studies I would think could take the form of perhaps

14   post-approval studies.                      But, otherwise, I think that

15   from the perspective of alternatives, the consumer/the

16   patient should have alternatives, and in that regard

17   the physician, of course, should have alternatives at

18   his or her disposal.

19                      I    think       that       this     device       conceptually

20   theoretically looks very, very promising, but I think

21   that there are additional studies more specific to the

22   intent as opposed to taking the OPCs and applying
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1    them.       Anyway, more specific studies would be nice and

2    they could take the form of post-approval studies.

3                     Thank you.

4                     CHAIRMAN LASKEY:        Thank you, sir.

5                     I would like to quickly, hopefully, open the

6    public hearing.         Anyone in the audience who wishes to

7    address the Panel on today's topic before we vote?

8                     (No response.)

9                     Thank you.      If not, we will close the open

10   public hearing.

11                    I would like to ask Geretta to read the

12   voting options.

13                    MS. WOOD:    "The medical device amendments to

14   the Federal Food, Drug, and Cosmetic Act, as amended

15   by the Safe Medical Devices Act of 1999, allows the

16   Food         and    Drug      Administration            to     obtain             a

17   recommendation         from     an     expert       advisory     panel       on

18   designated          medical       device         Pre-Market        Approval

19   Applications, PMAs, that are filed with the agency.

20                    "The PMA must stand on its own merits, and

21   your recommendation must be supported by safety and

22   effectiveness data in the application or by applicable
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1    publicly-available information.

2                         "Safety is defined in the Act as reasonable

3    assurance, based on valid, scientific evidence, that

4    the probable benefits to health under conditions on

5    intended use outweigh any probable risks.

6                         "Effectiveness         is        defined     as      reasonable

7    assurance             that    in    a     significant           portion       of      the

8    population the use of the device for its intended uses

9    and     conditions           of    use,    when        labeled,    will        provide

10   clinically-significant results.

11                        "Your recommendation options for the vote

12   are as follows:               approval if there are no conditions

13   attached, approvable with conditions.                             The Panel may

14   recommend that the PMA be found approvable subject to

15   specified            conditions         such     as    physician        or     patient

16   education, labeling changes, or a further analysis of

17   existing data.               Prior to voting, all of the conditions

18   should be discussed by the Panel.

19                        "Not approvable.             The Panel may recommend

20   that the PMA is not approvable if the data do not

21   provide          a    reasonable        assurance        that    the      device       is

22   safe, or if a reasonable assurance has not been given
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1    that the device is effective, under the conditions of

2    use      prescribed,       recommended,           or       suggested     in     the

3    proposed labeling.

4                     "Following the voting, the Chair will ask

5    each       Panel    member       to    present         a    brief      statement

6    outlining the reasons for their vote."

7                     CHAIRMAN LASKEY:            I now ask for a motion on

8    the PMA.         Anyone?     I now ask for a motion on the PMA.

9     May I have a motion?

10                    DR. TRACY:         I am making this motion as an

11   electrophysiologist with the understanding that the

12   reasonable safety and effectiveness of this device has

13   been shown.        I move to approve with conditions.

14                    CHAIRMAN LASKEY:            Is there a second?

15                    DR. GILLIAM:         I second.

16                    CHAIRMAN     LASKEY:          It has been moved and

17   seconded that the motion to approve with conditions

18   move forward.        May I have condition one for the PMA?

19                    DR. TRACY:           The first condition would be

20   some minor modification in the labeling to include

21   cryoglobulinemia               as        a       contraindication                to

22   cryoablation.
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1                      CHAIRMAN LASKEY:           Do we have a second?

2                      DR. GILLIAM:         Second.

3                      CHAIRMAN LASKEY:             Do you need a count for

4    these?           Can we have a hand-raising response to the

5    second,          the    seconding      of    the     first     condition         that

6    Cindy just raised?

7                      All        members            in          agreement            with

8    cryoglobulinemia to be added to the labeling, please

9    raise hands.

10                     (Show of hands.)

11                     It looks like unanimous.

12                     This is new for me, too, Rosie.

13                     DR. KRUCOFF:         Can I ask a clarification, Mr.

14   Chairman?

15                     CHAIRMAN LASKEY:             Yes, I was just about to

16   invite the Panel discussion on this condition.

17                     DR.    KRUCOFF:           Oh,      it     isn't     about        the

18   condition.

19                     CHAIRMAN LASKEY:           Oh.

20                     DR. KRUCOFF:         I am trying to understand what

21   we have moved in terms of the indication for ablation

22   and/or the indication for mapping.
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1                      DR. TRACY:         That's a condition.                  We have

2    moved for, what I was moving to approve was for the

3    condition of ablation in patients with AVNRT.

4                      DR.   KRUCOFF:          And    the       other   one     was     in

5    the --

6                      CHAIRMAN LASKEY:           We had previously agreed,

7    before we got to this point, to strike the second

8    bullet.          Is that correct?

9                      DR. ZUCKERMAN:          Right, but right now we are

10   voting to discuss each condition.                            You're going to

11   vote on each condition of approval, and you're going

12   to put the package together.

13                     So you have started with labeling Condition

14   No. 1, which refers back to cryoglobulinemia.                                     You

15   want to discuss that and have a vote.

16                     DR. TRACY:       We had the vote.            We did vote on

17   that, yes.

18                     CHAIRMAN LASKEY:          We had the vote.

19                     DR. ZUCKERMAN:         Fine.

20                     CHAIRMAN LASKEY:           There didn't seem to be a

21   lot of discussion.

22                     DR. ZUCKERMAN:           Then, Dr. Tracy, Condition
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1    No. 2?

2                     DR.    TRACY:        Condition            No.    2    is    that      we

3    strike the cryomapping from the indication.

4                     CHAIRMAN LASKEY:             Discuss first or before?

5    Yes.      Do we have a second?

6                     DR. GILLIAM:         Second.

7                     CHAIRMAN LASKEY:           We do.

8                     DR. PAGE:       I would just like to state that I

9    think it's useful to have that in there.

10                    CHAIRMAN        LASKEY:             Okay,            there's         the

11   discussion.            Okay, let's vote on the second condition

12   then.

13                    All in favor of striking the second bullet

14   from the current IFU?

15                    (Show of hands.)

16                    One, two, three, four, five in favor.

17                    All against?

18                    (Show of hands.)

19                    One, two, three, four, five against.

20                    DR.    ZUCKERMAN:           Okay,         it's       important        to

21   state who is in favor and who is against the vote for

22   the record.
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1                     CHAIRMAN       LASKEY:           I        have   to      name      my

2    colleagues in public?

3                     DR. ZUCKERMAN:          Yes.

4                     (Laughter.)

5                     CHAIRMAN       LASKEY:           How       about      we    do     it

6    henceforth or do you want another vote?                           Let's do this

7    procedurally correct then.                     Let's just do the hand

8    vote again.

9                     All in favor of Cindy's second condition,

10   which is the elimination of the second bullet?

11                    (Show of hands.)

12                    In favor are Cindy, Dr. Dullum, Kent Bailey,

13   Mitch Krucoff, and Dr. Gilliam.

14                    Okay, and those against this condition?

15                    (Show of hands.)

16                    Drs.    Haigney,       Vetrovec,           Waldo,     Aziz,       and

17   Page.

18                    I've never had to do that.                  All right.           It's

19   five/five.

20                    MS.    WOOD:          If     you      voted        against        the

21   condition, could you please raise your hand again?                                       I

22   missed -- okay.
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1                     CHAIRMAN LASKEY:              One, two, three, four,

2    five.

3                     MS. WOOD:      Okay.

4                     CHAIRMAN LASKEY:          It's five/five.

5                     Okay, is there a third condition?

6                     DR. TRACY:       Yes, a third condition --

7                     DR.   ZUCKERMAN:           Well, we need to decide

8    what's going on with this condition.

9                     CHAIRMAN LASKEY:          Of course.

10                    (Laughter.)

11                    You need a tie-breaker?

12                    DR. ZUCKERMAN:         Yes.

13                    CHAIRMAN     LASKEY:          Well, I vote with the

14   group that recommends striking it.

15                    The third?

16                    DR. TRACY:         I move that a formal training

17   program, the details of which can be worked out at a

18   later date, be part of the approval.

19                    CHAIRMAN LASKEY:          A second?

20                    DR. GILLIAM:        Second.

21                    CHAIRMAN LASKEY:          Thank you.     Do we have any

22   discussion on this one?
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1                     (No response.)

2                     Let's have a hand vote for all in favor of

3    the training criteria to be elaborated subsequently,

4    articulated subsequently.

5                     (Show of hands.)

6                     Drs. Haigney, Cindy, Dullum, Vetrovec -- we

7    have unanimous agreement on this, and I would agree

8    with that, too.           That's the third condition.

9                     Is there a fourth?

10                    DR. TRACY:         Maybe.        I move that there be

11   post-market surveillance to monitor for the incidence

12   of AV block.

13                    CHAIRMAN LASKEY:           May I have a second?

14                    DR. HAIGNEY:        Second.

15                    CHAIRMAN LASKEY:           And a vote?

16                    DR. DULLUM:       Can we have discussion?

17                    CHAIRMAN LASKEY:           Oh, I'm sorry.

18                    DR. DULLUM:         Yes.      I just want to go back

19   to, is that going to require a thousand patients, do

20   we think, and how is that going to be trackable and

21   relevant,        the    less     than     1    percent    incidence       most

22   places?
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1                       CHAIRMAN           LASKEY:           It      depends          on     what

2    happens,          I     guess.          All      right,      surveillance             for       a

3    relatively-rare                 event,        although          not       astonishingly

4    rare, if we think it is on the order of 1 percent?

5                       Kent, what would be a reasonable --

6                       DR. BAILEY:           Well, if it's really 1 percent,

7    then you can never show that it's less than 1 percent.

8     If it's really very low, like one in a thousand, then

9    you     should          be     able     to    show     it       in    a    few     hundred

10   patients.

11                      CHAIRMAN         LASKEY:          And that would be the

12   goal?

13                      DR. BAILEY:           But if it is a percent, then it

14   sounds           like    what        I'm      hearing        is      that      it's       not

15   necessarily any advantage over RF.                                So I think you're

16   really trying to show that it's better, which would

17   lead to, presumably, a lower sample size.

18                      CHAIRMAN LASKEY:               Than the equivalent, yes.

19                      MR. MORTON:             I have a question on this to

20   the       agency,             Dr.       Zuckerman.                   Is     post-market

21   surveillance             actually          not    an    early-warning              system,

22   something that we would look for for an event that we
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1    suspect could happen, an adverse event that we suspect

2    could happen?           In this case, we actually suspect just

3    the opposite?

4                     DR. ZUCKERMAN:         Right.       Again, I think there

5    are two issues.           One, we want to distinguish the need

6    for      post-market       surveillance           versus     the      need       for

7    addressing             interesting            scientific             questions.

8    Certainly, if someone wants to go out and organize

9    this registry of "X" thousand patients to definitively

10   prove that the incidence of heart block is less with

11   one form of therapy than the other, that's a very

12   interesting            scientific        question,          but      it's        not

13   necessarily in the purview of the FDA's post-market

14   authority.

15                    The    agency     would       be    more    interested           in

16   perhaps the following question:                     Perhaps if you add a

17   certain delta to that 1 percent level, and proposed a

18   registry         and     the     incidence          of    heart       block       is

19   unexpectedly a safety problem because it is coming in

20   at 3, 4, 5 percent, but I think one needs to pose the

21   right post-market question here initially:                               What is

22   the question?
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1                     DR. HAIGNEY:         Yes, I think the question is

2    not, is it better than RF ablation?                       I think it is, is

3    it worse than RF ablation?                     So I would be interested

4    if the incidents maybe blocked were 2 percent.                                       I

5    would consider that an important factor that I would

6    want to know before I used the catheter.

7                     DR.   DULLUM:           Well,       wouldn't       it        be     a

8    reportable event anyway, MDR, or not, AV block?

9                     CHAIRMAN LASKEY:              But, Mark, doesn't that

10   presuppose some kind of simultaneous or concurrent

11   control or would you resort back to the literature for

12   comparison?

13                    DR.   HAIGNEY:            I    would      resort        to        the

14   literature.

15                    CHAIRMAN LASKEY:          I mean, I personally don't

16   see what's wrong with a surveillance that looks for

17   the      incidence       of     complete         heart      block        in        "X"

18   consecutive patients undergoing this procedure.                                    I'm

19   not allowed to -- right, but that's my concept of the

20   surveillance; it's not necessarily a study, but it's

21   an observational approach to event-collecting.

22                    DR. HAIGNEY:         We were having trouble trying
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1    to find a number of patients that we want in the

2    registry, and I'm saying that I don't think we need to

3    look for the high standard of less than 1 percent

4    incidence.          Do you see what I'm saying?               I'm proposing

5    a more liberal --

6                      CHAIRMAN LASKEY:            Yes, but my point is we

7    can do better than 150 patients.                       I think we can come

8    up with a better estimate with more than 150 patients,

9    which is exactly what a post-marketing survey would do

10   for us.

11                     DR. HAIGNEY:           If I have learned anything

12   today, Dr. Laskey, it's that we need more than 150

13   patients.

14                     DR. WALDO:        Would it be permissible to use

15   people in other countries or would it only be people

16   in     the       United   States?          My     question    is,    in     this

17   surveillance, would it only be post-marketing in the

18   United States or could they use worldwide information?

19                     CHAIRMAN LASKEY:           You would have to ask the

20   agency for how they would receive that data.

21                     DR.     ZUCKERMAN:             Again,      what     is      the

22   question --
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1                     DR. WALDO:          But you get it much faster with

2    worldwide, the numbers anyway.

3                     DR.    ZUCKERMAN:             Right,        but    what    is     the

4    question being asked?                 The question that we would like

5    to ask is, for the label indication, is there an

6    unusual safety problem that produces heart blocks,

7    say, in 3 percent of patients?

8                     So if you were convinced that outside U.S.

9    data was being utilized, was being obtained in that

10   intended patient population, then, yes, a large simple

11   registry,         both        U.S.     and     OUS     patients,         might      be

12   applicable.             On     the    other      hand,       if    the   OUS     data

13   contains patients who are being treated multiple other

14   indications, it's not going to help us answer the

15   question.

16                    DR. TRACY:           I think that the intent of the

17   condition is to identify an unusually large number of

18   AV blocks, an unanticipated number of AV blocks.                                         I

19   think that right now I'm not certainly prepared to say

20   what that number of patients would be required, but I

21   think we could statistically come up with something

22   that      would    be     a     reasonable         number      of   patients        to
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1    survey for that phenomenon.

2                     CHAIRMAN LASKEY:            Yes, I agree.         I don't

3    think we should be on the hook for the study design

4    and      the     sample    size,      but     I    think   we're     simply

5    recommending that this be an additional condition.                               I

6    think it is designable.                  This is a study which is

7    designable.

8                     DR. WALDO:      So can we move the question?

9                     CHAIRMAN LASKEY:           So, therefore, we need to

10   vote on the fourth condition, which calls for the

11   configuration of a post-marketing surveillance for the

12   event of complete heart block in a sample size to be

13   defined.

14                    May I see all in favor?

15                    (Show of hands.)

16                    Drs. Haigney, Cindy, Dullum, Kent, Waldo,

17   Aziz, Page, and Gilliam.

18                    And those against?

19                    (Show of hands.)

20                    Dr. Vetrovec.       Okay.

21                    DR. VETROVEC:           I guess I am supposed to

22   state why.         My position would be, I think, reflecting
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1    the industry comment, which is we're really doing this

2    because of our interest.                  We don't think there is a

3    problem with heart block.                      We think there's not a

4    problem with heart block, but that's not sort of the

5    spirit of a post-marketing surveillance.

6                     DR. GILLIAM:        But we don't know that there's

7    not, and I think that's why the post-marketing is

8    necessary.         We haven't been presented enough data to

9    show that this is, in fact --

10                    DR.   VETROVEC:           I    would     suggest   you      not

11   suggest that when you're trying to convince some of us

12   that, because you're already off the beam, that may be

13   one of its advantages.

14                    CHAIRMAN      LASKEY:            Okay.       Any     further

15   conditions, Cindy?

16                    DR. TRACY:       Not for me.

17                    CHAIRMAN LASKEY:              So we have a motion.           We

18   have conditions.

19                    DR. ZUCKERMAN:           Okay, so now you're going

20   to --

21                    CHAIRMAN LASKEY:              Do we need to raise any

22   other conditions?            Are there any other conditions that
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1    any other members of the Panel want to raise besides

2    Cindy?

3                     (No response.)

4                     Good.    All right, and I think at this point

5    we're ready to vote on the motion presented, which is

6    to move to approve with the following five conditions:

7                     To add the contraindication that patients

8    with cryoglobulinemia be excluded from consideration

9    for this treatment.

10                    The second condition being that we strike

11   the       second   bullet       on    the      IFU    pertaining        to     the

12   mapping.

13                    The third condition being the establishment

14   of    a     better-articulated           and    more-specific         training

15   criteria, perhaps including the number of cases for a

16   learning curve.

17                    The fourth condition being -- there's only

18   four       conditions        here      --      being      the    post-market

19   surveillance for heart block as a measure of safety of

20   the procedure.

21                    So the one motion with four conditions.

22                    DR.   KRUCOFF:          Do    we    discuss     the     motion
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1    itself?

2                      DR. ZUCKERMAN:           Sure.

3                      CHAIRMAN        LASKEY:          Yes,      we    can,     as     is.

4    That's en bloc now, yes, before we vote.                            Sir?

5                      DR. KRUCOFF:           I would just like, before we

6    vote, to encourage everybody to think about what this

7    vote means beyond just this product, but with regard

8    to    the        process     of    designing        a   trial      prospectively

9    between a sponsor and the agency, and then having to

10   expend this kind of energy to really salvage what

11   amounts to the wrong trial or a trial whose pivotal

12   data suggests the opposite of what you're intuitively

13   inclined to do.

14                     That may well be the right decision for this

15   device, but what it will stop is any ability to answer

16   that question, and whether it will roll over to then,

17   as a precedent, for future studies to leave it to this

18   body to bail out trial designs that don't answer the

19   questions          that     actually       are     brought        forward     as    an

20   indication question, and I'm really concerned about

21   that.

22                     It's really not an issue of whether -- you
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1    know, I don't think there's any question about the

2    diligence with which this trial was done, about the

3    interest          of   the     sponsor        of    bringing        this     device

4    forward, or about the interest and the passion of the

5    investigators who have had their hands on it.                                       In

6    fact,       we're      looking       at     a      very     similar     situation

7    upcoming with a coronary device.

8                      But I really do think that the process of

9    prospectively designing a clinical trial that actually

10   addresses a question that has to do with an indication

11   is a vital process.                If we decide to vote around that

12   today, that there's a bigger issue that impacts by

13   setting that precedent that ultimately this body would

14   be put in a position to suggest to the FDA or for a

15   sponsor to rely on to bail out having done the wrong

16   trial, or whatever, to bring a device forward.                               So I'm

17   really concerned about where we go with this.

18                     CHAIRMAN LASKEY:              I think we all appreciate

19   that.            The reason we're here until six o'clock is

20   because we were giving due diligence to the process

21   and realizing how the serious the task is.

22                     So   it    being      six     o'clock       and     with     those
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1    reminders, let's vote.                 May I see, by a show of hands,

2    all     in       favor   for    approval        with        the   conditions        as

3    enumerated?

4                      (Show of hands.)

5                      In favor for:          Drs. Haigney, Tracy, Dullum,

6    Waldo, Aziz, Page, and Gilliam.

7                      And those against?

8                      Drs. Vetrovec, Bailey, and Krucoff.

9                      How did Dr. White vote?

10                     DR. ZUCKERMAN:          He didn't vote.

11                     CHAIRMAN LASKEY:           He didn't?           He did, but he

12   didn't.

13                     DR. ZUCKERMAN:          But you could guess.

14                     (Laughter.)

15                     CHAIRMAN LASKEY:           Okay.

16                     DR. ZUCKERMAN:           Dr. White, for the record,

17   is no longer present.

18                     CHAIRMAN LASKEY:            So the motion passes by a

19   vote of six to three.

20                     I would like to spend 60 seconds or less for

21   each member of the Panel to please state your name and

22   the reason for your vote, please.                       Dr. Haigney?
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1                     DR. HAIGNEY:         Mark Haigney.           I thought the

2    sponsor showed that the device is safe.                         I think that

3    the      clinical    trial,        as     it    was       designed,     it     was

4    entirely appropriate because of the way this device is

5    going to be used.            I think I'll stop at that point.

6                     DR. TRACY:         Cindy Tracy, and I voted for

7    approval         because     I    think        the    sponsor     has        shown

8    reasonable safety and effectiveness for the device.

9                     DR. DULLUM:        Mercedes Dullum.            I voted for

10   approval because of showing the reasonable safety and

11   efficacy.

12                    DR. VETROVEC:           I voted against because I

13   think that every time we say something is reasonable

14   but it didn't hit the target that the sponsors said

15   they would hit, we're really leaving ourselves open

16   for question as to why we made that decision.                           I'm not

17   comfortable in this circumstance, and would almost

18   like to encourage this as a reason that people really

19   should answer the question that they set out to or set

20   up studies that approach that.

21                    CHAIRMAN LASKEY:              Yes, I think that today

22   this has probably been one of the more difficult sharp
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1    edges to sit on.              We didn't have with support what our

2    clinical intuition suggested.

3                      I    would          strongly        recommend,        just       as        a

4    personal opinion, that we relook at the concept of

5    OPCs.            They're moving targets, particularly in the

6    technologic             arena,          where         things          move      awfully

7    dramatically and they can be better or worse within a

8    six-month period of time as the numbers accumulate.

9    So     I    would       be    wary       of     those        kinds      of    strawmen

10   basically to design a study, and there's nothing like

11   a    good,         old,      randomized,          controlled           trial       that,

12   hopefully,            will        answer       the         question         with     more

13   statistical rigor.

14                     DR. BAILEY:            Kent Bailey.             I voted against

15   approval          based      on    the    evidence          that      was    presented

16   today.            Although        I    think     the       sponsor      demonstrated

17   reasonable            efficacy,         that     is    not       --    although         the

18   device works in a vacuum, you can't look at that in a

19   vacuum.

20                     It's     probably        not        as    efficacious         as      the

21   other conventional approach.                           So, well, maybe it's

22   safer.            Well,      it       didn't    met        the   safety       standard
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1    either.          So we can't really say that it's safer.

2                      But, well, it has less heart block, but we

3    don't have the evidence to show that either.                                    So,

4    potentially it's not as good in any of those three

5    categories.

6                      I also agree with the process question, that

7    this is a bad precedent to set, although I think it is

8    a very promising device and I would have liked to have

9    seen data presented that showed that it was as good or

10   superior in at least one category.

11                     DR. WALDO:            Dr. Waldo.          I voted for.              I

12   would like to just second what Dr. Laskey said.                                       I

13   think he said it succinctly and well after a long

14   afternoon.

15                     I voted for it because I thought that the

16   efficacy          and    safety      was     reasonably       presented         and

17   reasonably demonstrated.                  I really think that it would

18   serve us well to relook at some of the criteria that

19   were the strawmen in this target, the strawmen targets

20   in this study.            Thanks.

21                     DR. AZIZ:        Salim Aziz.          I voted in favor of

22   the      device         because     I    think,       firstly,     it     showed
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1    relative safety and efficacy.                        I think it adds a new

2    way of dealing with a somewhat difficult problem for

3    the       EP       and     people,        and,      hopefully,            with      the

4    surveillance the evidence will bear out the fact that

5    it has a low incidence of problem.

6                       DR. PAGE:         Rick Page.              I was convinced by

7    the evidence that there is reasonable assuredness that

8    this device is efficacious and safe, and I think it

9    will         be       a      useful         tool        to       the       clinical

10   electrophysiologist.

11                      DR.    KRUCOFF:           Mitch      Krucoff.           I     voted

12   against because, while it is obvious that from the

13   user's point of view, this really does look like a

14   promising device, that the lesson we have is that

15   intuition in medicine is a very dangerous direction to

16   follow           exclusively,       and    that's       why     we   do    clinical

17   trials.            In this particular clinical trial, neither

18   the safety or the efficacy data landmarks were hit.

19                      An OPC trial, by and large, we consider to

20   be an easier target to hit than a randomized trial,

21   and that's why I voted against it.

22                      DR. GILLIAM:           Roosevelt Gilliam.                I voted
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1    for the motion, aware that it did not meet the OPC

2    trials of radiofrequency device, a device that has an

3    extraordinarily high standard of success and safety

4    that's been proven over years.

5                       I     recognize       that      this        device,           I    felt,

6    demonstrated it has a reasonable degree of safety and

7    efficacy, although both may be close to, or at least

8    falling          short      of,    the     accepted           radiofrequency,              it

9    provides          a    different       approach          to    a    very      difficult

10   problem.           So it provides an additional tool.

11                      I   think      that     insofar        as       this     is       not   to

12   replace radiofrequency ablation, I think the data so

13   we can have a relative appreciation of its safety was

14   there,           and   I    was    comfortable           with       that      level        of

15   safety.           Thus, I voted for the device.

16                      CHAIRMAN LASKEY:               Mr. Morton, Mr. Hughes,

17   any final words?               No?

18                      DR.     HUGHES:          Yes,     I    have       just        a    quick

19   comment to send out to the manufacturer, and that is,

20   with regards to the post-market surveillance, I feel

21   like in the long run that it will be a good thing for

22   the manufacturer.
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1                     In fact, I think we have been, or the Panel

2    has      been,     somewhat         mild      with         regards    to     those

3    recommendations              with         regards           to       post-market

4    surveillance.            A very thorough kind of post-approval

5    study I think would be in order, including such things

6    as the potential for cryomapping.                          I think that, once

7    again, in the long run this would be beneficial not

8    only to the consumer, to the patient, but also to the

9    manufacturer overall.

10                    There are regulatory kinds of issues that

11   have to be taken care of by the FDA, but that does not

12   preclude the manufacturer from taking additional steps

13   voluntarily, and I want to urge the manufacturer to

14   consider that as it goes forward.

15                    Thank you.

16                    CHAIRMAN LASKEY:              Okay, on behalf of the

17   Panel members, I want to thank the sponsor for a

18   superb presentation and for sitting here with us until

19   this late hour.            Thank you again.

20                    This          concludes            the          report          and

21   recommendations           of    the     Panel      on      PMA   P020045       from

22   CryoCath         Technologies           for       the       Freezor        Cardiac
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1    Cryoablation        Catheter       for     cryoablation    of     cardiac

2    tissue to treat patients with AV tachycardia.

3                     Thank you again, and good evening.

4                     (Whereupon,       the       foregoing    matter         was

5    concluded at 6:06 p.m.)

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