1

                                  FOOD AND DRUG ADMINISTRATION

                            CENTER FOR DRUG EVALUATION AND RESEARCH

                          PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE

                                           Wednesday,
                                         July 19, 2000

                                   Versailles Ballroom I-III
                                      Holiday Inn Bethesda
                                     8120 Wisconsin Avenue
                                       Bethesda, Maryland

                                                                            2

                  IN ATTENDANCE:

                  CAROL A. TAMMINGA, M.D., Chairperson
                  Professor, Department of Psychiatry
                  University of Maryland at Baltimore
                  Maryland Psychiatric Research Center
                  Spring Grove Hospital, White Building
                  Baltimore, Maryland  21228

                  SANDRA TITUS, Ph.D., Executive Secretary
                  Food and Drug Administration
                  Center for Drug Evaluation and Research
                  HFD-021
                  5630 Fishers Lane, Room 1093
                  Rockville, Maryland  20857

                  EDWIN H. COOK, JR., M.D.
                  Director, Laboratory of Developmental Neuroscience
                  Department of Psychiatry, MC3077
                  University of Chicago
                  5841 South Maryland Avenue
                  Chicago, Illinois  60637

                  ABBY J. FYER, M.D.
                  Anxiety Disorders Clinic
                  New York State Psychiatric Institute
                  College of Physicians and Surgeons
                  Columbia University
                  722 West 168th Street, Unit 82
                  New York, New York  10032

                  TANA A. GRADY-WELIKY, M.D.
                  Associate Professor of Psychiatry
                  University of Rochester Medical Center
                  300 Crittenden Boulevard
                  Rochester, New York  14642

                  ROBERT M. HAMER, Ph.D.
                  Associate Professor
                  Department of Psychiatry
                  R.W. Johnson Medical School, D-331 UBHC
                  University of Medicine and Dentistry of New Jersey
                  Piscataway, New Jersey  08854

                                                                            3

                  IN ATTENDANCE:

                  RICHARD P. MALONE, M.D.
                  Associate Professor
                  Eastern Pennsylvania Psychiatric Institute
                  MCP Hanneman University School of Medicine
                  3200 Henry Avenue
                  Philadelphia, Pennsylvania  19129

                  DAN A. OREN, M.D.
                  Associate Professor of Psychiatry
                  Psychiatric Department
                  Yale University
                  9050 Campbell Avenue, Mail Stop 116A
                  West Haven, Connecticut  06516

                  IRENE E. ORTIZ, M.D.
                  Assistant Professor of Psychiatry
                  Veterans Administration Medical Center (116C)
                  1501 San Pedro S.E.
                  Albuquerque, New Mexico  87108

                  MATTHEW V. RUDORFER, M.D.
                  Associate Director of Treatment Research
                  National Institute of Mental Health
                  Division of Services and Intervention Research
                  6001 Executive Boulevard, Room 7163, MSC 9635
                  Rockville, Maryland  20892

                  ANDREW WINOKUR, M.D., Ph.D.
                  Director of Psychopharmacology

                  Department of Psychiatry-NTRTC
                  University of Connecticut Health Center
                  263 Farmington Avenue, MC 1517
                  Farmington, Connecticut  06030-1517

                                                                            4

                  IN ATTENDANCE:

                  Voting Consultants (Cardiology)

                  ROBERT CALIFF, M.D.
                  Professor of Medicine
                  Director, Duke Clinical Research Center
                  2024 West Main Street, Box 31123
                  Durham, North Carolina  27707

                  JOANN LINDENFELD, M.D.
                  Professor of Medicine
                  Division of Cardiology
                  4200 East Ninth Avenue, B-130
                  Denver, Colorado  80282

                  Voting Consultant (Psychiatry)

                  STEPHEN MARDER, M.D.
                  Chief, Psychiatry Service
                  West Los Angeles Veterans Affairs Medical Center
                  Psychiatry Service (116A)
                  11301 Wilshire Boulevard
                  Los Angeles, California  90072

                  Nonvoting Consultant (Cardiology)

                  ARTHUR MOSS, M.D.
                  University of Rochester
                  P.O. Box 653
                  Rochester, New York  14642

                                                                            5

                                        C O N T E N T S

                                                                         PAGE

                  Call to Order and Introductions

                        Carol A. Tamminga, M.D.
                        Chairperson                                         8

                  Conflict of Interest Statement

                        Sandra Titus, Ph.D.
                        Executive Secretary                                10

                  Welcome

                        Russell Katz, M.D.
                        Director
                        Neuropharmacological Drug Products                 12

                  Historical Review and Issues for Today's Discussion

                        Thomas Laughren, M.D.
                        Team Leader
                        Psychiatric Drug Products Group                    14

                  Presentations by the Sponsor, Pfizer,
                  of NDA 20-825, Zeldox
                  (ziprasidone hydrochloride capsules)

                  Safety and Efficacy of Zeldox

                        Edmund P. Harrigan, M.D.
                        Pfizer Global Research and Development
                        Executive Director, CNS Therapeutics           20, 29

                  Schizophrenia and Unmet Medical Needs

                        Daniel E. Casey, M.D.
                        Professor of Psychiatry and Neurology
                         Oregon Health Sciences University
                        Chief of Psychiatry Research
                         Veterans Administration Medical Center            21

                  Questions to the Sponsor                                 69

                                                                            6

                                        C O N T E N T S

                                                                         PAGE

                  Presentations by FDA

                  Introduction

                        Thomas Laughren, M.D.                              91

                  Introduction to QTc Prolongation

                        Arthur Moss, M.D.                                  98

                  Antipsychotics

                        Gregory M. Dubitsky, M.D.
                        Medical Officer
                        Psychiatric Drug Products Group                   109

                  Antiarryhthmics and Other CV Drugs

                        Douglas C. Throckmorton, M.D.
                        Medical Officer
                        Division of Cardiorenal Drug Products             121

                  Antihistamines

                        Badrul Chowdhury, M.D., Ph.D.
                        Acting Medical Team Leader
                        Pulmonary and Allergy Drug Products               134

                  Quinolone Antibiotics

                        Joyce Korvick, M.D.
                        Medical Officer
                        Division of Special Pathogens and
                         Immunological Drug Products                      141

                  Cisapride and Compliance with Labeling Advice

                        Evelyn Rodriguez, M.D., M.P.H.
                        Director
                        Division of Drug Risk Evaluation II
                        Office of Postmarketing Drug Risk Assessment      151

                  Questions to the FDA                                    157

                                                                            7

                                        C O N T E N T S

                                                                         PAGE

                  Open Public Hearing

                        Jacqueline Shannon
                        President, Board of Directors
                        National Alliance for the Mentally Ill            174

                        Shannon Flynn
                        Consumer Member
                        National Alliance for the Mentally Ill            178

                        Rex Cowdry, M.D.
                        Medical Director
                        National Alliance for the Mentally Ill            181

                  Committee Discussion                                    184

                  Vote on Questions                                       261

                                                                            8

             1                       P R O C E E D I N G S        (8:10 a.m.)

             2                DR. TAMMINGA:  I'd like to call this meeting to

             3    order.  This is a meeting of the Psychopharmacological

             4    Drugs Advisory Committee.  The topic of the meeting is NDA

             5    20-825, ziprasidone hydrochloride, as presented by Pfizer.

             6                What I'd like to do first is to welcome the

             7    committee to discuss the material that will be presented to

             8    us over the course of the day, and I'd like the committee

             9    to introduce themselves, please, and to say your name and

            10    your affiliation.

            11                Perhaps we could start with you at the end of

            12    the table, Dr. Moss.

            13                DR. MOSS:  I'm Dr. Moss, Professor of Medicine

            14    and Cardiology at the University of Rochester School of

            15    Medicine and Dentistry.  I've had a longstanding interest

            16    in long QT syndrome, both primary genetic and drug-induced.

            17                DR. CALIFF:  I'm Rob Califf.  I'm a

            18    cardiologist at Duke University and director of the Duke

            19    Clinical Research Institute.

            20                DR. GRADY-WELIKY:  Tana Grady-Weliky, Associate

            21    Professor of Psychiatry at the University of Rochester

            22    School of Medicine and Dentistry.

            23                DR. OREN:  Dan Oren at Yale University and the

            24    Department of Veterans Affairs.  I'm not representing the

            25    Department of Veterans Affairs.

                                                                            9

             1                DR. ORTIZ:  Irene Ortiz.  I'm with the

             2    University of New Mexico and the Albuquerque VA.

             3                DR. FYER:  Abby Fyer from Columbia University.

             4                DR. HAMER:  I'm Bob Hamer from Psychiatry and

             5    Biometrics at UMDNJ.

             6                DR. MARDER:  I'm Steve Marder.  I'm from the

             7    Department of Psychiatry at the UCLA School of Medicine and

             8    the VA Greater Los Angeles Health Care System.

             9                DR. LINDENFELD:  I'm JoAnn Lindenfeld from the

            10    University of Colorado.  I'm a cardiologist.

            11                DR. RUDORFER:  I'm Matthew Rudorfer, Associate

            12    Director for Treatment Research, Division of Services and

            13    Intervention Research, at the National Institute of Mental

            14    Health.

            15                DR. TITUS:  I'm Sandy Titus.  I am with the FDA

            16    and the Advisory Committee staff, and I'm the Executive

            17    Secretary for this committee.

            18                DR. COOK:  Ed Cook from Departments of

            19    Psychiatry, Pediatrics, and Committee on Clinical

            20    Pharmacology at the University of Chicago.

            21                DR. WINOKUR:  Andy Winokur, Department of

            22    Psychiatry, University of Connecticut Health Center.

            23                DR. MALONE:  Richard Malone, Department of

            24    Psychiatry, MCP Hanneman University.

            25                DR. KORVICK:  Joyce Korvick, medical officer,

                                                                           10

             1    infectious disease specialist from Division of Special

             2    Pathogens, FDA.

             3                DR. CHOWDHURY:  I'm Badrul Chowdhury.  I'm with

             4    the Division of Pulmonary and Allergy Drug Products, FDA.

             5                DR. THROCKMORTON:  Doug Throckmorton.  I'm with

             6    the Division of Cardiorenal Drug Products, Food and Drug

             7    Administration.

             8                DR. DUBITSKY:  Greg Dubitsky.  I'm from the

             9    Division of Neuropharmacological Drug Products at the FDA.

            10                DR. LAUGHREN:  Tom Laughren, Neuropharm

            11    Division at FDA.

            12                DR. KATZ:  Russ Katz, Neuropharm, FDA.

            13                DR. TAMMINGA:  And I'm Carol Tamminga, and I'm

            14    the Chair of this committee, and I'm from the University of

            15    Maryland, the Maryland Psychiatric Research Center.

            16                Now our Executive Secretary, Sandra Titus, will

            17    read the conflicts of interest of the committee.

            18                DR. TITUS:  The following announcement

            19    addresses the issue of conflict of interest with regard to

            20    this meeting and is made a part of the record to preclude

            21    even the appearance of such at this meeting.

            22                Based on the submitted agenda and the

            23    information provided by the participants, the agency has

            24    determined that all reported interests in firms regulated

            25    by the Center for Drug Evaluation and Research present no

                                                                           11

             1    potential for a conflict of interest at this meeting with

             2    the following exceptions.  In accordance with 18 USC

             3    Section 208(b), full waivers have been granted to Dr.

             4    Guardia Banister, Dr. Robert Hamer, Dr. Stephen Marder, and

             5    Dr. Andrew Winokur.

             6                A copy of these waiver statements may be

             7    obtained by submitting a written request to the agency's

             8    Freedom of Information Office, located in Room 12A-30 of

             9    the Parklawn Building.

            10                In addition, we would like to disclose that

            11    Drs. Robert Califf, Carol Tamminga, and Stephen Marder have

            12    interests which do not constitute financial interests

            13    within the meaning of 18 USC Section 208, but which could

            14    create the appearance of a conflict.  The agency has

            15    determined, notwithstanding these interests, that the

            16    interest of the government in their participation outweighs

            17    the concern that the integrity of the agency's programs and

            18    operations may be questioned.  Therefore, Dr. Tamminga and

            19    Dr. Marder may participate fully in today's discussions and

            20    vote concerning Zeldox.  Dr. Califf may participate in the

            21    discussions.  However, he is excluded from any vote

            22    concerning Zeldox.

            23                With respect to FDA's invited guest, Dr. Arthur

            24    Moss has reported an interest which we believe should be

            25    made public in order to allow the participants to

                                                                           12

             1    objectively evaluate his comments.  Dr. Moss has been asked

             2    to consult with Eli Lilly on Zyprexa regarding QT wave

             3    prolongation.  He will receive nominal compensation for his

             4    consulting.

             5                In the event that the discussions involve any

             6    other products or firms not already on the agenda for which

             7    an FDA participant has a financial interest, the

             8    participants are aware of the need to exclude themselves

             9    from such involvement, and their exclusion will be noted

            10    for the record.

            11                With respect to all other participants, we ask

            12    in the interest of fairness that they address any current

            13    or previous financial involvement with any firm whose

            14    products they may wish to comment upon.

            15                DR. TAMMINGA:  We'll start our meeting with a

            16    welcome by Dr. Russell Katz, who is the Director of the

            17    Neuropsychopharmacology Drug Products.

            18                DR. KATZ:  Thank you.  I really just want to be

            19    very, very brief and welcome you back again.  We have a

            20    very long program, as you can see.

            21                PARTICIPANT:  We can't hear.

            22                DR. KATZ:  I gather you still can't hear me. 

            23    Is that correct?

            24                Anything now?

            25                PARTICIPANT:  Getting better.

                                                                           13

             1                DR. KATZ:  Better.  Anyway, I just really

             2    wanted to welcome you.  We brought you back again to deal

             3    with an interesting and a particularly thorny problem, in

             4    particular the meaning of a particular degree of QTc

             5    prolongation.  We know that the range of opinion on these

             6    matters is wide, ranging from folks who believe that any

             7    prolongation is problematic to those who feel that maybe

             8    there's a threshold below which we don't have to really

             9    worry too much, and I'm sure the range of opinion varies

            10    beyond that as well.

            11                We also know that the definitive evidence that

            12    we would like to have to be able to address the clinical

            13    meaning of this is not available, so it's in that context

            14    that we come to you for your comments and your advice and

            15    guidance on what you think we ought to do in this

            16    particular case.

            17                Having said that, I'd just like to welcome

            18    folks again.  In particular, I'd like to welcome our

            19    invited consultants who we've asked here to add their

            20    particular expertise to the discussion, Drs. Califf,

            21    Lindenfeld, Marder, and Moss; and in particular also, our

            22    FDA colleagues from other divisions who are here to present

            23    to you how the agency has dealt with this problem across a

            24    wide span of drug products.

            25                In addition, we have five new members of the

                                                                           14

             1    committee we'd like to welcome in particular.  Hopefully,

             2    this will be the beginning of a long and fruitful

             3    relationship with the Division.

             4                With that, I will turn it over to Tom Laughren,

             5    who will give the introductory remarks.

             6                DR. TAMMINGA:  We've been informed that they

             7    still can't hear in the back.  So Sandra Titus has asked us

             8    to wait a minute.

             9                If I could have your attention, the problem is

            10    actually -- it's determined that the problem is with these

            11    table microphones, but not with the podium microphones.  So

            12    that gives us license to move ahead with Dr. Thomas

            13    Laughren's presentation, who is the team leader for the

            14    Psychiatric Drug Products Group, who will go to the lectern

            15    and present the historical review and issues for today's

            16    discussion.

            17                Dr. Laughren?

            18                DR. LAUGHREN:  I'd like to also welcome

            19    everyone to the meeting today.  My comments are also going

            20    to be fairly brief.  Basically, what I'd like to do is to

            21    give a little bit of an historical perspective so you can

            22    understand how it is we got here today.

            23                If I could have the first slide?

            24                This NDA was submitted in March of 1997, and

            25    there was a non-approval letter sent in June of 1998.  I'm

                                                                           15

             1    reading directly from that letter.  The non-approval action

             2    was based on "the judgment that ziprasidone prolongs the

             3    QTc and that this represents a risk of potentially fatal

             4    ventricular arrhythmias that is not outweighed by a

             5    demonstrated and sufficient advantage of ziprasidone over

             6    already marketed antipsychotic drug products."  So that was

             7    the basis for the non-approval action.

             8                If I could have the next slide?

             9                That judgment was based on findings in the

            10    short-term, fixed-dose, placebo-controlled Phase II/III

            11    studies of a dose-related tendency for ziprasidone to

            12    increase the QTc.  The size of that QTc increase was judged

            13    to be, compared to placebo, about 10 milliseconds in the

            14    160 milligram per day dose, which was the top recommended

            15    dose.

            16                An additional concern at that time was that

            17    that 10 millisecond increase may be an underestimate of the

            18    effect given the likelihood that the EKGs in those studies

            19    were probably obtained at trough, or at some time other

            20    than Cmax.

            21                Next slide, please.

            22                Now, the letter went on to talk a little bit

            23    about the issue of the extent of the prolongation and

            24    expressed the view that the size of the QTc increase is

            25    probably a factor in determining the degree of risk of

                                                                           16

             1    ventricular arrhythmias.  Again, I'm reading directly from

             2    that letter.  It suggested that "we would find QTc

             3    prolongation at maximum blood levels in the 5-10

             4    millisecond range, with adequate assurances that there are

             5    very few outliers and that there are no factors that lead

             6    to substantially greater values in individuals (such as

             7    drug-drug interactions) sufficiently reassuring, in the

             8    absence of contrary evidence, to support the approval of a

             9    new antipsychotic such as ziprasidone."

            10                Next slide, please.

            11                The letter went on to recommend that the

            12    sponsor do an additional study to determine the QTc effect

            13    of ziprasidone at peak plasma concentrations in comparison

            14    with other atypical antipsychotics and with several

            15    standard antipsychotics.

            16                Next slide, please.

            17                Over the next few months, we worked with the

            18    company to design a study.  That study was Study 054.  It

            19    has been completed, and you will hear a lot more about that

            20    today.  But basically, that is a study that looks at

            21    ziprasidone at its optimal dose in a head-to-head

            22    comparison with other antipsychotics at their optimal

            23    doses.  The other drugs include two older drugs,

            24    haloperidol and thioridazine, and the three newer

            25    antipsychotics, olanzapine, risperidone, and quetiapine.

                                                                           17

             1                The EKGs in this study were done at the

             2    estimated Tmax for each drug.  So the timing was worked out

             3    exactly for each drug.  There was also a phase in Study 054

             4    adding metabolic inhibitors to determine the additive

             5    effects on the QTc under the conditions of maximal

             6    inhibition of clearance of each of those drugs.

             7                Next slide, please.

             8                Basically, the point I want to make in this

             9    slide -- again, you're going to hear a lot more about the

            10    details of this study -- is that we are in agreement with

            11    the company on the basic outcome, and that is the

            12    positioning of ziprasidone relative to the other drugs in

            13    terms of QT prolongation.  That is basically that

            14    ziprasidone had an approximately 10 millisecond greater

            15    effect than that observed with four of the other drugs,

            16    with haloperidol and the three atypical antipsychotics, and

            17    an approximately 10 millisecond lesser effect than

            18    thioridazine.  So it was right in the middle.

            19                What was not clear to us was how to interpret

            20    the apparent increase from baseline for the other drugs,

            21    for haloperidol and the three atypicals.  There was no

            22    placebo in the study for comparison.  The reason that we

            23    tend to perhaps doubt that the change represents a real

            24    change for the other drugs is that in many other studies in

            25    which haloperidol has been the active control, we've seen

                                                                           18

             1    no difference at that same dose between haloperidol and

             2    placebo on the QT.  But this is an issue that I think we'll

             3    have some additional discussion about over the course of

             4    the day.

             5                Next slide, please.

             6                Other areas of agreement.  We are in agreement

             7    with the company that they have demonstrated that

             8    ziprasidone has an antipsychotic effect.  This is based on

             9    both the short-term fixed-dose studies, and also one

            10    longer-term study.  However, it's important to note that

            11    there's no evidence from these trials that ziprasidone has

            12    a superior antipsychotic efficacy to these other drugs.

            13                We also are in agreement that the other risks

            14    associated with ziprasidone can be handled in labeling and

            15    would not be a barrier to approvability.

            16                Next slide, please.

            17                I want to comment briefly on the consult from

            18    the Cardiorenal Division.  We asked them to review Study

            19    054 and its findings, and they did.  They reached a

            20    conclusion that the greater QTc effect for ziprasidone

            21    predicts excess risk of potentially fatal ventricular

            22    arrhythmias, and they went on to recommend that without a

            23    demonstrated greater benefit, they would recommend either

            24    non-approval of this application or a second-line status.

            25                Now, I want to point out that clearly that's

                                                                           19

             1    one of several conclusions one might reach from that study. 

             2    The Division and the Office have not yet reached a

             3    conclusion on this matter, and it's precisely for that

             4    reason that we're bringing it to you to get your advice.

             5                Next slide, please.

             6                The program for today's meeting will, first of

             7    all, include a presentation by Pfizer.  They're going to

             8    give a brief overview of the overall safety and efficacy of

             9    ziprasidone, clearly with an emphasis on the QTc findings. 

            10    FDA's presentation will follow.  That will focus

            11    exclusively on the QTc issue.  What we're going to try to

            12    do is review the CDER experience with drugs that have this

            13    problem, and then you'll have a chance to discuss those

            14    issues.

            15                Is there a final slide?  Okay, go ahead.

            16                Our questions for you will be the questions

            17    that we always ask about the overall safety and efficacy of

            18    the application.  In particular, of course, here we're

            19    concerned about the relevance of the 10 millisecond

            20    prolongation in the QTc observed for ziprasidone and not

            21    seen for several other drugs in Study 054 on the

            22    approvability decision for this drug.

            23                I'm going to stop at this point, but I will be

            24    returning just before the FDA presentation to talk in a

            25    little bit more detail about what we hope to accomplish in

                                                                           20

             1    the FDA presentation, and also I want to talk in more

             2    detail about some additional questions beyond the two

             3    general questions that we'd like the committee to address. 

             4    I'm going to stop at this point.

             5                DR. TAMMINGA:  Thank you, Dr. Laughren.

             6                Now we will begin the Pfizer presentation, and

             7    the Pfizer presentation will begin with Dr. Ed Harrigan,

             8    who is the Executive Director of Pfizer Global R&D, CNS

             9    Therapeutics, who will talk about the safety and efficacy

            10    of Zeldox.

            11                DR. HARRIGAN:  Thank you and good morning, Dr.

            12    Laughren, Dr. Katz, Dr. Tamminga, members of the committee,

            13    and FDA staff.  My name is Ed Harrigan, and I'll be

            14    introducing the sponsor's presentation today.

            15                But before beginning the presentation, I'd like

            16    to introduce to the committee the consultants who have

            17    helped us to understand the issues with ziprasidone and who

            18    were able to be here today to help us to address your

            19    questions.

            20                What follows on the next slide is an outline of

            21    our presentation, which we've divided into six sections. 

            22    As Dr. Laughren has pointed out, the Division and the

            23    sponsor agree that the efficacy of ziprasidone has been

            24    demonstrated in the NDA.  So I'll spend more time reviewing

            25    the effect of ziprasidone upon the ECG.  To provide some

                                                                           21

             1    context for judging the clinical significance of this

             2    effect, I will contrast it with terfenadine and cisapride. 

             3    I'll then review the clinical safety experience to date

             4    with ziprasidone and close with a review of the favorable

             5    effects of ziprasidone compared to other antipsychotics on

             6    three well-established cardiovascular risk factors: 

             7    namely, body weight, lipids, and diabetes.

             8                Before beginning the review of the benefit/risk

             9    of ziprasidone, Dr. Daniel Casey of the Oregon Health

            10    Sciences University and Portland VA Medical Center will

            11    describe for the committee the unmet medical need which is

            12    currently recognized by patients, caregivers, and

            13    prescribers who are confronted with this illness.

            14                Dr. Casey?

            15                DR. CASEY:  Thank you, Dr. Harrigan.  I

            16    appreciate the opportunity to meet with the committee today

            17    and the agency to briefly provide an overview of the key

            18    issues about the epidemiology and unmet treatment needs for

            19    schizophrenia.

            20                There are three points I'd like to make about

            21    the epidemiology.  First, that schizophrenia is a highly

            22    prevalent disorder.  It occurs in 1 percent of the

            23    population throughout the world.  Thus, approximately 3

            24    million people in the United States suffer from this

            25    illness.  It accounts for 25 percent of all hospital bed

                                                                           22

             1    days in the U.S.

             2                Secondly, this is a difficult and challenging

             3    disease to treat.  Twenty to 30 percent of our patients

             4    respond poorly or not at all to our current pharmacopeia

             5    for the treatment of this illness.  We have distressingly

             6    high relapse rates.  Twenty percent of patients will

             7    relapse while they continue to take their medicine, and for

             8    those who discontinue their medicine, 70 percent will

             9    relapse within one year.

            10                We also have disturbingly high non-compliance

            11    rates.  Forty percent of patients are not taking their

            12    medicines as prescribed at six months.  Finally, we have

            13    adverse effects that are affecting compliance and outcome. 

            14    The old drugs, called the typical antipsychotic agents,

            15    primarily had neurological side effects affecting the motor

            16    system, and the new compounds bring an additional side

            17    effect profile, affecting weight and metabolic parameters.

            18                Finally, the third point is that schizophrenia

            19    is a highly lethal illness, and this is much under-

            20    appreciated.  Patients with schizophrenia die at excess

            21    rates of natural diseases such as cardiovascular illness,

            22    and they die at excess rates from unnatural causes such as

            23    suicide, where 10 percent of patients with schizophrenia

            24    commit suicide.  So it is clearly a highly lethal illness.

            25                The typical neuroleptic drugs -- haloperidol or

                                                                           23

             1    Haldol, chlorpromazine, thorazine, thioridazine, Mellaril

             2    -- have been the mainstay of treatment for the past several

             3    decades.  Their efficacy was better in treating the

             4    positive symptoms of schizophrenia -- hallucinations,

             5    delusions, disorganized thinking -- and they were less

             6    effective in treating the negative symptoms of withdrawal,

             7    apathy, and anergia.

             8                Additionally, they had the neurological

             9    syndromes as adverse effects that were very common and

            10    intolerable for many patients.  The extrapyramidal

            11    syndromes of akathisia, Parkinsonism and dystonia occurred

            12    in 50 to 100 percent of patients, particularly in the

            13    elderly and high-risk groups, requiring additional

            14    medicines as antidotes, and those medicines had their own

            15    complications.  Tardive dyskinesia, a potentially

            16    irreversible neurological syndrome of choreoathetoid

            17    dyskinesias occurred on average in 20 percent of patients,

            18    and occurred in up to 70 percent of high-risk patients such

            19    as the elderly.  So the typical drugs clearly had

            20    limitations.

            21                Over the past few years, we've had the advent

            22    of the atypical antipsychotic drugs, as they've been come

            23    to be known.  They have become first-line treatments in

            24    most medical settings, and that's because of improved

            25    efficacy in positive symptoms, negative symptoms, affective

                                                                           24

             1    symptoms, and improved treatment of the cognitive

             2    disabilities that are associated with schizophrenia.

             3                They also have an adverse effect profile that's

             4    improved by decreasing the neurological syndromes of EPS

             5    and TD, but they do bring additional challenges in terms of

             6    adverse effects.  So limitations clearly do remain.  The

             7    new drugs bring increased emphasis and focus on the issues

             8    of weight gain and the consequent metabolic abnormalities

             9    associated with weight gain.  It's not uncommon for our

            10    patients to gain 10 to 20 pounds within the first year of

            11    treatment, and it's fairly common for patients to gain 30

            12    to 40, sometimes 50 pounds within a year or more with an

            13    extended treatment.  This weight gain is turning out to

            14    affect compliance for many patients, so we're seeing that

            15    our new drugs that have brought many opportunities and

            16    improvements also bring new challenges.

            17                The weight gain issue can be summarized on the

            18    slide from a meta-analysis by Dr. Allison, published in the

            19    American Journal of Psychiatry last year that looked at

            20    increases in weight during the first 10 weeks of treatment. 

            21    The color code for understanding this graph is that the

            22    blue bars represent the typical neuroleptic drugs, and the

            23    individual colors represent the atypical drugs.

            24                Our traditional neuroleptics are typical agents

            25    such as chlorpromazine or thorazine do show that there was

                                                                           25

             1    a weight gain profile to some of the compounds.  Even

             2    haloperidol had some weight gain.  But as you look at this,

             3    you see that the atypical antipsychotic drugs tend to

             4    cluster toward the higher end of the weight gain continuum,

             5    and this is during the first 10 weeks of treatment, and

             6    this weight tends to increase or stay at this level during

             7    long-term treatment.

             8                In contrast, ziprasidone, the compound of

             9    interest today, is weight neutral during the first 10 weeks

            10    of treatment, and as you'll hear from Dr. Harrigan, during

            11    longer-term treatment as well.

            12                In any consideration of the long-term treatment

            13    of a chronic illness like schizophrenia, we have to look at

            14    other comorbid illnesses and risk factors.  So we look at

            15    both the risk factor prevalence and our ability to

            16    intervene in risk factors of comorbid illnesses.  Patients

            17    with schizophrenia are clearly overweight.  When one looks

            18    at the body mass index or BMI, and set the cutoff at 27,

            19    clearly in the overweight category, 42 percent of patients

            20    with schizophrenia are overweight, compared to 25 percent

            21    of the general population.  Smoking is alarmingly high in

            22    patients with schizophrenia.  Seventy to 90 percent of

            23    patients with this disorder smoke cigarettes, versus 25

            24    percent in the general population.

            25                When we turn to our ability to intervene with

                                                                           26

             1    these risk factors, it's also an important consideration to

             2    recognize that patients with schizophrenia do less well

             3    with our proposed interventions.  We have poor compliance

             4    rates, in part due to the impaired insight in people with

             5    schizophrenia, which is part of the illness.  We have

             6    compliance issues that are related to the adverse effects. 

             7    With the typical neuroleptic drugs, we have the

             8    neurological problems of EPS and tardive dyskinesia.  With

             9    the atypical agents, we're struggling in many patients with

            10    weight gain and metabolic changes.

            11                When we look to see what kinds of medical

            12    treatments patients with schizophrenia are getting, we also

            13    see consistently that patients get under-treated.  In a

            14    study looking at the treatment of patients with high lipid

            15    levels, 25 percent of patients with schizophrenia, compared

            16    to their matched controls, received lipid-lowering

            17    prescription drugs.  So they clearly are not getting

            18    treated for high lipid levels.

            19                When we look at treatment for post-MI care, we

            20    see that 40 percent of patients with schizophrenia are

            21    getting the standard of care that the matched cohort is

            22    receiving.  So clearly, patients with schizophrenia have

            23    high risks and have less participation in our

            24    interventions.  This means that we're seeing higher death

            25    rates in patients with schizophrenia.  The evidence is that

                                                                           27

             1    patients with schizophrenia have a 20 percent shorter life

             2    span.

             3                A meta-analysis recently published looking at

             4    studies at the beginning of the modern antipsychotic era,

             5    starting in 1952, has showed that the death by natural

             6    causes in schizophrenia is 34 percent higher than expected. 

             7    So for every 100 expected deaths, there are 134 deaths in

             8    patients with schizophrenia.  Deaths by cardiovascular

             9    disease, which is a high cause of death to begin with, is

            10    10 percent higher in schizophrenia.

            11                This meta-analysis is likely to conservatively

            12    underestimate the morbidity and mortality because

            13    ascertainment rates in cause of death during the 1950s,

            14    1960s and 1970s were much less precise than our current

            15    interest and focus on these issues.  So a recent study that

            16    is available from the Saskatchewan Health Database, a

            17    province in Canada which has a single-payer system and a

            18    uniform method for collecting data, has shown that the

            19    mortality rate for schizophrenia overall has a relative

            20    risk of 2.7, and when we look at cardiovascular death, 2.0

            21    or doubling the relative risk of death from cardiovascular

            22    disease.

            23                When we look at the prevalence issues of

            24    diabetes, we see a relative risk of 1.9, confirming very

            25    nicely what we have seen in several other studies, that

                                                                           28

             1    patients with schizophrenia have nearly twice the

             2    prevalence of diabetes, and the risk of developing new

             3    cases of diabetes is a relative risk of 1.6.

             4                So we're currently faced with the challenging

             5    situation in treating schizophrenia of our new medicines

             6    bringing some improved efficacy, but still many patients

             7    inadequately responding to current treatment options,

             8    whether it be in the treatment of their acute exacerbation

             9    of psychosis or during the important long-term phases of

            10    relapse prevention.

            11                Safety issues are important in emphasizing the

            12    high medical risk liabilities that are comorbid with

            13    schizophrenia and are limited risk factor interventions. 

            14    It's important to emphasize that the new antipsychotic

            15    drugs, as well as the old agents, may exacerbate these

            16    underlying medical morbidities in schizophrenia.

            17                So we clearly need additional medicines in our

            18    armamentarium to address both the unmet psychiatric and

            19    medical needs in patients with schizophrenia to offer

            20    valuable new options for treatment for patients who suffer

            21    from this highly prevalent, highly morbid, and highly

            22    lethal illness that causes immense pain and suffering in

            23    patients and their families.

            24                Dr. Tamminga, Dr. Laughren, Dr. Katz and the

            25    committee, thank you very much for allowing me the time to

                                                                           29

             1    present the current challenging situation in the treatment

             2    of schizophrenia.  I'll turn the program over to Dr.

             3    Harrigan.  Thank you.

             4                DR. HARRIGAN:  Thank you, Dr. Casey.

             5                I'll now proceed to introduce ziprasidone,

             6    which is a benzosothiasol, a structurally unique member of

             7    the generation of so-called atypical antipsychotic agents. 

             8    The pharmacology of these drugs is somewhat complex and

             9    varied, as shown on the next slide.  This class of drugs is

            10    often referred to as 5-HT2A/D2 antagonists, and they do

            11    have that pharmacology in common; that is, antagonist

            12    activity at the serotonin Type 2A and dopamine Type 2

            13    receptors.  However, a comparison of the broader

            14    pharmacology of these compounds reveals a number of

            15    properties which distinguish them from each other.

            16                Clearly, some of these differences may increase

            17    or decrease liability for certain adverse events, such as

            18    alpha-1 adrenal receptor antagonist activity in

            19    hypotension, or activity at the muscarinic M1 receptor in

            20    gastrointestinal symptoms.  Whether these or other

            21    properties might have psychotropic implications is more

            22    speculative.  But it is widely recognized that, on the

            23    basis of pharmacology alone, it's an oversimplification to

            24    lump these agents together.  It is inaccurate to consider

            25    ziprasidone as simply another atypical.

                                                                           30

             1                The pharmacokinetics of ziprasidone are fairly

             2    straightforward, as shown on the next slide.  Here's a

             3    high-level summary of the clinical pharmacokinetics, which

             4    are linear.  All of the clinical trial protocols have

             5    called for administration of ziprasidone with food in view

             6    of the increased absorption, which would be expected. 

             7    Ziprasidone is extensively metabolized.  I'll have more to

             8    say about that in a few minutes.  At this time, however,

             9    I'd like to briefly review the evidence for efficacy,

            10    describe the effective dose range and the design of the

            11    trials which have established that dose range.

            12                In order to establish the claim of efficacy in

            13    the treatment of acute exacerbation, ziprasidone was

            14    studied in four trials in a population of nearly 1,000

            15    recently hospitalized patients.  As described in your

            16    briefing document and as we'll see in a moment, daily doses

            17    of 80 to 160 milligrams were most consistently effective in

            18    the treatment of acute exacerbation.  Relapse prevention,

            19    on the other hand, was studied in a single trial of 294

            20    chronically and continually hospitalized patients.  In this

            21    trial, a daily dose as low as 40 milligrams was effective

            22    at preventing relapse.

            23                One word about dose.  I'll be stating total

            24    daily dose, which the label would recommend be divided into

            25    two equal doses and taken with meals, as was done in nearly

                                                                           31

             1    all ziprasidone clinical trials.

             2                First, a summary graphic of the treatment

             3    effects in the short-term studies.  This figure illustrates

             4    the placebo-corrected change from baseline with 95 percent

             5    confidence intervals for each fixed-dose treatment group

             6    studied in these trials.  It is proposed that the 40

             7    milligram daily dose is insufficient to treat acute

             8    exacerbation.  Efficacy has clearly been demonstrated at

             9    daily doses of 80 to 160 milligrams.  The 200 milligram per

            10    day dose appeared to offer no advantage in terms of

            11    efficacy.  It was associated with increased adverse events. 

            12    So the recommended effective dose range is 80 to 160

            13    milligrams daily.

            14                Efficacy data from a long-term trial is

            15    presented in the next slide as a Kaplan-Meier graph,

            16    showing time to relapse, which was the primary pre-defined

            17    endpoint.  As you can see, all three ziprasidone dose

            18    groups -- 40, 80, and 160 milligrams daily -- were

            19    effective in preventing relapse, suggesting that there is

            20    room for individualization of treatment during maintenance

            21    therapy.

            22                To provide a general sense of the side effect

            23    profile of the compound, this is a list of adverse events

            24    which occur with a frequency of at least 5 percent, and

            25    greater incidence in ziprasidone-treated patients than in

                                                                           32

             1    placebo-treated patients.  Somnolence was described in

             2    approximately 14 percent of patients, most cases being mild

             3    and transient.  Respiratory disorders, the other term here,

             4    which is statistically significantly more commonly

             5    occurring in ziprasidone-treated patients than placebo-

             6    treated patients, this term includes investigator terms or

             7    symptoms such as nasal congestion and carisa, generally

             8    mild and symptoms which are commonly reported in other

             9    drugs of this class as well.

            10                As noted in the briefing document, 4 percent of

            11    ziprasidone-treated and 2 percent of placebo-treated

            12    patients discontinued from these studies for adverse

            13    events.  As you can see, the mean treatment duration in

            14    these 4- to 6-week trials was approximately four weeks,

            15    across the second row here, which is quite different from

            16    the adverse event collection period in the relapse

            17    prevention trial.  The adverse event picture in the long

            18    term shows only insomnia to occur with a frequency of

            19    greater than 10 percent, but insomnia occurred with fairly

            20    high frequency in placebo-treated patients as well.

            21                Only asthenia occurred with significantly

            22    higher incidence in ziprasidone-treated compared to

            23    placebo-treated patients.  The primary investigator term

            24    coding to asthenia is fatigue.  Overall, ziprasidone was

            25    well tolerated during this mean treatment period of over

                                                                           33

             1    seven months.

             2                So far, this introduction to ziprasidone has

             3    focused on areas which were agreed between the sponsor and

             4    the agency at the time of the original NDA.  As stated in

             5    the not approvable letter and again noted in the agency's

             6    briefing document, the efficacy of ziprasidone has been

             7    established.  I'll now take the bulk of the presentation to

             8    review data which we have collected in order to better

             9    characterize the effect of ziprasidone on the QTc.

            10                In the course of this review, we'll address the

            11    following questions.

            12                What is the effect of ziprasidone on the QTc?

            13                Have there been clinical manifestations of an

            14    effect?

            15                What can we learn by considering ziprasidone in

            16    the context of the terfenadine and cisapride experience?

            17                Finally, what other properties of this drug

            18    should be considered in a determination of benefit-risk?

            19                It's likely that no one in this room is

            20    completely naive to the QT interval, and I'll spend only a

            21    short time on some general orientation.  This is a stylized

            22    ECG complex, with a P wave, QRS complex, and T wave.  The

            23    QT interval, of course, is measured from the beginning of

            24    the Q wave to the end of the T wave, representing the time

            25    required for depolarization and repolarization of the

                                                                           34

             1    ventricles at a standard paper speed of 25 millimeters per

             2    second.

             3                One of these small boxes illustrated up in the

             4    corner of this slide is equal to 40 milliseconds, one

             5    millimeter in width.  So 10 milliseconds would be equal to

             6    the width of one-quarter of one box.  The QT interval on

             7    this slide is 10 millimeters long, or 400 milliseconds, 10

             8    boxes in width.

             9                The duration of the QT interval is affected by

            10    a number of physiologic and pathologic factors, including

            11    importantly by the heart rate at which the QT interval is

            12    measured.  As you can see in the six seconds of ECG

            13    displayed in each of these two sample tracings, the

            14    presence of more complexes per unit time will simply have

            15    the effect of shortening the intervals between each

            16    complex.  In addition, however, the QT intervals within

            17    each complex are shortened as well.  So a perfectly normal

            18    heart has a longer QT at a lower heart rate than it does at

            19    a higher heart rate.

            20                The one option for expression of QT might

            21    simply be to state the heart rate at which it is measured: 

            22    a QT of 420 milliseconds at a rate of 66 beats per minute,

            23    for instance.  However, by convention, the QT interval is

            24    instead corrected for heart rate by application of a

            25    mathematical correction formula.  This formula incorporates

                                                                           35

             1    terms for heart rate and QT, and produces a QTc or

             2    corrected QT.  The correction formula first proposed by

             3    Bazett in 1920 became the standard used in the literature

             4    and remains the most commonly employed.  However, there are

             5    others, and I'll later review the effects of correction

             6    formula upon the results and the findings of our QTc study

             7    054.

             8                While it is true that an average QTc in an

             9    average population is a difficult number to pin down, 400

            10    milliseconds is a reasonable estimate.  It is consistent

            11    with much of the epidemiological literature.  Nonetheless,

            12    there is a considerable amount of variability between

            13    individuals which we can illustrate using the ziprasidone

            14    Phase II/III database.

            15                What we've done here is simply counted the

            16    number of QTc measures at baseline.  This is pre-

            17    randomization in patients enrolled in Phase II/III studies. 

            18    We placed QTc in 10-millisecond bins; that is, counted the

            19    number of QTc's in each 10-millisecond bin.  Then we've

            20    drawn a curve over the top of the distribution columns. 

            21    For this population, the shortest QTc was 314 milliseconds,

            22    the longest QTc was 494 milliseconds, and the median was,

            23    in fact, 400 milliseconds.

            24                One of the reasons for this variability across

            25    a population is variability within each person.  The three

                                                                           36

             1    carefully conducted studies have examined this by measuring

             2    QTc a number of times within individuals.  This slide

             3    summarizes the findings of these three studies.  As you can

             4    see, the range of QTc -- that is, the longest minus the

             5    shortest -- for individuals within these populations ranged

             6    from 66 to 95 milliseconds and is partially dependent upon

             7    the number of times the observation is made.  So in the

             8    third study on the list here by Molnar, the range of 95

             9    milliseconds was found in patients when measures were taken

            10    every five minutes for 24 hours using a Holter technique.

            11                In addition to diurnal influences, it has also

            12    been demonstrated that the QTc will increase following a

            13    meal by approximately 20 milliseconds.  There are

            14    therapeutic drugs which prolong the QTc, as shown in this

            15    list, which was compiled from two Websites, the Canadian

            16    Adverse Drug Reaction Newsletter and a site maintained by

            17    the Georgetown University Department of Pharmacology.  As

            18    you can see, there are a number of psychotherapeutic agents

            19    on the list highlighted in light blue on this slide.  I'll

            20    soon be providing you with a quantitative estimate of the

            21    effects of four of those named antipsychotic agents.  But

            22    such precise data is generally not available on the other

            23    psychotherapeutic agents on the list, and many non-

            24    psychotropic agents on this list as well.

            25                In addition to those drugs listed here, there

                                                                           37

             1    are other agents that have been associated with QTc

             2    prolongation.  During my presentation, I'll be contrasting

             3    the effects of ziprasidone to those seen with the

             4    antihistamine terfenadine, the gastrointestinal motility

             5    agent cisapride, and an antipsychotic.

             6                Let's look first at the ziprasidone QTc data

             7    which caused concern at FDA.  Recall the four short-term,

             8    fixed-dose, placebo-controlled studies in hospitalized

             9    patients which underwrite the claim of efficacy in the

            10    treatment of acute exacerbation.  This table displays the

            11    mean change in QTc in the right-hand column at least visit

            12    compared to baseline for placebo in each fixed-dose

            13    ziprasidone group, and for haloperidol comparative group. 

            14    As you can see, ziprasidone, in doses up to and including

            15    40 milligrams, was associated with little or no change.

            16                However, across the 80 to 160 milligram dose

            17    groups, one can see a prolongation of 6 to 10 milliseconds,

            18    which does not increase further at the highest dose

            19    studied.  Based upon this evidence, FDA asked Pfizer, as

            20    Dr. Laughren described, to measure the effect of

            21    ziprasidone on the QTc in a comparative clinical trial with

            22    ECGs timed to match the maximum concentrations of

            23    ziprasidone and comparators.

            24                Study 054 was an ECG study which enrolled 183

            25    patients.  By protocol, 30 ECGs were obtained per patient. 

                                                                           38

             1    Tracings were obtained in the fasting state, timed to

             2    capture the Cmax of each agent, both in the absence and

             3    presence of a metabolic inhibitor which was selected

             4    specifically to match the metabolic pathway of each

             5    antipsychotic.  ECGs were stripped of patient and treatment

             6    identification and sent to a blinded central reader.

             7                I'd like to take a short side-step now to

             8    consider the metabolic inhibitor phase of this protocol. 

             9    The objective was to select a metabolic inhibitor which

            10    would perturb the metabolism of parent drug and be

            11    informative of potential drug interaction risks.  An

            12    inhibitor was therefore selected with the principal

            13    metabolic pathway of each antipsychotic in mind.

            14                Looking more closely at ziprasidone, this chart

            15    illustrates the fate of ziprasidone following oral

            16    administration in humans, which, as you can see, is

            17    determined by two principal enzymatic pathways.  The first

            18    is cytochrome P450 3A4, CYP3A4, which is ultimately

            19    responsible for the production of three metabolites which

            20    we have designated M1, M2, and M10.  The numbering system

            21    reflects only the sequence of elution in a chromatographic

            22    analysis.  It has no other significance.

            23                The second enzymatic pathway is mediated by

            24    aldehyde oxidase, a non-P450 enzyme, which is the first

            25    step in the formation of M9 and is responsible for

                                                                           39

             1    approximately two-thirds of ziprasidone metabolism.  These

             2    four compounds -- M1, M2, M9, and M10 -- are the principal

             3    metabolites of ziprasidone and circulate with ziprasidone

             4    after oral administration.

             5                For Study 054, we selected ketoconazole for co-

             6    administration with ziprasidone.  As the most potent known

             7    inhibitor of CYP3A4, ketoconazole represents a worst-case

             8    surrogate for the large number of drugs which are known to

             9    inhibit this system.  CYP3A4 interactions have been quite

            10    prominent in the evaluation of QTc prolongation with a

            11    number of agents, including terfenadine and cisapride.

            12                I'd like to point out again this second

            13    aldehyde oxidase-mediated pathway for ziprasidone

            14    metabolism.  It plays an important role in the clinical

            15    behavior of ziprasidone.  The literature provided no

            16    clinical examples of drug interactions with the aldehyde

            17    oxidase system, suggesting that this metabolic pathway is

            18    robust and resistant to induction or inhibition. 

            19    Importantly, ziprasidone, M9 and M10 have been found to

            20    have potassium channel -- that's IKr -- blocking properties

            21    in preclinical models, while ziprasidone and M9

            22    additionally have modest L-type calcium channel blocking

            23    properties.  M1 and M2 are inactive in these models.

            24                For now, I'd like to maintain the focus on the

            25    QTc measures in the clinic, though we're prepared to

                                                                           40

             1    provide more details on the preclinical findings if the

             2    committee requests later on.

             3                This kinetic is identical with the previous

             4    slide.  It illustrates that ketoconazole inhibition of

             5    CYP3A4 would be expected to shift more of the metabolism of

             6    ziprasidone through the aldehyde oxidase pathway, leading

             7    to an increase in M9 at the expense of M1, M2, and M10.

             8                Perhaps also of importance in the context of

             9    CYP3A4 inhibition is the degradation of M10, illustrated

            10    here and here.  This is also mediated by CYP3A4 and

            11    suggests the potential for an increase in M10 in spite of

            12    inhibition of its formation.  As we describe the results of

            13    Study 054, we will report the effect of ketoconazole

            14    administration upon serum levels of ziprasidone, M9, and

            15    M10.

            16                Back to Study 054.  Schematically, the study

            17    looked like this.  Previous antipsychotic treatment was

            18    tapered as appropriate for the individual prior to

            19    randomization at the initiation of a five-day, single-blind

            20    placebo washout.  During that time, nine baseline ECGs were

            21    obtained, time to match the Cmax of the drug to which the

            22    patient had been assigned.  Patients were then titrated to

            23    a target dose according to the package insert and held at

            24    that target dose long enough to reach steady state.

            25                Three ECGs per day were obtained on three

                                                                           41

             1    consecutive days at each of the three principal time

             2    points:  baseline, steady state, and again, in the presence

             3    of metabolic inhibitor.  At the request of the agency,

             4    three ECGs were also obtained on the second day of the dose

             5    titration period.

             6                Here's a profile of the patient population

             7    enrolled into the trial.  Note that the treatment duration

             8    varied according to the approved dosing instructions for

             9    each antipsychotic agent.  Ninety percent of the patients

            10    who enrolled in this study completed the trial.

            11                Now I'd like to take a moment to review the

            12    specifics of the treatment groups.  Ziprasidone has a mean

            13    Tmax of six hours.  So ECGs were obtained at five, six, and

            14    seven hours post-dose, fasting, on three consecutive days. 

            15    This was done again at baseline, steady state, and steady

            16    state in the presence of ketoconazole.  As you can see,

            17    ziprasidone was studied at the highest recommended dose of

            18    160 milligrams daily.  Risperidone, olanzapine, and

            19    quetiapine were also titrated to maximum recommended doses,

            20    while haloperidol and thioridazine were studied at doses of

            21    15 milligrams and 300 milligrams respectively.  Finally, we

            22    also incorporated the agency's suggestion to study

            23    risperidone at two doses.  So ECGs were also obtained at 6

            24    to 8 milligrams daily.

            25                This slide shows the mean increase in QTc

                                                                           42

             1    measured in each treatment group at steady state.  As you

             2    can see, thioridazine at 300 milligrams showed the greatest

             3    change at approximately 36 milliseconds.  Other mean

             4    changes were ziprasidone at 20 milliseconds, quetiapine at

             5    14.5, risperidone at 11.6, olanzapine at 6.8, and

             6    haloperidol at 4.7.  This graph illustrates the point

             7    estimate of the mean with 95 percent confidence intervals. 

             8    The study was in fact powered to measure a mean change with

             9    a 95 percent confidence interval of plus or minus 7

            10    milliseconds, as stated in the protocol and agreed with the

            11    agency during protocol design.  In fact, the confidence

            12    intervals are approximately plus or minus 5 to 6

            13    milliseconds.

            14                This trial was not powered to provide a precise

            15    estimate of the incidence of uncommon events, such as 60-

            16    millisecond increases in QTc, a point I will return to

            17    shortly.

            18                Recall again our discussion from the schematic

            19    of Study 054, that after obtaining three days of ECGs at

            20    steady state, a metabolic inhibitor was added to the study

            21    drug.  As you can see here, the metabolic inhibitor was

            22    selected for each study drug according to its principal

            23    P450 metabolic pathway.  As we described for ziprasidone, a

            24    CYP3A4 substrate, the inhibitor was ketoconazole, as it was

            25    for quetiapine.

                                                                           43

             1                Paroxetine, a CYP2D6 inhibitor, was chosen for

             2    risperidone and thioridazine; fluvoxamine, a CYP1A2

             3    inhibitor, for olanzapine; and both CYP3A4 and CYP2D6 were

             4    inhibited for haloperidol, as it is a substrate for both

             5    enzyme systems.

             6                This slide is a reproduction of Table 30 from

             7    the briefing document.  The last row of each column

             8    presents an estimate of the effect of metabolic inhibitor

             9    on antipsychotic drug concentration.  So for ziprasidone,

            10    M9 and M10, increases of 39, 55, and 8 percent in mean

            11    serum concentrations were measured.  Concentrations

            12    increases in the other treatment groups ranged from 4

            13    percent for thioridazine to 400 percent for quetiapine.

            14                Here is a graphic display of the overall

            15    results.  This slide includes the findings at steady state

            16    as presented earlier.  Those are the yellow point estimates

            17    with confidence intervals.  And alongside each of those is

            18    the mean change from baseline in the presence of metabolic

            19    inhibitor.  As you can see, the effect of ziprasidone on

            20    the QTc interval, measured at steady state, at Cmax at the

            21    highest recommended dose, remained essentially unchanged

            22    despite co-administration of the potent CYP3A4 inhibitor

            23    ketoconazole.  For thioridazine and risperidone, slight

            24    decreases were measured.  For haloperidol and quetiapine,

            25    slight increases were noted.

                                                                           44

             1                Now, the QTc values that we've presented so far

             2    have been calculated using the Bazett formula.  As I

             3    mentioned earlier, there are a number of other formulas

             4    which have been proposed to correct the QT interval for the

             5    heart rate at which it is measured.  What distinguishes one

             6    formula from another is the way in which the heart rate

             7    term is handled.  So in the Bazett formula, the QT interval

             8    is divided by the square root of the RR interval, or the RR

             9    interval to the 0.5 power.

            10                The Bazett formula may have been the first, but

            11    there are at least 17 unique QT correction formulas which

            12    have been published over the years, and we're showing you

            13    six of those formulas here.  Since each handles the RR term

            14    differently, then a QT measured at a heart rate of 80 will

            15    calculate to a different QTc with each formula.  Among this

            16    group of formulas, the Bazett formula will give you the

            17    longest QTc for a heart rate above 60 and the shortest QTc

            18    for a heart rate below 60.  To understand the effects of

            19    the correction formula upon the magnitude of the QTc

            20    changes seen in Study 054, we'll look first at the effects

            21    of the study drugs on heart rate and QT.

            22                As you see in this table, each compound has its

            23    own pattern of effects on the heart rate and the QT

            24    interval.  Thioridazine 300 milligrams, haloperidol 15

            25    milligrams, and ziprasidone all effect the QT interval, but

                                                                           45

             1    have more modest effects on heart rate than quetiapine,

             2    risperidone, and olanzapine.  Haloperidol was associated

             3    with a decrease in heart rate, the minus 2.9 on the last

             4    column.

             5                Now I'll go back to our graphic illustration of

             6    the QTc findings from Study 054.  For this slide, we've

             7    taken all the mean changes that you've seen already and

             8    pushed them over to the left-hand side of the slide.  So

             9    you see thioridazine with the greatest effect, haloperidol

            10    with the least effect.  This is measured at steady state

            11    using the Bazett correction formula.

            12                Next we'll add on this slide the mean QTc

            13    change in the presence of metabolic inhibitor.  Again, the

            14    results you've already seen using the Bazett correction

            15    formula.  Thioridazine, risperidone and olanzapine show a

            16    slight decrease in QTc effect; quetiapine and haloperidol

            17    an increase; ziprasidone unchanged.  So ziprasidone the

            18    yellow dots, haloperidol light blue, quetiapine in white. 

            19    Thioridazine, the greatest change, in red.

            20                Here I've added two alternative correction

            21    formulas, one derived from our own patient population at

            22    baseline, the other published a number of years ago by the

            23    Framingham investigators.  I won't try to describe the

            24    migration of each individual data point, but I will point

            25    out that the difference between the Bazett formula and the

                                                                           46

             1    others is that the QTc with the other formulas will be

             2    smaller for drugs that increase the heart rate, and larger

             3    for drugs that decrease the heart rate.  In this study,

             4    most notably that's haloperidol.  Overall, I would suggest

             5    that there is no one correct correction formula, and I

             6    would point out that QTc prolongation appears common.  All

             7    point estimates of the mean are above zero.  They're not

             8    scattered above and below zero.  Thioridazine 300

             9    milligrams remains on top regardless of the correction

            10    formula selected.

            11                The difference between ziprasidone and these

            12    other approved non-thioridazine agents varies somewhat

            13    according to the correction formula used and the absence or

            14    presence of a metabolic inhibitor.  Remember, non-Bazett

            15    formulas reduce the magnitude of the effect of ziprasidone

            16    and several other drugs.  However, whichever formula you

            17    select, the effect of ziprasidone in the absence of

            18    metabolic inhibition is within 6 or 9 milliseconds of

            19    quetiapine or haloperidol respectively.  So with the Bazett

            20    formula, ziprasidone in yellow, within 6 milliseconds of

            21    quetiapine in white, with either of the other correction

            22    formulas, ziprasidone in yellow, within 9 milliseconds of

            23    haloperidol in light blue.

            24                In the presence of metabolic inhibitor, the

            25    difference between ziprasidone and quetiapine is zero

                                                                           47

             1    milliseconds with the Bazett formula; between ziprasidone

             2    and haloperidol, 3 milliseconds using either of the other

             3    two correction formulas illustrated here.  There are a

             4    number of other correction formula calculations presented

             5    in the briefing document as well.

             6                The briefing documents provided by both the

             7    sponsor and the agency report the incidence of incremental

             8    increases in QTc in this study.  This slide displays the

             9    incidence of 60-millisecond increase in each treatment

            10    group at steady state and with metabolic inhibitor, side by

            11    side, same order, ziprasidone on the left, risperidone,

            12    olanzapine, quetiapine, thioridazine, and haloperidol.  As

            13    you can see, because this trial was not powered to provide

            14    a precise estimate of the frequency of relatively uncommon

            15    events, there is considerable variability in these

            16    estimates.

            17                For the ziprasidone group, as we just saw, the

            18    mean effect on QTc was unchanged with metabolic inhibition. 

            19    However, the incidence of 60-millisecond increase fell from

            20    7 out of 31 individuals, or just over 20 percent, to 3 out

            21    of 31 individuals with the addition of metabolic inhibitor,

            22    the rate with metabolic inhibitor in the ziprasidone group

            23    lower than that seen in the quetiapine or the thioridazine

            24    group.  Again, this is with the Bazett formula.

            25                In fact, none of the apparent differences

                                                                           48

             1    between these treatment groups in the incidence of 60-

             2    millisecond increase are statistically significant.  This

             3    is true whether the Bazett formula is used on that slide to

             4    calculate QTc or whether the baseline correction formula is

             5    used as illustrated on this slide.  I'm showing you again

             6    the incidence of QTc prolongation above 60 milliseconds

             7    with 95 percent confidence intervals.

             8                If we now consider the broad objectives of

             9    Study 054, I would suggest that this is the most rigorous

            10    examination of the effects of antipsychotic drugs on the

            11    QTc under controlled conditions, at Cmax, at steady state,

            12    at relevant doses, with metabolic inhibition, and with the

            13    results expressed using a number of different correction

            14    formulas.  With regard to the second objective, I believe

            15    the experiment has perturbed ziprasidone metabolism in the

            16    most appropriate way to look for evidence of risk of drug

            17    interaction.  I'll now show you additional data collected

            18    in our Phase II/III development program which contributes

            19    to an examination of the risk of drug interaction.

            20                In the course of conducting our clinical

            21    trials, we obtained almost 10,000 serum ziprasidone

            22    measurements from over 3,000 individuals.  Overall, the

            23    mean concentration was 70 nanograms per milliliter.  In

            24    addition, over 2,000 measurements of metabolites M9 and M10

            25    were obtained, ziprasidone measurements M9 and M10.  The

                                                                           49

             1    third column of this slide notes the highest concentrations

             2    of ziprasidone, M9 and M10, which were measured in Study

             3    054.  As pointed out in the briefing document, 61, 13, and

             4    9 patients respectively had measures which exceeded the

             5    highest serum levels of ziprasidone or those two

             6    metabolites in Study 054.

             7                Our focus, of course, remains on ECG data. 

             8    Within that data set, we have 1,359 individuals for whom a

             9    QTc was obtained within one hour of the ziprasidone serum

            10    measurement, creating a data set of over 2,400 QTc

            11    concentration data points.  The mean concentration in this

            12    data set was 63 nanograms per milliliter, very similar to

            13    that seen in the overall data set.  Over 700 QTc

            14    concentration data points are available for each of the

            15    metabolites M9 and M10, as well.  There are 12, 5, and 4

            16    individuals in this data set with serum values above the

            17    highest level measured in Study 054 for ziprasidone, M9, or

            18    M10.

            19                This figure is in the briefing document.  It

            20    plots the change in QTc on the vertical axis and

            21    concentration on the horizontal axis for these 2,435

            22    ziprasidone concentration QTc data points.  For this

            23    display we're using QTc calculated according to the

            24    baseline correction formula, which is QT divided by RR to

            25    the 0.38 power.  The vertical line on the right-hand side

                                                                           50

             1    marks the highest concentration seen in Study 054 with

             2    ziprasidone.  That's 380 nanograms per milliliter.  The

             3    concentration axis on this slide is truncated at 400

             4    nanograms per milliliter.

             5                The data overall are very consistent with ECG

             6    data that were seen in the short-term, fixed-dose, placebo-

             7    controlled trials in Study 054.  At the concentration range

             8    where most patients spend most of their time, the mean QTc

             9    effect is less than 10 milliseconds.  If we look at the

            10    highest recommended dose at Cmax in the absence or presence

            11    of ketoconazole, the mean change measured in Study 054 is

            12    15 to 20 milliseconds, depending upon the correction

            13    formula.

            14                Clinically, one might reasonably have the

            15    greatest interest in those individuals with the highest

            16    exposure.  These 12 patients with serum measurements

            17    exceeding 380 nanograms per milliliter are indicated on the

            18    right side of the figure, three of them just above the

            19    vertical line at 380 nanograms per mil, the other nine

            20    indicated at the appropriate level on the vertical axis to

            21    match the QTc change which was associated with that serum

            22    level in nanograms per milliliter.

            23                The next slide provides a closer look at these

            24    individuals.  These 12 individuals, along with four

            25    additional patients who had concentrations of the M9 or M10

                                                                           51

             1    metabolites which exceeded those seen in Study 054, are

             2    presented on this table.  We're showing you the age,

             3    gender, baseline QTc, treatment day, QTc change associated

             4    with serum concentration of ziprasidone, M9, or M10.  The

             5    highest serum ziprasidone concentration of 955 nanograms

             6    per milliliter was seen in a 44-year-old woman who had a

             7    QTc change from baseline of plus-2 milliseconds.  Her

             8    baseline QTc was 423 milliseconds, and her QTc at the time,

             9    within one hour of that serum measurement, was 425

            10    milliseconds.

            11                The three greatest QTc changes seen on this

            12    table -- 60, 57, and 50 milliseconds -- were measured in

            13    patients with baseline values of 380, 385, and 346

            14    milliseconds.  I'll mention the relationship between

            15    baseline QTc and change in QTc in just a moment.  For these

            16    16 individuals who represent the top of the ziprasidone-

            17    treated patient population by exposure, the QTc measures

            18    obtained within one hour of serum measurement are still

            19    contained within the range of those QTc measures seen in

            20    the overall ziprasidone database.  There are no QTc values

            21    exceeding 500 milliseconds among these 12 individuals, 12

            22    patients with the highest serum levels.

            23                One important issue we're addressing today is

            24    not whether ziprasidone lengthens the QTc slightly, but

            25    whether that effect predicts a measurable increase in

                                                                           52

             1    clinical risk.  In addition to reviewing the clinical

             2    experience with ziprasidone, we have looked for ways to

             3    assess the clinical relevance of modest QTc changes.  We

             4    have consulted experts with regard to the ways to link QTc

             5    prolongation to risk.  We will shortly be contrasting

             6    ziprasidone with other well-studied agents such as

             7    terfenadine and cisapride.  Later today you'll hear of a

             8    formula to assess QTc risk which was obtained and developed

             9    by identifying patients with congenital long QTc syndrome

            10    who suffered a clinical event.  These affected patients,

            11    along with unaffected family members, form the database

            12    from which this formula was developed or calculated.

            13                We ask you to carefully assess the validity of

            14    this formula as we do not feel it is appropriate to apply

            15    this formula to the modest QTc changes seen with many

            16    drugs.

            17                In the recent past, there have been several

            18    drugs which have caused problems with drug interaction and

            19    QTc prolongation.  The fact that terfenadine was withdrawn

            20    from the market because of its potential to prolong QTc and

            21    cause torsade and sudden death is well known and might lead

            22    one to expect that ziprasidone might have some increased

            23    risk of such events.  On close examination, however, the

            24    evidence suggests a different conclusion.

            25                This concern was raised in the 1997 review of

                                                                           53

             1    the original ziprasidone NDA, articulated here by the

             2    consulting cardiologist from the Cardiorenal Division.  In

             3    his summary and impressions of his consultation on the

             4    ziprasidone NDA, he pointed out that "Although the mean

             5    increase in QT interval appears minimal and clinically

             6    unremarkable, on the order of 10 milliseconds with 160

             7    milligrams per day, it should be recognized that the ECG

             8    data were obtained at trough and the magnitude of the

             9    increase is similar in magnitude to what is observed with

            10    therapeutic doses of terfenadine.  Under circumstances

            11    where metabolism is impaired, terfenadine has been

            12    associated with torsade de pointes.  The same could be

            13    expected with ziprasidone."

            14                First, some background on terfenadine.  Seldane

            15    was prescribed well over 100 million times between the time

            16    of its launch in 1979 and its withdrawal from many markets

            17    more than 15 years later.  The mean effect of terfenadine,

            18    or Seldane, on the QTc has been characterized by a number

            19    of investigators as approximately 6 to 8 milliseconds.  As

            20    described in the briefing document, a close review of our

            21    ECG data, obtained in a trial conducted by Dr. Craig Pratt

            22    and colleagues, reveals that terfenadine was associated

            23    with a prolongation of 18 milliseconds when measured at

            24    peak; that is, at one hour after dosing.

            25                Importantly, examination of considerable

                                                                           54

             1    epidemiological evidence has failed to demonstrate that

             2    terfenadine alone was associated with an increased risk of

             3    sudden death, despite its ability to prolong QTc in this

             4    fashion.  However, as FDA's Cardiorenal review mentions,

             5    the profile of terfenadine changes considerably in the

             6    presence of CYP3A4 inhibition.  Honig et al. measured the

             7    QTc effect of terfenadine administered with ketoconazole as

             8    82 milliseconds.  The QTc in that trial was measured at

             9    trough, that is on ECG tracings taken in the morning before

            10    the first dose of terfenadine, and so may not be

            11    representative of the effect at Cmax.

            12                Concomitant administration of terfenadine and

            13    CYP3A4 inhibitors such as ketoconazole has been associated

            14    with increased risk of sudden death.

            15                Data from Study 054 now directly addressed the

            16    concern raised by the Cardiorenal reviewer.  The profiles

            17    of terfenadine and ziprasidone -- terfenadine illustrated

            18    here on the left, and ziprasidone on the right -- similar

            19    in the absence of metabolic inhibition, become quite

            20    different in the presence of CYP3A4 inhibition.  The mean

            21    effect of terfenadine is at 82 milliseconds, unchanged mean

            22    effect of ziprasidone.  The potent CYP3A4 drug interaction

            23    liability present with terfenadine is not present with

            24    ziprasidone.

            25                In addition to terfenadine, cisapride is

                                                                           55

             1    another agent where QTc prolongation was exacerbated by a

             2    significant drug interaction.  Cisapride is a gastric

             3    prokinetic agent which increases acetylcholine release.  It

             4    is primarily metabolized by CYP3A4.  Launched in 1993,

             5    cisapride was widely used throughout the world.  However,

             6    cisapride blocks IKr as a CYP3A4 substrate, and became

             7    associated with the occurrence of torsade.  In this

             8    context, a drug interaction study was carried out with

             9    cisapride and fluconazole, an antifungal agent.

            10                In this trial, 20 volunteers were randomized

            11    for treatment with placebo or fluconazole.  After one week,

            12    cisapride 20 milligrams was added to each treatment group. 

            13    In the cisapride plus placebo group, QTc changes were 12

            14    milliseconds when averaged across the dosing interval, and

            15    23 milliseconds at peak cisapride concentrations.  Twelve

            16    milliseconds averaged across the dosing intervals at non-

            17    peak, 23 milliseconds when measured at peak cisapride

            18    concentrations.

            19                In the cisapride plus fluconazole group, the

            20    peak QTc effect of 50 milliseconds was measured, in

            21    association with an approximately three-fold increase in

            22    cisapride concentrations.  These findings are consistent

            23    with a separately conducted clarithromycin interaction

            24    study.  Both of these agents -- that is, clarithromycin and

            25    fluconazole -- are modest inhibitors of CYP3A4. 

                                                                           56

             1    Ketoconazole, however, is a potent inhibitor.  As reported

             2    in the U.S. package insert, it's causing an eight-fold

             3    increase in cisapride AUC, compared to the three-fold

             4    increase seen with fluconazole, which was associated with a

             5    50-millisecond peak QTc effect.  The QTc effects in the

             6    ketoconazole interaction study are not described.

             7                The experience with terfenadine and cisapride

             8    is a reminder of the potential importance of metabolic

             9    inhibition in the assessment of drugs which have the

            10    potential to prolong QTc.  This issue has been directly and

            11    carefully addressed in Study 054.  It is clear that

            12    ziprasidone does not have the potent CYP3A4 interaction

            13    liability seen with terfenadine and cisapride.  Broader

            14    conclusions regarding drug interaction liability are

            15    supported by the understanding of the critical role of

            16    aldehyde oxidase in the metabolism of ziprasidone, and most

            17    importantly, by the Phase II/III database.

            18                There is no universal definition of QTc

            19    outlier.  The incidence of QTc values crossing a number of

            20    different thresholds is presented in the briefing document. 

            21    However, a frequently used cutoff for clinically

            22    significant prolongation is 500 milliseconds, and this is a

            23    threshold value which has been discussed before this

            24    committee in the past.  Within our Phase II/III database,

            25    Pfizer has collected 7,876 ECGs on 3,095 patients treated

                                                                           57

             1    with ziprasidone.  Two of these patients had a QTc in

             2    excess of 500 milliseconds.  One patient had a baseline

             3    clinical diagnosis of long QT, a screening QTc of 489,

             4    baseline QTc of 466 milliseconds.  On treatment, QTc of 503

             5    milliseconds led to discontinuation.

             6                The other was a patient whose QTc was not

             7    prolonged while taking ziprasidone, but who then

             8    discontinued ziprasidone and was treated with thioridazine

             9    prior to the emergence of QTc prolongation.

            10                Overall incidence.  Two patients of 3,095, 0.06

            11    percent.  There was one patient in the placebo group of 440

            12    with a QTc of 500 milliseconds.

            13                At this point, I'd like to speak to the

            14    comparison between ziprasidone and sertindole, which was

            15    mentioned in the FDA briefing document which was provided

            16    to the committee.  The 21-millisecond mean effect of

            17    sertindole which was described as 20 to 30 milliseconds

            18    before this committee in the past, in 1996, was not

            19    measured at Cmax in a controlled trial such as Study 054. 

            20    That estimate was derived from therapeutic clinical trials

            21    and may be more analogous to the data acquired of

            22    hospitalized patients in the ziprasidone short-term, fixed-

            23    dose, placebo-controlled trials, which showed a mean effect

            24    of ziprasidone of approximately 10 milliseconds.

            25                Even more importantly, the incidence of QTc

                                                                           58

             1    over 500 milliseconds was reported to this committee as 7

             2    to 8 percent at therapeutic doses of sertindole of 20 and

             3    24 milligrams daily.  As I just pointed out, 2 of 3,095

             4    patients in the ziprasidone database, one of whom had

             5    discontinued ziprasidone and begun treatment with

             6    thioridazine, experienced a QTc of 500 milliseconds.  We

             7    don't have access to sufficient data to characterize the

             8    reasons for the difference, but it is possible that

             9    sertindole, a 2D6 and 3A4 substrate, may be more

            10    susceptible to drug interactions than ziprasidone.

            11                Even though a proportion of patients with

            12    individual QTc changes of 60 milliseconds is small, how do

            13    these occur if the QTc effect of ziprasidone remains stable

            14    even in the presence of metabolic inhibition?  And how

            15    could there have been increases to this extent in the

            16    ziprasidone database without QTc values exceeding 500

            17    milliseconds?

            18                This figure provides the answer to those

            19    questions.  It displays QTc change across the entire Phase

            20    II/III database, the entire population of the Phase II/III

            21    database, by QTc at baseline.  So QTc change from baseline

            22    with a zero line, by baseline QTc.  This figure includes

            23    every post-baseline tracing across the entire program,

            24    excluding the one individual who experienced a profound

            25    increase in QTc after treatment with thioridazine.  The

                                                                           59

             1    data from that patient would include a baseline of 409

             2    milliseconds.  The post-baseline QTc in that patient was

             3    nearly 600 milliseconds.  So the change would have been off

             4    the scale at 180 or so milliseconds.  There is no evidence

             5    of that kind of effect with ziprasidone, even in the same

             6    individual, whose final QTc on ziprasidone before she was

             7    treated with thioridazine was 392 milliseconds.

             8                Clinically, one would be interested in points

             9    in the upper right-hand corner.  That is, these would

            10    represent large QTc increase in patients with a long

            11    baseline QTc, with a longer baseline QTc represented out

            12    here.  This figure, however, shows that the individuals

            13    with the greatest change in QTc tend to be those with the

            14    shortest baseline QTc.  Within the ziprasidone database,

            15    therefore, there's no evidence that a patient with a higher

            16    baseline QTc will have a larger change from baseline.  It's

            17    quite the opposite.

            18                I'll now move on from a description of the QTc

            19    effect of ziprasidone to an examination of the ziprasidone

            20    clinical database for any evidence to suggest that this

            21    effect may be clinically meaningful.

            22                First of all, there have been no reports of

            23    torsade.  Other areas of particular relevance are

            24    mortality, syncope, and the overdose experience.  This

            25    graph presents the all-cause mortality rate of 1.6 per 100

                                                                           60

             1    patient years for ziprasidone alongside the comparator

             2    groups in the ziprasidone development program:  placebo,

             3    haloperidol, and risperidone, with 95 percent confidence

             4    intervals.  Patient years exposure and number of events are

             5    noted on the left-hand side.

             6                Now, on the lower half of the slide, we see as

             7    well the all-cause mortality rates for three recently

             8    approved antipsychotic agents, each with its own patient

             9    years of exposure at the time of marketing approval in the

            10    U.S.  Meta-analysis, the bottom row, refers to a recent

            11    publication by Brown in which an all-cause mortality rate

            12    among patients with schizophrenia was calculated to be 1.9. 

            13    While the data upon which this was calculated included a

            14    wide variety of populations, the mortality rate again

            15    appears consistent with that observed in contemporary

            16    antipsychotic development programs, and, as reported in the

            17    briefing document, there is no suggestion of an increase in

            18    mortality in the ziprasidone treatment group.

            19                It is recognized that torsade is not always

            20    fatal but can present clinically as a syncopal event.  This

            21    slide shows the incidence of syncope in our Phase II/III

            22    development program, up to the original NDA filing across

            23    the top half of the slide, and cumulative up to the recent

            24    safety update across the bottom.  As you can see, there is

            25    no excess of syncope in the ziprasidone group measured as

                                                                           61

             1    percent incidence or as syncopal events per 100 years of

             2    exposure in the ziprasidone group relative to the

             3    comparator groups.

             4                The overdose experience with ziprasidone

             5    includes 10 individuals who have ingested doses of up to

             6    4,600 milligrams.  There have been no significant

             7    cardiovascular adverse events.  Unfortunately, we do not

             8    have serum ziprasidone levels measured coincident with any

             9    of these overdose events.  But for two of them, we do have

            10    ECGs which were obtained around the time of the overdose.

            11                One patient in Australia reportedly ingested

            12    3,240 milligrams of ziprasidone.  Symptoms included and

            13    were limited to sedation and slurred speech.  ECGs were

            14    obtained approximately 4, 6, and 9 hours after the overdose

            15    and reveal a prolongation of approximately 20 milliseconds,

            16    compared to the three available pre-randomization QTc

            17    values.  The other individual had an ECG approximately two-

            18    and-a-half hours following a reported overdose of 1,880

            19    milligrams of ziprasidone taken with alcohol and

            20    paroxetine.  Post-overdose QTc was 372 milliseconds.  Pre-

            21    randomization QTc's were 331 and 385 milliseconds.

            22                I'd like to just summarize now the ziprasidone

            23    data concerning QTc and safety.  Studies conducted during

            24    the NDA development program and during the last two years

            25    since receipt of the non-approvable letter have well

                                                                           62

             1    characterized the QTc effect of ziprasidone.  It is modest,

             2    with a 6- to 10-millisecond change found in random ECGs

             3    obtained throughout the dosing interval at the therapeutic

             4    dose range of 80 to 160 milligrams daily.

             5                A peak effect of 15 to 20 milliseconds has been

             6    measured at the highest recommended dose of 160 milligrams

             7    per day.  The QTc effect appears to be limited as a

             8    function of its pharmacology, and importantly, due to the

             9    stability of the metabolism of ziprasidone.  There have

            10    been only two of 3,095 patients, with over 7,800 ECGs, two

            11    patients with a QTc of 500 milliseconds.  Unlike

            12    terfenadine and cisapride, the co-administration of

            13    ketoconazole with ziprasidone does not cause an increase in

            14    QTc prolongation.  In over 1,700 patient years of

            15    experience, there is no increase in mortality or syncope,

            16    and no cases of torsade.

            17                Finally, among 10 individuals who have reported

            18    overdoses with ziprasidone, there have been no significant

            19    cardiovascular adverse events, and no excessive QTc

            20    prolongation was found in two of these individuals.

            21                Having reviewed the effect of ziprasidone on

            22    the QTc and considered the clinical relevance of that

            23    effect, I'd now like to spend a short period of time

            24    discussing the effect of ziprasidone upon three major, well

            25    known cardiovascular risk factors:  body weight, lipids,

                                                                           63

             1    and glucose.

             2                The U.S. package inserts for antipsychotic

             3    drugs have, for a number of years, reported the incidence

             4    of clinically significant weight gain, defined as 7 percent

             5    of baseline body weight, in short-term placebo-controlled

             6    trials.  As shown on this slide, just under 10 percent of

             7    patients treated with ziprasidone experience this gain,

             8    compared to approximately 4 percent of placebo-treated

             9    patients.  The right-hand side of this slide shows the same

            10    information for the development programs for risperidone,

            11    quetiapine, and olanzapine, as reported in their U.S.

            12    package inserts.  Incidence rates of 18 percent, 23

            13    percent, and 29 percent were reported in association with

            14    those compounds, with rates in their placebo-control groups

            15    of 9 percent to 2 percent.

            16                Mean weight gains in the same patient

            17    populations are presented on this slide, the vertical axis

            18    on the left being marked in kilograms, on the right in

            19    pounds.  These mean weight changes, mean weight gains,

            20    range from 0.9 kilograms in ziprasidone-treated patients to

            21    2.8 kilograms in patients treated with olanzapine.  This is

            22    in short-term placebo-controlled trials.  Mean weight

            23    changes over longer treatment periods are shown on this

            24    slide; again, kilograms on the left, pounds on the right,

            25    number of kilograms indicated on the tops of the columns.

                                                                           64

             1                For ziprasidone patients, there's very little

             2    mean weight change, 0.2 kilograms.  The mean treatment

             3    duration is 83 weeks.  The haloperidol and risperidone data

             4    on the left side of this slide were obtained in the

             5    ziprasidone clinical development program, where increases

             6    of approximately 1 kilogram and 3 kilograms were measured

             7    over mean treatment periods of about a year.  The right-

             8    hand side of this slide displays data from U.S. package

             9    inserts or product monographs for risperidone, quetiapine,

            10    and olanzapine, with mean weight increases of 2.3, 5.6, and

            11    5.4 kilograms, over 6-, 12-, and 8-month treatment periods,

            12    respectively.

            13                In terms of body weight gain, ziprasidone

            14    appears weight neutral, a property which contrasts strongly

            15    with several recently approved antipsychotic agents.

            16                A measure of the effect of ziprasidone upon

            17    lipids was obtained in Study 054, where fasting lipid

            18    profiles were obtained.  This slide displays change from

            19    baseline, median change from baseline, with favorable

            20    changes highlighted in green, unfavorable changes in red. 

            21    Six treatment groups in Study 054 are ziprasidone,

            22    risperidone, olanzapine, quetiapine, thioridazine, and

            23    haloperidol.

            24                Although the treatment periods were short, as

            25    described earlier, decreases in serum cholesterol, LDL

                                                                           65

             1    cholesterol, and especially triglycerides, were seen with

             2    ziprasidone.  These favorable effects contrasted with

             3    several of the comparative drugs, where increases in

             4    triglycerides in particular were observed.  This pattern of

             5    change with ziprasidone can be confirmed over longer

             6    treatment periods with cholesterol.  Routine laboratory

             7    safety testing in our clinical development program included

             8    measurement of total cholesterol and samples obtained

             9    randomly in relation to meals.  This slide shows the median

            10    change in total cholesterol in patients receiving 28, 40,

            11    and 52 weeks of treatment, these three columns for the

            12    ziprasidone group.

            13                The picture in the ziprasidone-treated patients

            14    is fairly consistent with a median decrease of 10 to 12

            15    milligrams per deciliter observed.  Haloperidol and

            16    risperidone treated patients did not show this favorable

            17    change.

            18                Finally, I'd like to consider the properties of

            19    ziprasidone in relation to glucose intolerance.  As Dr.

            20    Casey mentioned, the prevalence of diabetes in the

            21    population with schizophrenia is higher than that in the

            22    general population.  There is some literature to suggest

            23    that this predates the usage of many of the newer atypical

            24    agents.  However, in the past several years, there's been a

            25    notable increase in case reports linking antipsychotic drug

                                                                           66

             1    therapy to diabetic ketoacidosis and new-onset diabetes,

             2    including the case series noted here, where previously non-

             3    diabetic patients in this series by Henderson from Mass

             4    General Hospital, previously non-diabetic patients were

             5    observed to develop diabetes over a five-year treatment

             6    period with clozapine, or to convert from a normal to an

             7    abnormal fasting blood sugar, as in Dr. Casey's patients at

             8    the Portland, Oregon VA Medical Center, with clozapine and

             9    olanzapine.

            10                These reports have caught the attention of the

            11    FDA.  Dr. Elizabeth Koller of the Endocrine Division

            12    reported what she described as unusually severe cases of

            13    hyperglycemia and diabetes in association with clozapine,

            14    and quite recently the Neuropharmacology Division cited

            15    these reports when requesting sponsors of atypical

            16    antipsychotic drugs to submit all data "which may assist us

            17    in more fully evaluating the possibility that atypical

            18    antipsychotics may produce disturbances in glucose

            19    regulation."

            20                In response to this request from the agency,

            21    Pfizer has recently submitted a summary of all data

            22    relevant to the issue of glucose intolerance.  Beyond

            23    randomly obtained glucose, two ziprasidone studies have

            24    included measures of fasting glucose, insulin, and related

            25    variables.  I am presenting laboratory data collected from

                                                                           67

             1    patients in Study 054, as well as data from an interim

             2    analysis of an ongoing, six-week, double-blind olanzapine

             3    comparative trial.  These data are not included in the

             4    briefing document.

             5                This slide shows the median change from

             6    baseline in body weight, triglycerides and insulin

             7    associated with both treatments.  Study 054 on top, Study

             8    R0548, the double-blind, six-week olanzapine comparative

             9    trial on the bottom.  As you can see, the increases in each

            10    of these three measures -- body weight, triglycerides, and

            11    insulin -- seen in association with olanzapine treatment,

            12    are not seen in ziprasidone-treated patients.  A consistent

            13    pattern of increasing body weight, triglycerides and

            14    insulin is suggestive of the insulin-resistant syndrome. 

            15    It is not seen with ziprasidone.

            16                To summarize these benefits, the effects of

            17    ziprasidone upon body weight and lipids have been observed

            18    consistently over short- and long-term treatment periods

            19    and contrast favorably with the adverse effects of several

            20    treatment alternatives.  Furthermore, there is no evidence

            21    of an association between ziprasidone and an insulin-

            22    resistant syndrome or glucose intolerance.

            23                The QTc effect of ziprasidone has been closely

            24    examined.  The effect of ziprasidone upon the QTc is well

            25    characterized and appears to be limited as a function of

                                                                           68

             1    its pharmacology and the stability of its metabolism. 

             2    Examination of over 2,000 QTc concentration data points

             3    reveals no suggestion of increased risk which might be

             4    associated with a subset of high exposure individuals.  In

             5    the 1,700 patient years of exposure to ziprasidone, there

             6    have been no reports of torsade and no suggestion of

             7    increased risk of arrhythmia-related clinical events.

             8                Ziprasidone is an effective and well tolerated

             9    treatment for a severe illness, and in contrast with the

            10    adverse effects of many other approved treatments,

            11    ziprasidone has favorable effects on well documented

            12    cardiovascular risk factors.  I propose that ziprasidone

            13    represents an important treatment option for patients with

            14    psychosis.

            15                Thank you, Dr. Tamminga and committee members,

            16    Dr. Katz and Dr. Laughren.  The sponsor is available to

            17    answer questions.

            18                DR. TAMMINGA:  Thank you, Dr. Harrigan, for

            19    your presentation.

            20                I'd like to do a short test of the microphone

            21    system before the committee starts asking its questions.

            22                THE REPORTER:  I think if participants speak

            23    close to the microphone, we'll be in good shape.

            24                DR. TAMMINGA:  Close to the microphone.

            25                Thank you, Dr. Harrigan and Pfizer, for your

                                                                           69

             1    presentation.

             2                The committee is welcome to ask Dr. Harrigan

             3    and any of the Pfizer people questions about their

             4    presentation.  It might be useful for us to limit our

             5    questions now to questions of clarification and not to

             6    necessarily get into the discussion of issues, which we can

             7    get into in more detail this afternoon.

             8                Dr. Lindenfeld?

             9                DR. LINDENFELD:  If I could start, I have just

            10    a few questions for Dr. Casey.

            11                Could you tell us the gender distribution of

            12    schizophrenia?  I'm sorry, but the cardiologist doesn't

            13    know that.

            14                DR. CASEY:  I'd be glad to.  Gender

            15    distribution is equally distributed in both men and women.

            16                DR. LINDENFELD:  I will come back to this point

            17    because I think a far greater number of the patients in

            18    these studies were men than women.

            19                Smoking.  Do the typical antipsychotics alter

            20    the incidence of smoking in these patients?

            21                DR. CASEY:  There's mixed evidence about that. 

            22    Some studies suggest they may modestly decrease smoking

            23    rates, and other studies show that there's no decrease.

            24                DR. LINDENFELD:  I guess we'll come back to

            25    that, because I'm wondering if this has any influence on

                                                                           70

             1    the weight change in these patients, if there's a

             2    differential incidence of smoking.

             3                Could you give us some idea of the number of

             4    other medications the average patient with schizophrenia is

             5    taking, and what general classification those would be? 

             6    Just roughly.  In other words, antihistamines.  I know

             7    Benadryl is used with these patients not infrequently.

             8                DR. CASEY:  I'm not able to recall a

             9    comprehensive survey of the total medicine regimen that

            10    patients with schizophrenia take, but they often take at

            11    least one antipsychotic, perhaps an antidepressant.  One-

            12    quarter to 50 percent of patients will be taking an

            13    antidepressant at one time or another.  If they're taking

            14    the typical neuroleptic or antipsychotic drugs, they'll be

            15    taking an anticholinergic drug, 50 percent of the patients. 

            16    Then they're likely to be taking other medicines for

            17    concomitant illnesses, such as diabetes or hypertension or

            18    other illnesses that the general population receives.

            19                DR. LINDENFELD:  I want to come back to this

            20    with Dr. Harrigan to just ask if the patients in 054 were

            21    on this typical range of medications.

            22                Let me ask you one other question, again from a

            23    cardiology viewpoint.  In a patient who doesn't have a good

            24    response to one of these atypical antipsychotics that's

            25    currently available, what is the incidence of an improved

                                                                           71

             1    response if one switches drugs, on the average?

             2                DR. CASEY:  There are very few studies to guide

             3    us to precise numbers.  The general clinical impression is

             4    that one should not reach therapeutic nihilism by people

             5    failing one drug and should continue to try with different

             6    medicines, as people do respond to one medicine when they

             7    fail to respond to another.  There is a substantial

             8    proportion of patients, 20 to 30 percent, who appear to

             9    repeatedly fail to respond to a series of medicines,

            10    indicating that we don't yet have a fully effective

            11    pharmacopeia for a large group of people.

            12                DR. LINDENFELD:  Do you have a rough idea of

            13    the incidence of response to one drug when you've failed

            14    another?  High?  Low?  Medium?

            15                DR. CASEY:  I'd put it in the medium category.

            16                DR. LINDENFELD:  Okay, good.  Then you said

            17    that 40 percent of these patients are not taking their

            18    medicines as prescribed.  Could you give me a rough idea of

            19    what that means?  They're overdosing themselves? 

            20    Underdosing themselves?  Or do we know?

            21                DR. CASEY:  The compliance studies usually

            22    assess whether people are taking their medicines or not,

            23    and the compliance numbers usually mean not taking the

            24    medicines.  The compliance studies are mostly verbal

            25    reports, and sometimes reporting accuracy is somewhat

                                                                           72

             1    imprecise, as I imagine it is in hypertension and other

             2    areas.

             3                DR. LINDENFELD:  And then just a couple of

             4    quick questions for Dr. Harrigan.  You showed us the

             5    overall QTc data.  Could you divide that up between men

             6    versus women?  We know there's a propensity for women to

             7    have torsade, and I'm interested if there's a difference. 

             8    There's a small number of women here.

             9                DR. HARRIGAN:  Sure.  If we could look at Slide

            10    M43, what we're showing you here is the mean change from

            11    baseline.  This is the short-term, fixed-dose, placebo-

            12    controlled.  So we're looking at change from baseline by

            13    dose in men versus women, with males in blue and the green

            14    bars being female.  You see it in the legend here.  So a

            15    dose is less than 40, 40, 80, 120, 160, and 200 milligrams

            16    or more per day.

            17                There appear to be no consistent suggestions of

            18    a greater increase in females compared to males.  This is

            19    using the Bazett formula.

            20                DR. LINDENFELD:  How many women in this group?

            21                DR. HARRIGAN:  In this group, the N of females

            22    -- let's see, we could add them up -- is 173.

            23                DR. TAMMINGA:  Dr. Harrigan, are these data

            24    from the Phase II/III studies or from Study 054?

            25                DR. HARRIGAN:  Phase II/III studies.

                                                                           73

             1                DR. TAMMINGA:  Do you have the same data from

             2    Study 054?  Do you have gender data from 054?

             3                DR. HARRIGAN:  M181.  In Study 054, the number

             4    of females was, of course, smaller.  But here it is for all

             5    of the treatment groups.  This is mean change at steady

             6    state by gender.  Again, male is blue and female is green. 

             7    For ziprasidone, nine females, 22 males, as you see for the

             8    other antipsychotic groups as well.

             9                DR. LINDENFELD:  Slide number 61, where you

            10    showed us the distribution of the change in QTc according

            11    to the baseline QT, that was not the Bazett correction,

            12    right?

            13                DR. HARRIGAN:  Correct.  That's the baseline

            14    correction.

            15                DR. LINDENFELD:  So we might see a slightly

            16    different distribution if we had the Bazett correction in

            17    there.  The reason I ask that is because that's sort of the

            18    standard way that most people evaluate the QTc still, we

            19    look in the literature.

            20                DR. HARRIGAN:  We could show you that if you'd

            21    like to see it.

            22                DR. LINDENFELD:  That would be great.

            23                DR. HARRIGAN:  The Bazett formula.

            24                DR. TAMMINGA:  While you're looking for that

            25    slide, Dr. Harrigan, would you like to comment on Dr.

                                                                           74

             1    Lindenfeld's other question?  Would you like to remark on

             2    the gender distribution in these studies?

             3                DR. HARRIGAN:  The gender distribution in these

             4    studies is probably close to 70 percent male, 30 percent

             5    female.

             6                DR. LINDENFELD:  I thought you said 75 percent

             7    for 054.

             8                DR. HARRIGAN:  For 054, yes.

             9                So this is, again, change from baseline,

            10    baseline, and this is using the QTc correction formula of

            11    Bazett.

            12                DR. LINDENFELD:  Thank you.

            13                DR. TAMMINGA:  Dr. Oren?

            14                DR. OREN:  One question for Dr. Harrigan.  You

            15    presented data on the particular effect of ziprasidone on

            16    lipid levels.  Do you have any additional data dividing

            17    that by baseline levels of lipid levels?

            18                DR. LINDENFELD:  The same slide as for the QTc?

            19                DR. HARRIGAN:  Right.  No, we don't.

            20                DR. TAMMINGA:  Dr. Califf?

            21                DR. CALIFF:  Dr. Lindenfeld took most of the

            22    questions right out of my mouth.  I guess it's evidence of

            23    having been on the same committee for a few years.  But I

            24    think what she was getting at, I'd really hope to find out

            25    a little bit more about whether the patients that you've

                                                                           75

             1    enrolled in these studies represent the patients who are

             2    likely to be treated in practice.  I think she was getting

             3    at it in several different ways.

             4                Were the number of medications these patients

             5    were on the same as what you would see in clinical

             6    practice?  Was the age distribution the same?  And I'm

             7    particularly interested in the mortality rate.  I think the

             8    mortality rate you have in your studies is quite a bit

             9    lower than what's in the general population of people with

            10    schizophrenia, but I'm not sure about that.  Do you have

            11    data that would allow us to compare the patients that are

            12    in your studies, both with regard to baseline

            13    characteristics, treatment, and outcome, with what's seen

            14    in the general population of people with schizophrenia?

            15                DR. HARRIGAN:  In terms of the mortality rate

            16    in the general population with schizophrenia, I think the

            17    Brown meta-analysis and a very similar meta-analysis

            18    written by Harris using pretty much the same data came out

            19    with the 1.9 figure, and that data is fairly similar.  I

            20    don't know of any other mortality studies other than the

            21    Saskatchewan data that Dr. Casey presented.

            22                In terms of the population in the ziprasidone

            23    clinical trials, if we could look at G11 and G12, we did

            24    look at the incidence of three cardiovascular conditions at

            25    baseline in the ziprasidone Phase II/III program.  So the

                                                                           76

             1    number of patients entering studies with hypertensive

             2    disease, ischemic heart disease, and other forms of heart

             3    disease, for hypertensive disease, 8.4 percent of the

             4    population in the ziprasidone clinical trials had a history

             5    of hypertensive disease at baseline.

             6                If we could look at the next slide, we went

             7    back and looked at the Saskatchewan database that Dr. Casey

             8    described, those 3,022 patients in the Saskatchewan public

             9    health database who have schizophrenia.  The incidence of

            10    hypertension in that group is 9.9 percent, compared to the

            11    8.4 percent seen in the ziprasidone clinical trial

            12    population.  So the clinical trial population is just a

            13    little bit younger than that Saskatchewan population.  It's

            14    similar to the age distribution of the clinical development

            15    programs for the other antipsychotic drugs and the tendency

            16    to enroll patients who are somewhat younger, unless the

            17    drug is being developed for dementia as well, in which case

            18    older patients are in the trials.

            19                DR. CALIFF:  Do you have a list of the

            20    inclusion and exclusion criteria from these studies?

            21                DR. HARRIGAN:  Yes, we do.  G19.  G9.

            22                This N doesn't add up to the full N of the

            23    development program.  We really selected a subset of trials

            24    with at least 100 patients to get an estimate.  Clinical

            25    exclusion criteria were fairly broad.  Clinically

                                                                           77

             1    significant and/or relevant physical illness for some of

             2    the European studies, significant cardiovascular disease,

             3    including uncontrolled hypertension, hypotension,

             4    congestive heart failure, angina, myocardial infarction

             5    within the past six months.

             6                The QTc issue in terms of enrolling patients,

             7    almost 90 percent, 89 percent of patients were enrolled in

             8    the ziprasidone clinical ECG database prior to the request

             9    by FDA that QTc's be screened and 450-millisecond QTc's be

            10    identified prior to enrollment.  So there were no

            11    enrollment restrictions on baseline QTc for the vast

            12    majority of EKG data you're seeing.

            13                DR. CALIFF:  Were there concomitant medication

            14    exclusions?

            15                DR. HARRIGAN:  There were in the efficacy

            16    trials.  Certainly, some of the psychotherapeutic agents

            17    were excluded.  Lorazepam and benzotropine were the

            18    sedative and anticholinergic agents of choice in those

            19    double-blind efficacy trials.  The exclusions widened or

            20    broadened as you got into the longer-term studies,

            21    particularly the open-label extension studies.

            22                Table 35 on page 95 of the briefing document

            23    presents a list of selected concomitant medications to give

            24    you an idea of how many patients on different concomitant

            25    medications were enrolled in the ziprasidone development

                                                                           78

             1    program, and I think it provides the QTc changes in those

             2    patients as well.

             3                DR. TAMMINGA:  Dr. Moss has a question.

             4                DR. MOSS:  Were any Holter recordings obtained

             5    during the course of any of the studies?  And were QTc

             6    measurements made during any Holter recordings or during

             7    exercise testing?

             8                DR. HARRIGAN:  No Holter recordings, and no

             9    specific exercise testing of patients.

            10                DR. TAMMINGA:  Dr. Winokur?

            11                DR. WINOKUR:  A couple of questions.  First,

            12    going back to data you presented earlier on the dose range

            13    for efficacy, you mentioned a range of 80 milligrams to

            14    160, and it looks like, if I read the figure on 17

            15    correctly, that there were two studies that you've

            16    indicated at 80 milligrams, one of which shows improvement,

            17    one which doesn't, the 104.  I'm wondering if there's a

            18    reason why the 80 milligram dose is viewed as being

            19    clinically effective even with one of two trials not

            20    showing that.

            21                DR. HARRIGAN:  I guess there are two parts to

            22    the answer.  The 80 milligram dose in Study 104 was not

            23    more effective than placebo.  None of the three ziprasidone

            24    doses in that study -- that was essentially a failed study. 

            25    There was no active comparator.  The data I think is

                                                                           79

             1    described in a little more detail in the briefing document,

             2    as you know.  So we do have one study with an 80 milligram

             3    per day dose, Study 114, with fairly robust efficacy. 

             4    There was also Study 115 with a 40 milligram per day dose

             5    being more effective than placebo, significantly more

             6    effective.

             7                So as a sense of the data and having to

             8    interpret sometimes inconsistent data across different

             9    studies, it seems that the most prudent choice for acute

            10    exacerbation would be about 40 milligrams per day,

            11    ineffective in two out of three trials, but at 80

            12    milligrams per day.

            13                DR. WINOKUR:  And the other question I had, I

            14    think you made reference to, among other factors that can

            15    affect QTc is circadian factors, and I think you've already

            16    answered this, but was there any assessment in this study,

            17    for example with Holter monitoring, for sleep-related

            18    changes?

            19                DR. HARRIGAN:  No.

            20                DR. TAMMINGA:  Dr. Rudorfer?

            21                DR. RUDORFER:  Just to clarify the concomitant

            22    medication issue, the taper and washout only applied to

            23    existing antipsychotic drugs in Study 054?

            24                DR. HARRIGAN:  No.  Patients were tapered

            25    pretty much from all concomitant medications.  There is

                                                                           80

             1    some lorazepam that was permitted, and benzotropine was

             2    permitted for extra-prandial symptoms, if necessary.

             3                DR. RUDORFER:  Okay.  So at the time of

             4    baseline ECG, patients had been totally med free for five

             5    days?  Is that correct?

             6                DR. HARRIGAN:  No, for at least two days. 

             7    There is a five-day placebo washout.  It was on the last

             8    three of those days that ECGs were obtained.  So the

             9    patients were tapered prior to the beginning of the

            10    washout, as much as was felt to be appropriate by the

            11    investigator for that patient.  They then began the single-

            12    blind placebo washout.  So there were two days of pure

            13    washout, and then the next three days we obtained ECGs on

            14    each of those three days.

            15                In analyses that we don't have, there didn't

            16    appear to be any evidence of QTc change over those last

            17    three days of the baseline period.

            18                DR. RUDORFER:  Thank you.

            19                DR. TAMMINGA:  Dr. Fyer?

            20                DR. FYER:  I just have one quick clarification

            21    question.  You cited this figure looking at all the patient

            22    years and the number of people with heart rate greater than

            23    500, QTc interval greater than 500.  I know in the 054

            24    study, you did things at the maximum drug level.  That's

            25    sort of putting everything together, not just the 054.  I

                                                                           81

             1    wondered if the other reportings, they were not done at the

             2    maximum level.  Is that correct?  They were just done

             3    whenever they were done, or mainly during the trial period?

             4                DR. HARRIGAN:  No, they were done pretty much

             5    at random.  I mean, some were from hospitalized patients

             6    with dose-administered BID.  There may have been slight

             7    consistencies in the time of the ECGs relative to dose, but

             8    overall they were random, and many of the studies were

             9    outpatient studies.  So there's no timing in relation to

            10    dose, with the exception of Study 054.

            11                DR. FYER:  So it doesn't reflect the maximum

            12    level, like the 054.

            13                DR. HARRIGAN:  The 054 is the only study that

            14    was specifically designed to reflect the Cmax.

            15                DR. TAMMINGA:  Dr. Marder?

            16                DR. MARDER:  I just have one question.  If you

            17    could go back to Study 054, what proportion of patients who

            18    were screened were excluded for having a prolonged QTc?

            19                DR. HARRIGAN:  Zero.  We had no one excluded

            20    from Study 054 for prolonged QTc at baseline.

            21                DR. TAMMINGA:  Dr. Lindenfeld?

            22                DR. LINDENFELD:  Just one other question.  You

            23    said aldehyde oxidase, there were no metabolic interactions

            24    that had been reported.  Is that affected by alcohol?

            25                DR. HARRIGAN:  I might ask Dr. Christine

                                                                           82

             1    Beedham to address that question.

             2                DR. BEEDHAM:  Good morning, ladies and

             3    gentlemen.  Aldehyde oxidase does metabolize acetaldehyde,

             4    which is generated from alcohol.  But it's not thought to

             5    contribute to the metabolism of ethanol in vivo.  Aldehyde

             6    dehydrogenase is usually the enzyme that is thought of as

             7    the main contribution.  So ethanol is not reported to have

             8    any effect on aldehyde oxidase activity, either as an

             9    inducer, because it does induce some forms of cytochrome

            10    P450.  But it's not been shown to induce aldehyde oxidase,

            11    and it is not thought to inhibit aldehyde oxidase either.

            12                Does that answer your question?

            13                DR. TAMMINGA:  Could you further clarify for us

            14    if there are common inhibitors of aldehyde oxidase?

            15                DR. BEEDHAM:  There are a few inhibitors that

            16    have been identified in vitro.  Menadione is the one that

            17    is usually used to characterize aldehyde oxidase in vitro,

            18    and you can see later that ziprasidone metabolism was

            19    inhibited by menadione in vitro.  But there are no reported

            20    drug interactions in vivo with aldehyde oxidase.

            21                Phenothiazines are actually in vitro

            22    inhibitors, but there are no reported drug interactions in

            23    vivo with this enzyme.

            24                There's very little known about it as far as

            25    the in vivo studies that have been done so far, so there

                                                                           83

             1    isn't an inhibitor that one could choose that would perturb

             2    the system.

             3                DR. TAMMINGA:  Dr. Moss?

             4                DR. MOSS:  This is for Dr. Harrigan.  Did

             5    anyone look at the morphology of the T waves?  All we've

             6    heard about is the QT interval, but was the configuration

             7    of the T waves altered at all by the medication?

             8                DR. HARRIGAN:  The ECGs in the ziprasidone

             9    development program were all submitted through a central

            10    reader for interval measurement.  The local readings were

            11    in the protocols in the U.S., which is probably two-thirds

            12    of the total database, by protocol required a board-

            13    certified internist or cardiologist to do the reading, and

            14    we collected that data.  There was data collection on T

            15    wave inversion in the clinical development program. 

            16    There's no evidence of T wave inversion in any particular

            17    treatment group.

            18                The morphology of ECGs in the individuals who

            19    experienced death were reviewed by Dr. Craig Pratt.  I'd

            20    like Dr. Pratt to help with this answer.

            21                DR. PRATT:  In the EKGs that pertained to the

            22    patients who had unexpected sudden death, we looked at all

            23    ECGs pre and post.  No T wave abnormalities.  In the one

            24    patient in Table 38 with QT prolongation at all was a

            25    patient off ziprasidone for two days and on thioridazine.

                                                                           84

             1                DR. TAMMINGA:  Dr. Laughren?

             2                DR. LAUGHREN:  I have a question for Dr.

             3    Harrigan, and this relates to the post-prandial effect on

             4    QTc that I didn't appreciate as much as I do now.  From one

             5    of your earlier slides you suggested that the post-prandial

             6    effect is somewhere in the vicinity of 16 to 23

             7    milliseconds.  I guess my question is, in Study 054, as I

             8    understand it, the baseline was done in a fasting state. 

             9    In the steady-state phase, I gather the patients --

            10    basically, this was in a fed state, perhaps not post-

            11    prandial, but patients were allowed to eat their usual

            12    meals during that phase.

            13                So I guess the question I'm asking is, is it

            14    possible that some of the QTc change that you're seeing,

            15    the change from baseline, is in part a food effect on the

            16    QTc?

            17                DR. HARRIGAN:  We believe we control for that. 

            18    The patients were allowed to take meals certainly, but the

            19    timing of the meals was rigidly controlled depending upon

            20    the timing of the dose, and the timing of the ECGs,

            21    actually.  All ECGs were obtained after at least three

            22    hours of fasting.  So we deliberately timed the ECGs to

            23    avoid the post-prandial effect that you described.

            24                DR. LAUGHREN:  So you're confident that none of

            25    that change is basically a post-prandial event.

                                                                           85

             1                DR. TAMMINGA:  Dr. Winokur?

             2                DR. WINOKUR:  I have a question for Dr. Casey. 

             3    If you can think of any data or from clinical experience

             4    about the extent to which obstructive sleep apnea is an

             5    important clinical issue for the schizophrenia population.

             6                DR. CASEY:  As far as we know, it is not

             7    increased risk for patients with schizophrenia at normal

             8    weights, but as one increases weight, like the general

             9    population, one increases the risk, as best we know.

            10                DR. TAMMINGA:  Dr. Katz?

            11                DR. KATZ:  Also a question for Dr. Harrigan. 

            12    You presented a number of slides talking about the long-

            13    term effects on what you called the cardiovascular risk

            14    factors, cholesterol and that sort of thing, maybe even

            15    weight gain and triglycerides.  Of course, the numbers

            16    decreased as time went on.

            17                I'm just wondering if you can comment about how

            18    many folks dropped out of those cohorts, why they dropped

            19    out.  I assume it's not complete follow-up on everyone who

            20    started.

            21                DR. HARRIGAN:  No.  The long-term measurements

            22    of cholesterol that we presented were in patients who had

            23    completed at least 28 weeks of treatment, and there you

            24    saw, whether we looked at 28, 40, or 52 weeks in those sets

            25    of patients, the change was fairly consistent, at 10 to 12

                                                                           86

             1    milligrams percent.  As you know, the dropout rate in

             2    trials in this area is generally over 50 percent, and

             3    that's been true of virtually all the trials that we've

             4    run.

             5                DR. TAMMINGA:  Dr. Harrigan, in this regard,

             6    don't you have data from a 12-month inpatient study where

             7    you had a much lower dropout rate?

             8                DR. HARRIGAN:  Yes, Study 303.  That was the

             9    relapse prevention study.  We do have data from that, but

            10    cholesterol was not measured in those patients.

            11                DR. TAMMINGA:  Dr. Cook?

            12                DR. COOK:  Getting back to the question about

            13    inhibitors of aldehyde oxidase, it was mentioned that there

            14    were in vitro inhibitors, specifically phenothiazine, but

            15    there was no in vivo inhibition, and I wanted to clarify

            16    whether it has actually been sufficiently tested in vivo to

            17    rule that out.

            18                I might as well ask the second question, which

            19    is any other evidence of concomitant use or sequential use

            20    close in time of thioridazine and ziprasidone, considering

            21    the fact that this might be given concomitantly, or

            22    certainly patients might be switched.

            23                DR. HARRIGAN:  We've generally excluded the

            24    concomitant antipsychotic medication in our clinical

            25    trials, including thioridazine.

                                                                           87

             1                I might ask Dr. Beedham to address the aldehyde

             2    oxidase part of the question.

             3                DR. BEEDHAM:  Could I have Slide 43 from the CP

             4    slides, please?

             5                The studies that we carried out with

             6    chlorpromazine and other inhibitors in vitro have generally

             7    been carried out on oxidation reactions that are catalyzed

             8    by aldehyde oxidase.  This tells you a little bit about the

             9    enzyme here.  It's a little less known than cytochrome

            10    P450, but it has a very wide substrate specificity.  As you

            11    can see from here, it's a molybdenum-containing enzyme,

            12    very high concentrations in the liver.  There's less found

            13    in the lung and the kidney.  It catalyzes the oxidation of

            14    a very wide range of nitrogen-containing heterocycles,

            15    compounds like zaladines, perimadines, purines,

            16    quinazolines, and quaternary compounds like nicotinamide.

            17                As you can see, it also catalyzes the oxidation

            18    of aldehydes.  But in addition to that, it will also

            19    catalyze the reverse reaction.  Once the enzyme has been

            20    reduced, it can transfer the electrons to a compound such

            21    as containing a nitro group, sulfoxides, isoxizoles, and in

            22    this case ziprasidone.  So it reduces ziprasidone, whereas

            23    most of the studies that have been carried out up to now

            24    have been on the oxidation of other substrates.

            25                Now, there are relatively few drugs that are

                                                                           88

             1    primarily cleared by this enzyme.  The one that we know

             2    most about is famciclovir.  Famciclovir is, in fact, a pro-

             3    drug.

             4                Can we go to slide 51, please, in this series?

             5                Famciclovir has been on the market I think

             6    around seven years.  Famciclovir itself is not active.  It

             7    has to be activated to the quanime nucleoside.  It

             8    undergoes two hydrolysis steps, one in the gut and one in

             9    liver, followed by an oxidation reaction that is catalyzed

            10    by aldehyde oxidase, and this produces the active moiety

            11    penciclovir.  So this has been on the market for around

            12    five to seven years.  There is no clinically significant

            13    drug interactions that have been observed with famciclovir

            14    over all that time.

            15                Cimetidine, which is a weak inhibitor of

            16    aldehyde oxidase, as indeed it is a weak inhibitor of

            17    cytochrome P450, actually causes an increase in the area

            18    underneath the curve.  Allopurinol, the reason this drug

            19    was tried in vivo is because this is a xanthene oxidase

            20    inhibitor, but it actually has no effect on aldehyde

            21    oxidase activity.

            22                So if we then go back to slide 43, there are no

            23    clinical drug-drug interactions resulting from the

            24    alteration of human aldehyde oxidase activity. 

            25    Athenoziasines inhibit oxidation in vitro.  In fact,

                                                                           89

             1    they're a potent inhibitor.  When they were tested with

             2    ziprasidone, they were weak inhibitors in vitro.  This is

             3    probably because you've got a reductive pathway rather than

             4    an oxidation pathway, and the substrates are acting at

             5    different sites on the enzyme.  So you would not

             6    necessarily expect that in vitro inhibition to be seen in

             7    vivo.

             8                I think there's a further point that could be

             9    made on the slide there, that there's very little variation

            10    that is known in humans.  For all the studies that have

            11    been done with famciclovir, there aren't any indications of

            12    any poor metabolizers, so you could get high concentrations

            13    of ziprasidone.  So there are no perturbations of the

            14    system that we're aware of at the moment that would either

            15    inhibit, induce, or interfere with the metabolism of

            16    ziprasidone by aldehyde oxidase.

            17                DR. COOK:  One follow-up question.  Could you

            18    comment more specifically on Sonata potential interactions,

            19    and also whether that was given concomitantly, although I

            20    suspect not.  I'm just curious, because that would be more

            21    likely, I suppose.

            22                DR. BEEDHAM:  Sonata is metabolized -- can you

            23    just go back to that slide, please, 43?  It's not

            24    completely cleared by aldehyde oxidase.  In fact, I think

            25    it's a 3A4 pathway plus an aldehyde oxidase pathway, so

                                                                           90

             1    it's similar in that respect to ziprasidone.

             2                They did I think a cimetadine interaction

             3    study, which caused very weak inhibition.  It had very

             4    little effect.  But the enzymology of the actual

             5    interaction hasn't been absolutely clear with Zalapron

             6    anyway, and as you can see, it's an oxidative reaction, not

             7    a reductive reaction, so you would not necessarily expect

             8    the same spectrum of inhibitor.

             9                DR. LINDENFELD:  Could I ask one more question?

            10                DR. TAMMINGA:  Yes, Dr. Lindenfeld.

            11                DR. LINDENFELD:  Because bradycardia is a

            12    predisposing factor for torsade, I wonder if Dr. Harrigan

            13    could tell us if there was a heart rate exclusion from

            14    these studies.

            15                DR. HARRIGAN:  There was no heart rate

            16    exclusion, no.

            17                One other additional point.  The package insert

            18    for Sonata mentions potential interactions with

            19    diphenhydramine and cimetadine, as Dr. Beedham I think

            20    mentioned.  We have conducted interaction studies with both

            21    of those compounds diphenhydramine and cimetadine, and

            22    found no significant interaction, no meaningful interaction

            23    between those drugs.

            24                DR. TAMMINGA:  The committee would like to

            25    thank Pfizer for their presentation, and we'll take a

                                                                           91

             1    break.  Before our morning coffee break, Sandra Titus has

             2    an announcement to make.

             3                DR. TITUS:  If there's anyone else who would

             4    like to participate in the open public hearing which will

             5    take place right after the noon hour, please come up and

             6    speak to me during this break.

             7                DR. TAMMINGA:  I'd like to ask people to come

             8    back at about 10:35, please, to take a 15-minute break. 

             9    Thank you.

            10                (Recess.)

            11                DR. TAMMINGA:  I'd like to start the second

            12    half of the morning.  This will include the FDA

            13    presentations.

            14                To begin the FDA presentations, we'll start

            15    with the introduction by Tom Laughren, who is the team

            16    leader for the psychiatric drug products.

            17                Dr. Laughren.

            18                DR. LAUGHREN:  I just want to make a few brief

            19    comments to introduce the FDA presentation.  If I could

            20    have the next slide?

            21                There are two parts to the presentation.  We've

            22    asked Dr. Moss to give a general overview of the QTc, talk

            23    about what it is, why one needs to be concerned about it,

            24    what sort of data are available to lead one to conclude

            25    that it's a problem and so forth, and then we're going to

                                                                           92

             1    have a number of speakers from the Center talk about the

             2    drugs in each of their areas that have a QT problem and the

             3    kind of thinking that's gone into working those drugs up

             4    and making decisions about them, so that you can get an

             5    overall perspective on how the Center has dealt with this

             6    issue.

             7                There isn't any clearly articulated policy

             8    about how to deal with the QTc issue, but I think what

             9    you'll see emerging from these talks is a series of

            10    principles that are looked at in working up drugs and

            11    making decisions.

            12                If I could have the next slide, what I'm going

            13    to do is try to take a stab at summarizing what I think

            14    these principles are so that as you hear these talks you

            15    can focus on these issues.

            16                One issue is the indication itself and the

            17    availability of treatments for the indication.  A second

            18    issue is the observed QTc effect.  A third is other

            19    evidence suggestive in the database of a serious outcome

            20    associated with the QTc effect.  Finally, this issue of a

            21    drug having a metabolic problem.

            22                If I could have the next slide, please.

            23                First of all, the indication itself.  One thing

            24    that I think you'll hear is the seriousness of the

            25    indication is one thing that factors into the thinking

                                                                           93

             1    about how to deal with the QT issue.  How effective are

             2    available treatments?  How many alternative treatments are

             3    available?  How does the new treatment compare with other

             4    treatments in the class with regard to efficacy, and also

             5    with regard to safety?

             6                Next slide, please.

             7                The second issue is the actual size of the QTc

             8    effect, both in terms of the mean effect in the dose range

             9    that's proposed, but also the proportion of outliers, any

            10    way that you look at outliers, whether you look at the

            11    proportion of patients who have a change of a particular

            12    size from baseline, or the proportion of patients meeting

            13    some threshold criterion such as 500 milliseconds.

            14                Next slide, please.

            15                A third issue is whether or not there's any

            16    other evidence of a drug with a QTc effect having any

            17    effect on either overall mortality or any evidence

            18    suggestive of sudden, unexplained deaths, whether that's in

            19    the NDA database or from some other source.  Another way of

            20    looking at that is actual cases of torsade or some other

            21    serious ventricular arrhythmia occurring again within the

            22    NDA database or from some other source.  Finally, as was

            23    pointed out earlier, sometimes torsade may present with

            24    syncopal episodes, so one would be interested in looking at

            25    syncope as a surrogate.

                                                                           94

             1                Next slide, please.

             2                Then finally this issue of the metabolic

             3    problem, and that is basically the vulnerability of a

             4    particular drug to have its plasma levels increased by

             5    virtue of its metabolism being inhibited by a co-

             6    administered drug that interferes with its clearance or its

             7    use in some subpopulation who don't have the ability to

             8    metabolize that drug very efficiently.

             9                Next slide, please.

            10                Now I want to turn briefly to the questions. 

            11    As I mentioned earlier, there are the two general questions

            12    that we always ask you to discuss.  First of all, has the

            13    sponsor provided evidence from more than one adequate and

            14    well-controlled clinical investigation that supports the

            15    conclusion that ziprasidone is effective for the treatment

            16    of schizophrenia?  Secondly, has the sponsor provided

            17    evidence that ziprasidone is safe when used in the

            18    treatment of schizophrenia?  Of course, the QT issue is

            19    embedded in the safety question.

            20                Next slide, please.

            21                Now, if you respond positively to the two

            22    general questions, there are a number of additional

            23    questions that we'd like you to discuss.  There isn't any

            24    need to actually have a vote on these additional questions,

            25    but we would like to have them fully discussed.

                                                                           95

             1                Next slide, please.

             2                This is really the hardest question:  Do you

             3    think that ziprasidone's risk of serious ventricular

             4    arrhythmias and sudden unexplained death is greater than

             5    that of most other drugs in this class, even if that excess

             6    risk cannot be quantified?

             7                Now, there are several ways you can think about

             8    this question, and it depends on really what your belief is

             9    about whether or not there's a continuum of drugs in this

            10    class and their effects on QT or whether in some sense

            11    ziprasidone stands apart.  From Study 054, there was a

            12    suggestion of a change from baseline in the four other

            13    drugs that it was compared with.  There was no placebo in

            14    that trial, so it's hard to know what that means.  In other

            15    settings, we've never seen a difference between haloperidol

            16    and placebo.  But if you think that this is a continuum,

            17    then the question is does this somewhat greater effect on

            18    the QTc with ziprasidone convert into some real greater

            19    risk of serious outcome?  So that's really the question.

            20                Next slide, please.

            21                If you believe there is some excess risk, even

            22    though it's not quantified, associated with this drug in

            23    terms of risk of ventricular arrhythmias or sudden

            24    unexplained death, and you nevertheless believe that the

            25    drug can be approved, the question for us is how should

                                                                           96

             1    this risk be handled in labeling?  That's a very difficult

             2    problem.

             3                Next slide, please.

             4                One way of handling this -- and, as you well

             5    know, from our recent action on thioridazine, I think the

             6    "Dear Doctor" letter probably went out last week, for that

             7    particular drug with its effect and the fact that there are

             8    cases of torsade reported with that drug, we've chosen to

             9    make it a second-line drug.  So that's the first question,

            10    whether or not the QT effect you're seeing here warrants a

            11    second-line status or if it can be a first-line status

            12    drug.

            13                Next slide, please.

            14                Another issue is how should the warning be

            15    conveyed in labeling?  Basically, what we're talking about

            16    here is a choice of two, either a black box or a more

            17    typical warning statement.

            18                Next slide, please.

            19                Finally, for drugs that have serious side

            20    effects, in recent years we have often prepared a patient

            21    package insert to inform patients and families about the

            22    risks of using the drug.  This is particularly important if

            23    there are conditions to be avoided.  So another question

            24    here is whether or not there should be some kind of patient

            25    material that would accompany the labeling of this drug.

                                                                           97

             1                Next slide, please.

             2                Finally, I want to talk about the possibility

             3    of asking for additional studies, focused both on safety

             4    and on efficacy.  A further question is if we were to ask

             5    for these studies, when should these studies be done? 

             6    Should these studies be done before any approval decision,

             7    or would this be a Phase IV commitment?

             8                If I could have the next slide, please.

             9                Assuming that there is some unquantifiable risk

            10    associated with this greater effect on the QTc, the next

            11    logical question is how would one go about quantifying

            12    that?  It would be a very difficult study to do, but one

            13    possible study would be to do a large comparative trial to

            14    try to estimate or rule out at some level a risk of excess

            15    sudden unexplained death associated with the use of the

            16    drug.  If there's interest, we can talk more about this. 

            17    As I say, it would be a difficult study to do.  It would

            18    have to be large, and there would have to be some further

            19    explanation of a number of kinds of information that would

            20    have to go into the design of that trial that are not

            21    easily available.

            22                Next slide, please.

            23                Finally, there's the question of whether or not

            24    there is something on the efficacy side to balance the

            25    excess risk that may be associated with the QTc effect.  So

                                                                           98

             1    the next question that comes up, should there be some kind

             2    of study to look to see if there is some extra benefit in

             3    terms of efficacy associated with the use of this drug? 

             4    The only other example that I can think of recently where

             5    we've done this is with the drug clozapine, where patients

             6    who were refractory to standard therapy were studied and it

             7    was shown that clozapine had an advantage over standard

             8    therapy.  So the question is, should this kind of study be

             9    done for a drug with this effect?

            10                I will stop at this point, and I think Dr. Moss

            11    is going to be the first speaker.

            12                DR. TAMMINGA:  Dr. Moss is professor of

            13    cardiology at Rochester Medical Center.

            14                DR. MOSS:  Dr. Tamminga, Dr. Katz, Dr.

            15    Laughren, members of the Advisory Committee and attendees,

            16    I've been asked to give an introduction to the QT issue

            17    problem, and I'll do so with some slides.

            18                If we could see the first slide?  I wonder if

            19    somebody could just turn on the slide machine?

            20                PARTICIPANT:  The carousel is empty.

            21                DR. MOSS:  The carousel is empty?  Well, there

            22    should be a carousel over there.

            23                That's what's called a double-blind

            24    presentation.

            25                (Laughter.)

                                                                           99

             1                DR. MOSS:  We may need the lights down just a

             2    little bit on this first slide and not on the rest of them. 

             3    This is really an overview of the whole relationship

             4    between the electrocardiogram with the QT interval, and

             5    what you can't see is that in the dotted line, the

             6    prolongation of the interval, the action potential -- that

             7    is, the characteristic cellular action potential -- and the

             8    prolongation of the action potential that occurs that is

             9    probably responsible for the manifest QT prolongation on

            10    the electrocardiogram, and the channels that are involved

            11    in the action potential, with particular focus on the

            12    potassium channels that are responsible for the

            13    repolarization phase.

            14                It's the repolarization that is the energy-

            15    requiring process, and the drugs that have some concern are

            16    drugs that seem to interfere with the potassium delayed

            17    rectifier occurrence.  As shown in a little bit more

            18    schematic over here on the right side, there are, in

            19    essence, two major groups of potassium channels that are

            20    currently well described.  There are many more potassium

            21    channels, but two are the so-called IKs, the slowly-

            22    activating potassium repolarization current, and it does

            23    not appear that there are a lot of drugs that have a lot of

            24    effect upon this potassium channel.

            25                But the other channel, the HERG channel, which

                                                                          100

             1    is co-assembled with another protein that is referred to as

             2    the IKr channel or the rapidly-activating delayed potassium

             3    repolarization channel, is the one where the drug seemed to

             4    have some effect in a variety of different studies.  It's

             5    this alteration that changes the kinetics of this channel

             6    that prolongs the action potential and is responsible for

             7    the QT prolongation.

             8                At the present time, one is simply measuring

             9    the QT interval, but these drugs and genetic disorders that

            10    affect the HERG channel also change the morphology of the T

            11    wave.

            12                Now, in terms of ionic channel dysfunction,

            13    there are genetic mutations involving the IKs, IKr, and the

            14    sodium channel.  We're not in any way interested in the

            15    sodium channel at this time.  The focus is on the IKr

            16    channel or the HERG gene, the gene that's altered

            17    genetically, and this is the genetic disorder.  Relative to

            18    drugs that bind the channel and modify their function, the

            19    classical one is terfenadine in a dose-response curve, and

            20    you've heard a lot about that.  Erythromycin and other

            21    antibiotics can also affect the HERG function in this

            22    acquired drug manner, and such classical drugs as quinidine

            23    are known to have significant effects on HERG, as well as

            24    on the sodium channel.

            25                But today, we're really talking about drugs

                                                                          101

             1    that may have effect upon the HERG channel and what their

             2    implications are.  The number of patients with genetic

             3    mutations is very small.  What we don't know is how many

             4    patients are out there with minor modifications, what we

             5    call polymorphisms of the channel, that may be a factor

             6    contributing to some differential sensitivity between

             7    patients.

             8                Now, this is an oversimplification and I only

             9    want to use it as emphasis.  We actually use the RR

            10    interval before the measurement of the QT.  But the

            11    measurement of the QT, as was nicely pointed out by Dr.

            12    Harrigan, has its errors in measurement, and this is the

            13    reason why it's important to have unbiased central

            14    measurement of the QT interval, and with enough patients,

            15    those measurement errors can even out.  But it ends up as a

            16    quantitative measurement and is, of course, what is most

            17    sensitive to any statistical test.  So this is just a

            18    schema of what is generally done.

            19                Now, the relationship between the QT interval

            20    and the cycle length is curvilinear, and the longer the

            21    cycle length, the greater the QT interval, and the reverse

            22    is the case, as was pointed out earlier.  What I happen to

            23    have drawn in in terms of the upper boundary here is based

            24    upon the Bazett formula of the square root.  At a heart

            25    rate of 60 beats per minute or a cycle length of 1 second,

                                                                          102

             1    one is talking about an upper limit of normal by the Bazett

             2    formula of about 440 milliseconds.  This is just a general

             3    approach.

             4                But as was also mentioned, it's more

             5    complicated because you could do any of a number of

             6    different formula, from the Fridericia formula that uses

             7    the cube root to various types of linear formulas. 

             8    Generally, in the range that one is dealing with for these

             9    types of studies, where the heart rate is between roughly

            10    60 and 80, you're in a range here where no real formula

            11    makes very much difference.  The problem comes when a drug

            12    has a very significant effect upon the cycle length, an

            13    increase in heart rate or a significant decrease in heart

            14    rate in terms of magnitude as well as significance, that

            15    other formulas and more appropriate formulas seem to be

            16    better indicated.

            17                But in what we're dealing with today, I

            18    personally don't think it makes very much difference

            19    whether one uses a cube root formula or a square root

            20    formula or a linear formula.  If you're looking for change,

            21    it's going to be very, very similar.

            22                So these are the three standard formulas that

            23    tend to be used most, the QT with the Bazett, the QT with

            24    the Fridericia using the cube root, and the so-called

            25    Framingham or linear expression formula.  The FDA has

                                                                          103

             1    become more intrigued by using correction formulas based

             2    upon the population of patients that one is generally

             3    dealing with, and this does give a little bit more

             4    precision because the fact of the matter is the Bazett

             5    formula is based originally on only 20 patients.  I mean,

             6    it's not a very big sample on which to base a lot of

             7    interpretation.

             8                So the Framingham formula is based on a much

             9    larger population of patients.  It's a little bit more

            10    cumbersome to use, and for the area of heart rate that

            11    we're dealing with, these give really roughly equivalent

            12    effects, particularly if one is looking for the change of

            13    effect, the delta effect.

            14                Now, what I'm showing here is based upon a

            15    large experience from the genetic long QT syndrome, and

            16    it's trying to get at some idea of the QT interval and

            17    risk.  We've been aware for some time that the patients

            18    with the longer QT intervals have the greater risk.  This

            19    information was developed before there was the genetic

            20    identification of patients who were affected and

            21    unaffected.  So this includes a large population of

            22    patients, upwards of 1,000 or more, in which we had long-

            23    term follow-up and looking at the risk as a function of the

            24    QT interval.

            25                Let me say at first that this is a continuous

                                                                          104

             1    expression, the QT interval, and it does appear that the

             2    interval does influence the risk, even when we don't do it

             3    quantitatively and, as I say, just looking at the patients

             4    who have had episodes for the most part are the ones who

             5    have had the longer QT interval.  But when we try to

             6    actually model this, we come out with an exponential risk

             7    assessment in which the risk related to the exponent of

             8    this base, if you will, and the risk being an increment of

             9    the millisecond increase above the baseline.  It turns out

            10    to be each unit being 10 milliseconds.  So we take the

            11    milliseconds and just simply divide by 10.

            12                So just in a rough comparison, once again based

            13    upon the genetic QT interval population, if we start with a

            14    QTc of a maximum of 440 milliseconds, we'll take this as

            15    our arbitrary reference, and 1.05 raised to the zero power

            16    would be a relative risk of 1.  If we go up to 500

            17    milliseconds -- that is, a 60-millisecond increase or a 6

            18    unit increase in this exponent -- we see a relative risk of

            19    1.4 relative to the baseline QT interval.  If we go to an

            20    extreme value of 640 milliseconds, we're talking about a

            21    relative risk of a person experiencing an arrhythmic event

            22    in the range of 2.8-fold greater than the patients who have

            23    a 440-millisecond baseline or a comparative individual with

            24    a 440-millisecond QT interval.

            25                So the point I want to emphasize is that there

                                                                          105

             1    is not an absolute cutoff.  There is some continuum of

             2    risk.  I think that the extrapolation to drug-induced

             3    prolongation has to be taken with a grain of salt, because

             4    this information is based upon a genetic population of

             5    which some patients had QT prolongations and were affected

             6    and some weren't.  But for the most part, the longer the

             7    QT, the greater the likelihood they were affected

             8    genetically, and also the greater the QT interval, the

             9    greater the likelihood of an episode, either a syncopal

            10    episode or a fatal arrhythmic event.

            11                I wouldn't want you to get hung up on these

            12    specific numbers, but it's fair to say that there is an

            13    increase in risk with greater QT prolongation, and probably

            14    the cutoff that's been used of 500 milliseconds is just

            15    based more on common sense than specific numbers.  But if

            16    we try to quantify it, we're talking about a risk over any

            17    period of time -- a month, a year, 10 years -- of being

            18    1.4-fold greater than patients who have a normal or a

            19    reference QT interval.

            20                This is just to point out the type of concern

            21    if one happens to record it in terms of an episode. 

            22    Obviously, you could consider this either a syncopal

            23    episode if it terminates or a fatal episode if it continues

            24    in this way.  But this is fundamentally what the FDA is

            25    concerned about, trying to protect patients who might have

                                                                          106

             1    this type of episode related to a drug as opposed to

             2    spontaneously.  This is just the continuation of this. 

             3    This patient just happened to stop, so this patient had a

             4    syncopal episode.  You can see the QT prolongation here

             5    very clearly.  In fact, this is a genetic disorder in this

             6    particular slide that I'm showing.

             7                Now, let me just get into the issues that are

             8    really what we're dealing with.  In one way or another, the

             9    greater the QT prolongation, the greater the risk.  We've

            10    put it in an exponential form, and I'm sure there can be

            11    more precision about this in the future.

            12                The second issue is the magnitude of the QT

            13    signal.  Most of the time, what's reported is the mean or

            14    median delta QTc interval, and this is what we've heard a

            15    lot about.  Because one is trying to determine if this is a

            16    meaningful signal or not, and one is generally dealing with

            17    a relatively small study population relative to the

            18    population that's going to have the drug administered if

            19    it's approved, a mean QTc of 10 milliseconds or 20

            20    milliseconds doesn't sound very long.  But the question is,

            21    what are the outliers?  That was the reason for looking at

            22    the range of values and the outliers, particularly the

            23    highest ones.

            24                These were reported earlier this morning by Dr.

            25    Harrigan.  So this magnitude of effect, what one is

                                                                          107

             1    particularly looking for is any signal.  Now, how much does

             2    one interpret a signal on 33 patients as opposed to 33,000

             3    patients is an area of extrapolation.  That's really where

             4    the judgment comes in, and there are no simple answers. 

             5    But this is really one of the issues that is faced by any

             6    advisory group.

             7                Then the other thing is to look at the effect

             8    of the drug on the QTc, and now we're talking about direct

             9    effects.  That is, does the drug have an effect upon the

            10    IKr channel?  This was studied in this particular

            11    situation, and this is now being done in a very regular way

            12    with expression studies in which one can put in the

            13    potassium channel into an embryonic kidney cell or an

            14    atrial tumor cell and actually express the gene, the normal

            15    gene, the normal channel, and then study the dose

            16    concentration in the preclinical studies.

            17                So, does the drug have an effect on the ion

            18    channel?  Sotalol and cisapride are yes, and so is the drug

            19    under consideration.  So there were studies that were

            20    reported in the handout in the booklet that was provided. 

            21    These are the direct effects, and one can get some idea of

            22    what is the likelihood of getting into problems clinically

            23    depending upon the magnitude of the effect that one sees in

            24    preclinical in vitro expression studies.

            25                Then one is looking for interactions, and one

                                                                          108

             1    is looking for two types of interactions, what can be

             2    referred to as drug-drug interactions, the classical one

             3    being the terfenadine-ketoconazole one that we're all

             4    familiar with.  But there are also drug-gene interactions

             5    which we don't completely understand.  Those rare

             6    individuals with mutations, long QT syndrome, would be more

             7    likely to get into problems, and the one patient who did

             8    get into problems apparently had at least a baseline QT

             9    interval that put him in that category.

            10                But what we don't understand and there is no

            11    information available at the present time is that there are

            12    polymorphisms in the gene.  The gene does not necessarily

            13    express itself in terms of QT prolongation, but such

            14    individuals may be more sensitive to the drug, and one

            15    would never see this in a small sample population.  That's

            16    why it becomes an issue after the drug is released.  So

            17    these are important considerations, the direct effects and

            18    indirect interactions.  Indirect interactions are tough to

            19    pick out statistically on small sample size populations.

            20                Then the final slide is what are really the

            21    questions.  It seems to me the questions go in some order

            22    like this.

            23                Do the preclinical studies indicate an effect

            24    on ventricular repolarization?  It seems to me that's done

            25    in expression studies or in some animal models, and that's

                                                                          109

             1    an important starting point.  If the drug has major effects

             2    in preclinical studies, it probably doesn't get to the

             3    clinical realm.

             4                Do clinical studies indicate a QT signal?  Now,

             5    we're not looking for, in small samples, does the QT

             6    produce mortality, because we wouldn't have enough

             7    patients, but is there a signal that's present.

             8                And what is the magnitude of the signal? 

             9    Because we do feel there is some relationship between the

            10    length of the QT interval and the occurrence of arrhythmic

            11    events.

            12                Then the fourth question, are there potential

            13    drug interactions?  I think this was what was addressed in

            14    the request that was made for the 054 study.

            15                Then finally, does the drug have unique

            16    characteristics?

            17                As a clinical cardiologist and with interest in

            18    QTc, this is the way I tend to look at these issues.  Thank

            19    you very much.

            20                DR. TAMMINGA:  Thank you, Dr. Moss.

            21                We'll turn now to the presentation of Dr.

            22    Dubitsky.  Dr. Greg Dubitsky is a medical officer at the

            23    Psychiatric Drug Products Group in the FDA.

            24                DR. DUBITSKY:  Good morning, Dr. Tamminga and

            25    members of the committee.  This morning I'd just like to

                                                                          110

             1    take a few minutes to present some important clinical data

             2    regarding three antipsychotic agents that I think are

             3    pretty well accepted by most people to have some cardiac

             4    effects of substantial importance; namely, thioridazine,

             5    pimozide, and sertindole.  I'd also like to present the

             6    regulatory actions that we've taken with respect to these

             7    drugs in response to these data.

             8                I'd like to start with thioridazine or

             9    Mellaril.  If you go back and look at some of the data in

            10    our files on Mellaril from the late 1950s and early 1960s,

            11    there's really very little mention of any EKG effect or

            12    sudden death, anything like that.  In fact, this is one of

            13    the first reports suggesting that thioridazine might have

            14    adverse cardiac effects.  It's reported by some of our

            15    Canadian colleagues and describes 28 electrocardiograms

            16    that showed an effect of thioridazine on ventricular

            17    repolarization.

            18                Next slide.

            19                For several years, Mellaril has been on the

            20    market and has had some mention of ECG effects in the

            21    labeling, but it's been rather inconspicuously labeled,

            22    until we got into the 1990s with a heightened awareness and

            23    sensitivity to the QT effects of drugs.  The first data I'd

            24    like to present come from a study that was done in Sweden

            25    by Hartigan-Go.  This was published a few years ago.  It

                                                                          111

             1    was a randomized, double-blind, three-period crossover

             2    study, a single dose that looked at two doses of

             3    thioridazine, 10 and 50 milligrams, and placebo, with a

             4    one-week washout in-between the periods.  This study was

             5    done in nine healthy males who were relatively young.  All

             6    the subjects completed the study, and all were rapid

             7    hydroxylators of debrisoquin.

             8                Next slide.

             9                Just focusing here, this study does have a lot

            10    of data, but I'm just going to focus for our purposes on

            11    the QTc data from this study.  This is a graph that showed,

            12    following single doses of placebo, 10 and 50 milligrams of

            13    thioridazine, what the changes were in the Bazett-corrected

            14    QTc.  I think it's pretty clear that the maximal effect was

            15    seen at about four hours post-dose.  Looking at that, you

            16    can see that for 50 milligrams of thioridazine, there was

            17    about a 23-millisecond change from baseline, or probably

            18    about a 28- to 30-millisecond increase over placebo at the

            19    four-hour time point.  For both doses of thioridazine at

            20    that time point, the changes were statistically

            21    significantly higher than for placebo.

            22                Next slide.

            23                There were no adverse cardiac effects or events

            24    reported in that study, and the QTc's were generally under

            25    440 milliseconds.  However, we did take these results with

                                                                          112

             1    a grain of salt because we felt that the effects seen here

             2    may in fact underestimate the experience that would

             3    actually occur in clinical practice, because these were

             4    single doses, they were low doses compared to what's

             5    usually used in clinical practice, which is probably more

             6    like 300 or 400 milligrams a day.  The study was done in

             7    healthy volunteers who were taking no concomitant

             8    medication.

             9                Next slide.

            10                The next piece of data comes from Study 054,

            11    which has already been discussed at some length, so I'll

            12    just hit the high points with respect to QTc and cardiac

            13    effects.  As was described, this was an open-label parallel

            14    group study in which patients were titrated to ziprasidone,

            15    thioridazine, haloperidol, at these dose levels.  There

            16    were also the other atypical antipsychotics that were used. 

            17    But for my purposes here, I'm just going to focus on these

            18    three treatment arms.  ECGs were done at the estimated Tmax

            19    at steady state.

            20                Next slide.

            21                The results without inhibitor, using the Bazett

            22    correction, were as shown here.  The change for ziprasidone

            23    was about 20.3 milliseconds, with a 95 percent confidence

            24    interval of 14 to 26 in 31 patients.  Thioridazine was

            25    considerably higher, and if you look at the 95 percent

                                                                          113

             1    confidence intervals, they really don't quite overlap. 

             2    Haloperidol was at about 4.7 milliseconds, considerably

             3    less than ziprasidone and thioridazine.

             4                Next slide.

             5                Looking at the categorical change in QTc from

             6    baseline, I'd just point out here that most of the

             7    ziprasidone patients -- or, actually, very few of the

             8    ziprasidone patients had changes from baseline greater than

             9    or equal to 60 milliseconds, and very few greater than or

            10    equal to 75 milliseconds.  The percentages were somewhat

            11    less than thioridazine but considerably higher than in the

            12    haloperidol arm.  No subject in this study had a QTc

            13    greater than or equal to 500 milliseconds.

            14                Next slide.

            15                In terms of clinical events, there were no

            16    deaths or other serious adverse events in this study. 

            17    There were no episodes documented of torsade de pointes,

            18    and no syncopal episodes reported.

            19                Next slide.

            20                Again, focusing on thioridazine, which is the

            21    main thing I'm talking about right now, there are several

            22    reports in the MedWatch database, in our postmarketing

            23    surveillance database, and from the medical literature with

            24    thioridazine of cases of torsade de pointes, other types of

            25    ventricular tachycardia, and sudden unexplained deaths.

                                                                          114

             1                Next slide.

             2                These data really constituted the bulk of the

             3    evidence that we used to request some significant labeling

             4    changes this year, and as Dr. Laughren pointed out, there

             5    has been a "Dear Doctor" letter sent out to highlight these

             6    changes.  One, of course, is a black box warning that does

             7    summarize the cardiac risks that we feel are associated

             8    with thioridazine.  We have made it a second-line agent,

             9    and we have restricted the indication to schizophrenia. 

            10    Previously there were some other non-psychotic conditions

            11    for which it was indicated in the PDR.

            12                We've added a number of contraindications

            13    specifically with respect to drug-drug interactions.  It

            14    does seem that patients who are poor hydroxylators of

            15    debrisoquin do develop significantly elevated levels of

            16    thioridazine, so we have contraindicated its use with

            17    inhibitors of CYP2D6.  It's also contraindicated with

            18    fluvoxamine, propranolol and pindolol, since those drugs

            19    have been shown to elevate thioridazine levels.  And, of

            20    course, it's contraindicated with other drugs that prolong

            21    the QT interval.  As well, we've contraindicated it in

            22    patients with congenital long QT syndrome and in patients

            23    known to be CYP2D6 poor metabolizers.

            24                Finally, we have recommended that all patients

            25    on thioridazine have baseline and periodic

                                                                          115

             1    electrocardiograms and serum potassium levels.

             2                Next slide.

             3                I'd like to move on to the second drug, which

             4    is pimozide.  I don't have a lot of data to present, but

             5    the data I will present are from an electrocardiography

             6    report from three studies that were done in acute

             7    schizophrenia back in the early 1980s.  This report

             8    essentially pools the data from these studies, and they

             9    were double-blind treatment studies that used pimozide and

            10    thioridazine treatment arms, with a pimozide dose in the

            11    range of 20 to 80 milligrams a day, a thioridazine dose of

            12    200 to 800 milligrams a day.  EKGs were recorded

            13    pretreatment and after 5 to 12 days of treatment with

            14    pimozide and thioridazine.

            15                Next slide.

            16                Unfortunately, these studies were interrupted

            17    due to three serious adverse events that occurred in

            18    pimozide patients.  In these studies there were two sudden

            19    deaths that occurred at doses of 70 and 80 milligrams a

            20    day.  Those patients had rather substantial increases in

            21    the QTc levels, at or above 500 milliseconds, and there was

            22    a third patient who had grand mal seizures and documented

            23    episodes of ventricular tachycardia.  That patient was

            24    being treated with 80 milligrams a day and actually had an

            25    increased QTc at baseline of 560 milliseconds, which

                                                                          116

             1    persisted on follow-up.

             2                It is interesting to note that among the

             3    pimozide patients, there were six patients who did have an

             4    increase in QTc greater than or equal to 100 milliseconds

             5    who apparently didn't have any significant cardiac events.

             6                Next slide.

             7                To summarize the QTc findings, after 5 to 12

             8    days on pimozide -- and, by the way, the lower range there

             9    of 5 days or so probably isn't even enough to attain steady

            10    state with pimozide, which has a half-life of about 50

            11    hours.  But the changes that were seen, there was a mean

            12    change from baseline of about 50 milliseconds in the QTc. 

            13    Fifteen percent of the patients on pimozide had a QTc

            14    greater than or equal to 500 milliseconds.  Looking at the

            15    categorical change from baseline, you can see that a little

            16    over half, 55 percent had an increase greater than or equal

            17    to 50 milliseconds, and about 1 in 10 had an increase

            18    greater than or equal to 100 milliseconds.

            19                Again, this is data from the early 1980s, prior

            20    to the FDA approval of pimozide for Tourette's.

            21                Next slide.

            22                In response to these data primarily, pimozide

            23    was approved but was not indicated for the treatment of

            24    schizophrenia.  It's indicated as a second-line agent for

            25    the use in Tourette's disorder.  It has been

                                                                          117

             1    contraindicated in patients with prolonged QTc's, with

             2    cardiovascular disease, and with drugs that prolong the QT

             3    interval.  Baseline and periodic ECGs are recommended, and

             4    we have placed limitations on the maximum dose, which I

             5    believe now is about 10 milligrams a day, considerably less

             6    than what you saw on the serious adverse events.

             7                Recently we've also contraindicated the use of

             8    pimozide with CYP3A inhibitors, such as ketoconazole, based

             9    on some data that does suggest that 3A is the primary

            10    metabolic pathway of pimozide and patients taking such

            11    drugs can develop quite marked increases in QTc and serious

            12    cardiac events.

            13                Next slide.

            14                The last drug some of you may remember was

            15    presented to the committee almost four years ago to this

            16    date, in July of 1996.  It was the subject of NDA 20-644,

            17    sertindole, which was considered for approval as an

            18    antipsychotic agent.  There were three adequate and well-

            19    controlled Phase II/III studies that contributed ECG data,

            20    and the findings were pretty much consistent across the

            21    three studies, so I'm just going to focus on one of the

            22    fixed-dose studies, Study 113.

            23                Next slide.

            24                Study 113 was an eight-week randomized double-

            25    blind study that had six fixed-dose parallel treatment

                                                                          118

             1    arms, three sertindole arms that used doses of 12, 20, and

             2    24 milligrams a day, three haloperidol arms using 4, 8, and

             3    16 milligrams a day, and placebo.  It was conducted in 497

             4    inpatients with schizophrenia, and a little bit atypical

             5    for many of our trials, this study did not exclude patients

             6    with significant cardiac defects.  They essentially took

             7    all comers.  The ECGs were done about every two weeks in

             8    this study.

             9                Next slide.

            10                To summarize the results, across the top are

            11    the seven treatment arms, placebo, three sertindole fixed

            12    doses, three haloperidol fixed doses.  You can see that for

            13    sertindole, the drug of interest here, the mean change from

            14    baseline to the final reading was statistically

            15    significantly greater than in the placebo group, where

            16    there was actually a slight decrease.  Just for your

            17    information, the target dose range that was being

            18    considered I believe at that time was about 12 to 20

            19    milligrams a day.  But at the two higher sertindole doses,

            20    at 20 and 24 milligrams a day, there were increases in the

            21    QTc of 20 and 22 milliseconds respectively.  This was not

            22    seen in the haloperidol arms.

            23                Likewise, if you look at the percentage of

            24    patients who had QTc readings greater than or equal to 500

            25    milliseconds, I think, as was presented earlier, in the two

                                                                          119

             1    higher sertindole arms, 7 and 8 percent met those criteria. 

             2    None of the haloperidol patients met the criteria.

             3                Next slide.

             4                Looking at the broader sertindole NDA database

             5    that included over 1,400 patients with about 476 person

             6    years of exposure, there were some relevant clinical

             7    findings that I believe we spent considerable time

             8    grappling with at that time.  There were 12 sudden

             9    unexplained deaths, or SUDs.  There was no symptomatic

            10    torsade documented, but of all the person time, there were

            11    only 30 to 40 hours of monitored time on telemetry on

            12    sertindole.  So we really couldn't be certain that perhaps

            13    we had missed some torsade.  There were also 23 cases of

            14    syncope.  Unfortunately, 22 of those patients did not have

            15    any relevant ECG data at the time of the event.

            16                Next slide.

            17                There was considerable time spent about four

            18    years ago trying to discuss the meaning of these data with

            19    respect to the cardiac risk of sertindole, and the question

            20    was posed to the committee:  Has the sponsor provided

            21    evidence that sertindole is safe when used for the

            22    treatment of psychotic disorders?  There was somewhat of a

            23    split vote; four voted yes, two voted no.  We took it, I

            24    think, with a huge grain of salt, and the outcome was that,

            25    to date, sertindole is not yet on the market in the U.S.

                                                                          120

             1                Next slide.

             2                Subsequently, just to report some of the

             3    foreign experience with sertindole, in December of 1998

             4    sertindole was voluntarily withdrawn from the U.K. due to

             5    several reports of cardiac arrhythmias and sudden deaths. 

             6    This was in a December 1998 message from the Medicines

             7    Control Agency.  More recently, in January of this year,

             8    European marketing authorization for sertindole has been

             9    suspended based on spontaneous adverse event data from the

            10    U.K. postmarketing database.  This information is on the

            11    Internet.  There have been reports of sudden unexplained

            12    deaths and fatal arrhythmias.

            13                If you look at them as a percentage of all the

            14    adverse event reports for particular drugs, the percentage

            15    is several-fold higher for sertindole compared to

            16    olanzapine and risperidone.  That is cited as the main

            17    evidence that they've suspended marketing authorization in

            18    Europe for sertindole.

            19                I think that's it.  Hopefully that will provide

            20    a little bit of framework for you to consider the cardiac

            21    safety of ziprasidone.

            22                DR. TAMMINGA:  Thank you very much, Dr.

            23    Dubitsky.

            24                We'll go on now with the FDA presentations and

            25    hear from Dr. Douglas Throckmorton, who is from the

                                                                          121

             1    Division of Cardiorenal Drug Products, Anti-Arrhythmics,

             2    and Other Cardiovascular Drugs.

             3                Dr. Throckmorton.

             4                DR. THROCKMORTON:  As a member of the Division

             5    of Cardiorenal Drug Products at the FDA, I was asked to

             6    summarize the Division's experience regarding compounds

             7    that prolong the QT.  I believe that I have the good

             8    fortune of not having to mention further either corrections

             9    of QT or potassium channels.  However, I would like to

            10    remark that there are two aspects of the Division's

            11    experience with regard to QT prolongation.

            12                First, our experience has been consultative,

            13    and we've been involved in the review of the majority of

            14    the compounds that have been under discussion today.  In

            15    particular, the Division's consultation for ziprasidone was

            16    performed by Dr. Maryann Gordon and has been provided to

            17    the advisory committee previously.

            18                I will not focus my attention on this

            19    consultative role, although I'd be happy to answer

            20    questions about any of those aspects I'm familiar with. 

            21    Instead, I would prefer to review those cardiovascular

            22    compounds that have also been shown to affect the QT

            23    interval.

            24                If I could have the next slide.

            25                I'd like to discuss two general issues.  First

                                                                          122

             1    I'd like to give the advisory committee some general sense

             2    about how the Division has approached approval of compounds

             3    that prolong the QT interval.  In this regard, I'll look at

             4    two broad classes of compounds.  The first class that I've

             5    chosen are the anti-arrhythmics developed for super-

             6    ventricular arrhythmias, atrial fibrillation, atrial

             7    flutter, and the examples I'll discuss are dofetilide and

             8    sotalol.  The second class of compounds I'll look at is a

             9    compound called bepridil, developed as an anti-anginal,

            10    although it was also found to have a marked effect on the

            11    incidence of both QT prolongation and torsade.

            12                The second issue that will be woven into these

            13    reviews will be an overview of the body of data available

            14    within the cardiovascular arena that allows us to make

            15    general comments about the association between QT

            16    prolongation and adverse clinical cardiovascular events.

            17                If I could have the next slide, please.

            18                Dofetilide and sotalol were both approved for

            19    the treatment of atrial arrhythmias, even though they are

            20    both known to prolong QT and to cause torsade.  Their

            21    approvability was also a possibility despite their

            22    pronounced effect on QT, first because it is known that

            23    their ability to affect cardiac repolarization was

            24    intrinsic to their mechanism as anti-arrhythmics, so that

            25    despite the fact that they prolonged QT was not something

                                                                          123

             1    that made it impossible for them to obtain approval. 

             2    Instead, the developers of these compounds demonstrated

             3    three additional things.

             4                First, they were able to demonstrate a

             5    symptomatic benefit in the populations at risk.  They were

             6    also able to obtain point estimates of mortality in

             7    populations at high risk for arrhythmic events, as well as

             8    in the target population that the drugs were developed for. 

             9    And finally, in both cases, the sponsors undertook an

            10    adequate characterization of the factors that could lead to

            11    increased risk for torsade in a patient also taking these

            12    products, and I'll comment on what that adequate

            13    characterization might mean a bit further later on.

            14                If I could have the next slide.

            15                D,L,-sotalol, which I'll call sotalol from now

            16    on, is a Class 3 anti-arrhythmic that carries an approval

            17    for the treatment of life-threatening ventricular

            18    arrhythmias, as well as for the maintenance of normal sinus

            19    rhythm in patients with atrial arrhythmias.  I'll focus on

            20    the second indication.  It's been found to have a mean

            21    effect on the QTc prolongation between 10 and 40

            22    milliseconds at the therapeutic doses, around 160

            23    milligrams to 640 milligrams per day, in a dose-dependent

            24    fashion, and to also influence the incidence of torsade in

            25    a similar way.

                                                                          124

             1                The next slide, please.  This slide summarizes

             2    the totality of the sotalol data that we have linking

             3    change in dose of sotalol along the X axis with a change in

             4    the mean QTc interval, shown in green, and a change in the

             5    incidence of torsade, shown in yellow.  Dr. Moss has

             6    suggested that there is an exponential association in the

             7    long QTc interval database.  I don't honestly know what

             8    these curves would fit, although it would be interesting to

             9    do as an exercise.  There are several points to be made.

            10                The first point is to note that these graphs

            11    have been constructed from an extraordinarily large

            12    database, almost 7,000 patients that have received the drug

            13    in doses that vary by almost an order of magnitude, ranging

            14    between 80 milligrams per day and up to almost 800

            15    milligrams per day.  This particularly large, particularly

            16    broad database allows us to make important inferences about

            17    the relationship between prolongation of QTc and the

            18    incidence of severe cardiac events, in this case torsade. 

            19    You can imagine that if a narrower range of doses had been

            20    explored, say between 70 and 150 milligrams, the observed

            21    change in the mean QTc would have been much smaller, and

            22    the relationship between that change and any change in the

            23    incidence of torsade would have been next to impossible to

            24    elucidate.  This is an argument for broad dose exploration,

            25    I believe.

                                                                          125

             1                For sotalol, then, there is a continuous

             2    relationship between drug dose, concentration of mean QTc,

             3    and the incidence of torsade.  We believe that there is no

             4    step function change here.  That is, it is continuous and

             5    gradual.  Again, given the large numbers, we can make that

             6    inference with more comfort.

             7                Next slide, please.

             8                Remember, I said that sotalol had a known

             9    effect prolonged QT, but that was because that was

            10    intrinsic to its mechanism of action.  It was also possible

            11    for us to consider it as approvable for a symptomatic

            12    claim.  The things in addition to demonstrating symptomatic

            13    benefit that the sponsor did was provide point estimates

            14    for mortality in patients at high risk for arrhythmic

            15    events, as well as patients in the target population for

            16    the compound.

            17                This slide summarizes the Julian trial, which

            18    is a trial in a post-myocardial infarction trial, patients

            19    perceived to be at high risk for arrhythmias.  The notion

            20    here was not that the product demonstrate that it is

            21    statistically significantly superior or anything like that. 

            22    What we needed to have was information that the product was

            23    not significantly adversely affecting mortality with

            24    relationship to placebo.  Actually, strike the word

            25    "significantly."  We wanted point estimates without really

                                                                          126

             1    getting too hung up about confidence intervals.  We wanted

             2    to know that this product did not look too much like other

             3    agents that we know have significant cardiac mortality of a

             4    kind that would have shown up in this kind of trial as

             5    mortality exceeding placebo.

             6                In fact, they succeeded.  Sotalol had a point

             7    estimate had a point estimate that was advantageous

             8    relative to placebo at one year.

             9                Next slide, please.

            10                The next thing that the sponsor also did was

            11    look at, again, point estimate for mortality in the

            12    population that the drug was being developed for.  In this

            13    case, patients with atrial fibrillation and flutter.  You

            14    can see that in a small database, a robust database but

            15    with relatively few deaths, there was no signal that

            16    sotalol had an adverse effect on mortality either with

            17    regard to quinidine, another anti-arrhythmic that's known

            18    to cause torsade, or relative to placebo.

            19                So the sponsor was able to convince us that

            20    there was no net adverse effect, and that we would be able

            21    to define the potential benefit, this potential symptomatic

            22    benefit to the patient and the informed physician, and they

            23    could determine whether the pro-arrhythmic risk that we had

            24    well characterized was worth taking the drug.

            25                Next slide, please.

                                                                          127

             1                To move to dofetilide, it is similarly a Class

             2    3 anti-arrhythmic.  It lacks the beta-blocking activity

             3    that D,L,-sotalol has but is otherwise similar.  It has

             4    been approved for maintenance of normal sinus rhythm and

             5    conversion of atrial fibrillation flutter to normal sinus

             6    rhythm.  It also has a pronounced effect on QTc, a mean 34-

             7    millisecond placebo-subtracted prolongation in the Phase

             8    II/III trials, and a dose-dependent concentration-dependent

             9    effect on mean QTc ranging between about 5 milliseconds and

            10    20 milliseconds at doses in the therapeutic range, between

            11    125 and 500 micrograms twice a day.

            12                Next slide, please.

            13                Dofetilide, like sotalol, has a relatively

            14    robust patient population, about 1,300 patients in this

            15    particular analysis.  Looking at the relationship between,

            16    in this case, torsade and the incidence of ventricular

            17    fibrillation in the database, I've said before that there

            18    was a relationship between QTc prolongation and torsade,

            19    although I haven't shown those data.

            20                As you can see, at the higher doses, the

            21    incidence of both torsade and ventricular fibrillation

            22    increased.  Although the greater than 500 microgram twice a

            23    day group is very small in this particular graph, the

            24    incidence in that population was quite high.  This again

            25    defined the association between torsade, QTc prolongation,

                                                                          128

             1    and in this case severe arrhythmic clinical adverse events.

             2                Next slide, please.

             3                Similar to what was performed for sotalol, the

             4    company undertook the task of obtaining mortality

             5    information in a high-risk population, as well as in the

             6    population to be served.  The DIAMOND CHF and MI trials

             7    enrolled patients with structural heart disease and

             8    congestive heart failure.  You can see that the mortality

             9    rates were substantially elevated.  But again, dofetilide

            10    was on the advantageous side of the point estimate as

            11    regards mortality.  There was no evidence that it had a

            12    substantial adverse effect relative to placebo.

            13                In the target population on the next slide, in

            14    the supraventricular arrhythmia trials, dofetilide

            15    mortality when compared with placebo in the atrial

            16    fibrillation-flutter-SVT population has a ratio of 1.1 when

            17    adjusted for baseline characteristics, suggesting again

            18    that there was no signal for marked adverse mortality.  So

            19    a symptomatic claim, a claim for conversion of atrial

            20    fibrillation was approvable because there was no

            21    substantial, demonstrable adverse mortality effect.

            22                Next slide, please.

            23                Dofetilide also did a very interesting thing,

            24    not prospectively, not because the Division required it,

            25    but as a way of exploring whether dose adjustment could in

                                                                          129

             1    some fashion be shown to adjust the risk that the patient

             2    population would have for suffering clinically adverse

             3    events, in this case torsade.  What they did was, about

             4    halfway through their development program, they began to

             5    require that renal function be measured or calculated using

             6    Cockroft-Gault and dose adjusted based on that renal

             7    function.

             8                In addition, they required baseline ECGs to

             9    determine whether the patient was eligible, and started

            10    dofetilide under continuous ECG monitoring with dose

            11    adjustment for marked prolongation of the QT.  At the end

            12    of the NDA, in a retrospective fashion, they looked at the

            13    incidence of torsade in the two groups; that is, the group

            14    before dose adjustment, if you will, based on renal

            15    function, and the group after.  Those results are on the

            16    next slide.

            17                The bar on the left, the green bar, shows the

            18    incidence of torsade in the population prior to the

            19    initiation of renal clearance adjustment, and the bars on

            20    the right show the incidence in the three large trials

            21    after.  I don't want to make large amounts out of this in

            22    the regulatory sense because it was something the sponsor

            23    chose to do.  This analysis was something the sponsor had

            24    chosen to do on their own, not something that we required. 

            25    But I think it serves as a model for investigation of those

                                                                          130

             1    factors, during the NDA development investigation of those

             2    factors that may mitigate the risk of significant

             3    cardiovascular events following the approval of the

             4    product.

             5                In this case, as a result of this and

             6    discussions with the agency, the dofetilide and the sotalol

             7    labels in fact recommend hospitalization and adjustment

             8    based on calculated renal clearance.

             9                Next slide, please.

            10                To summarize the experience in the atrial

            11    fibrillation flutter trials, then, these two products had

            12    dose-dependent effects on QT, QTc, torsade, and ventricular

            13    fibrillation for dofetilide.  Again, because the effects on

            14    QTc and torsade were anticipated, the sponsors were able to

            15    perform other things to obtain approval.  In particular,

            16    they obtained mortality information, and they characterized

            17    those factors placing the patients taking the product at

            18    increased risk for torsade.  They explored a broad dose

            19    range of their product, and they explored other risk

            20    factors, and in particular I'm using the example of

            21    dofetilide and renal function.

            22                There's been a lot of discussion today about

            23    the effect of marked prolongation of QTc as far as risk for

            24    torsade.  The sotalol database also has an analysis of that

            25    sort, and I believe it's the only database -- the

                                                                          131

             1    cardiologist can correct me if I'm wrong -- the only

             2    database that's been robust enough to look at that.  There

             3    are problems with those sorts of analyses, but we can talk

             4    about that in the afternoon if the advisory committee is

             5    interested.

             6                Next slide, please.

             7                To turn to the other class of drugs that we

             8    have approved in the agency despite knowledge of their

             9    effect on QT and torsade, I'd like to talk about bepridil,

            10    which is a drug that we know both causes marked

            11    prolongation of QT and torsade, which is a characteristic

            12    not seen with other anti-anginals that are currently

            13    approved.  So on the surface, that's bad and you would say

            14    that would make it quite difficult for bepridil to obtain

            15    approval, and you're right.  It would have normally.

            16                What bepridil undertook to show, however, was

            17    that they had a unique advantage.  That is, they had

            18    efficacy in a population currently not served by the

            19    available therapies.  In this case, they took a population

            20    that was resistant to current anti-anginals and

            21    demonstrated that they were able to affect anti-anginal

            22    efficacy there.

            23                Next slide, please.

            24                Just to summarize briefly, bepridil is a

            25    calcium channel blocker.  It is approved as a second-line

                                                                          132

             1    agent for the treatment of chronic stable angina in

             2    patients who are intolerant or resistant to other anti-

             3    anginals.  It has a mean effect on the QTc of between 30

             4    and 70 milliseconds.  Importantly, about 5 percent of the

             5    patients who took bepridil during the NDA had greater than

             6    a 25 percent increase in their QTc, which roughly takes you

             7    out into the 500 to 540 millisecond range, something like

             8    that.  In the NDA database there were cases of torsade, and

             9    in the postmarketing in France, 147, something like that,

            10    cases of torsade were reported.  So the association between

            11    the compound and torsade is unquestioned.

            12                Next slide, please.

            13                The trial that bepridil performed was to take

            14    86 patients who had stable angina refractory to diltiazem,

            15    a calcium channel blocker used commonly in this disorder,

            16    and randomized them equally to diltiazem or bepridil.  What

            17    they were able to demonstrate was that bepridil was a more

            18    effective anti-anginal in this population measured by the

            19    means that we use to commonly assess anti-anginal efficacy: 

            20    exercise stress testing markers; time to onset of angina

            21    with exercise; time to 1 millimeter ST-segment depression

            22    on an ECG during exercise; and total exercise time.

            23                Next slide, please.

            24                So bepridil, despite its dose-dependent effects

            25    on QT and the clear association with torsade, was an

                                                                          133

             1    approvable agent as a second-line agent because it

             2    demonstrated clear efficacy in a group of patients not

             3    currently served by other available therapies.

             4                Next slide, please.

             5                To summarize the experience of the Division of

             6    Cardiorenal Drug Products, then, regarding compounds that

             7    prolong QT, the use of cardiovascular drugs that prolong

             8    the mean QT in a dose-dependent fashion has been associated

             9    with an increased risk for torsade and sudden death.  In

            10    the databases that we have, they're substantially large,

            11    that risk appears to be continuous, and over a broad dose

            12    range.  There doesn't seem to be an upper limit where the

            13    risk does not continue to increase.

            14                Next.

            15                Cardiac drugs that seek approval for treating

            16    symptoms -- that is, atrial arrhythmia, for instance --

            17    have been approved with the following:  demonstration of

            18    symptomatic benefit, and sufficient information to

            19    adequately describe the nature of the arrhythmic risk

            20    during use of the compound.  That includes such information

            21    as description of the drug effect over a broad dose range,

            22    exploration of potential factors that modify the arrhythmic

            23    risk, and point estimates of total mortality in high-risk

            24    populations and target populations, again to make sure that

            25    there is no large adverse mortal effect.

                                                                          134

             1                Next, please.

             2                Cardiac drugs that cause QT prolongation can

             3    also be approved as second-line therapies by demonstrating

             4    a symptomatic benefit in a resistant population.  I think

             5    in this regard, our division is in agreement with the

             6    approach taken by the Neuropharm Division as well and

             7    comments they made earlier.

             8                Thank you.

             9                DR. TAMMINGA:  Thank you, Dr. Throckmorton, for

            10    your presentation.

            11                Now we'll hear from Dr. Chowdhury.  Dr.

            12    Chowdhury is from the FDA, from the Pulmonary and Allergy

            13    Drug Products, and he'll talk about antihistamines and QT.

            14                DR. CHOWDHURY:  I'm going to make a very brief

            15    presentation talking about antihistamines and not use any

            16    specific data for any of these molecules.  I'm going to

            17    talk about antihistamines and the view that we at the

            18    Division of Pulmonary and Allergy Drugs have taken in

            19    evaluation of antihistamines that are known to prolong QT

            20    or potentially can prolong QT.

            21                In my brief presentation for the next 5 to 10

            22    minutes, I will not specifically go into any database.  The

            23    one which is relevant has been covered adequately, which is

            24    the terfenadine database.  What I will go into is basically

            25    the philosophy that we have taken in looking into these

                                                                          135

             1    drugs and the thought process that has gone into our

             2    evaluation of these drugs.

             3                Now, before I go into the antihistamines

             4    itself, I should point out that the drug class we're

             5    talking about is indicated for allergic rhinitis.  The

             6    disease is not life-threatening, and the whole risk-benefit

             7    ratio here is pretty different than perhaps the drug

             8    classes that we're discussing here.  So the advisory

             9    committee might like to take that into consideration.

            10                Antihistamines classically are off two

            11    generations.  For the contemporary relationship, they are

            12    classified as first-generations and second-generations, and

            13    I have named them here just for the sake of reference. 

            14    Typically, the first-generation antihistamines are the

            15    older ones, and as you're aware of, are associated with a

            16    lot of adverse events, specifically sedation, decreased

            17    psychomotor function, and anticholinergic effects.

            18                The second-generations are more newer

            19    antihistamines, and they are free of these adverse events. 

            20    However, the price that perhaps one pays for these benefits

            21    is the risk of QT prolongation.  Some of them cause QT

            22    prolongation and have been associated with torsade. 

            23    Because of that, for any antihistamine, particularly the

            24    newer second-generation antihistamines, we are always

            25    sensitized to QT prolongation and possible effects that it

                                                                          136

             1    can have on ultimate approvability decisions.

             2                In my talk here, I will focus on four

             3    antihistamines that have some history in U.S. marketing: 

             4    terfenadine, which we have heard about; astemizole, which

             5    we have not, however this actually goes in parallel with

             6    terfenadine in terms of QT prolongation, torsade, and the

             7    marketing history.  Both of these drugs were marketed in

             8    the U.S., and the FDA has determined that they cause

             9    serious cardiac problems, and both have been withdrawn from

            10    marketing.  So all of the second-generations, what we have

            11    left in the market, are cetirizine, loratadine, and

            12    fexofenadine.  For the next few minutes, I'll basically

            13    compare and contrast all of these drugs and try to get a

            14    feeling of how we're looking at these drugs and potential

            15    new drugs of the class which we have looked at.

            16                Next transparency.

            17                This is an overview summary looking at the

            18    points that you have talked about here, which are QT

            19    prolongation, PK interaction, and ultimate association with

            20    cases of torsade.  The drugs here are listed

            21    alphabetically, and the asterisks are the two drugs which

            22    have been withdrawn because of convincing cases of torsade

            23    postmarketing.  Just to point out, these are very rare

            24    events.  For terfenadine, it took a long marketing, long

            25    postmarketing experience to actually pick up these events. 

                                                                          137

             1    Now it has become essentially the poster child for torsade. 

             2    However, they are very rare events to pick up.

             3                Having said that, most of these drugs have

             4    significant PK interactions to the extent of log or much

             5    more with classic CYP3A4 inhibitors, and the QT

             6    prolongation with these drugs at the recommended doses do

             7    occur.  For astemizole, 10 QD is the proposed recommended

             8    dose.  At that dose, in the label before it got withdrawn,

             9    the QT prolongation was about 7 milliseconds or so, and we

            10    have heard that number before today.

            11                For terfenadine, perhaps the same number. 

            12    Going to the label, at about five times the recommended

            13    dose, the QT prolongation was 46.  So these are two drugs

            14    with these two boxes checked as yes, which really has led

            15    into torsade and ultimately withdrawal.

            16                Looking at three other drugs which are on the

            17    market right now, cetirizine, fexofenadine, and loratadine. 

            18    Fexofenadine and loratadine have some interaction, although

            19    very small.  In terms of percentage, perhaps 1/64 percent

            20    or so increase in the AU when given concomitantly with

            21    ketoconazole.  However, these drugs do not prolong QT in

            22    clinical trials.

            23                Going to cetirizine, it does not have an

            24    interaction.  If one looks at the QT effect, perhaps it is

            25    not there.  In the product label, if you look at it, out of

                                                                          138

             1    four studies, only one study showed some QT prolongation. 

             2    This is again not consistently seen.  However, this drug

             3    does not have an interaction.

             4                So essentially, if these two, which is

             5    interaction and QT prolongation, are present, we looked at

             6    them really very conservatively, and the ones which do not

             7    have both of them so far have been okay.

             8                Now, when we look at antihistamines from a

             9    marketing approvability standpoint, we have to look at the

            10    cardiac arrhythmias and the risk for that.  I won't go into

            11    the list here, just to point out that the list is very

            12    exhaustive, very extensive.  Possibly one can add more

            13    factors here, but the bottom line here is that it is very

            14    difficult to really control for all the risk factors,

            15    predict for all of them.  As a result, we have taken the

            16    position that almost any convincing QT prolongation for a

            17    drug which has got an indication which is very minor is

            18    potentially a risk factor for torsade, and it's very

            19    difficult to really control for all the risk factors and

            20    label accordingly.

            21                When we look at the QT effect, of course we

            22    have heard about the clinical studies, and that's where we

            23    really look at.  The clinical studies that we usually look

            24    at are the drug interaction studies which we have heard

            25    this morning about, and also the high-dose safety studies

                                                                          139

             1    at a steady-state level.  Sometimes, depending on what we

             2    see in the clinical studies, we obviously go into

             3    preclinical.  Dr. Moss has summarized those for us.

             4                So when we look at an antihistamine, we look at

             5    the whole picture.  Does it prolong QT in the whole animal

             6    model?  Does it prolong the action potential duration in in

             7    vitro models; for example, Purkinje fibers?  Does it have

             8    clinical effect?  And look at the ion channels in micro

             9    studies.  Looking at the whole picture, we try to come to a

            10    consensus whether it prolongs QT or not, and in the

            11    clinical study, if it has prolonged QT in a dose-dependent

            12    fashion, we really become very conservative on

            13    antihistamines.

            14                The last summary slide here.  So basically, for

            15    looking at antihistamines that potentially can prolong QT,

            16    we have taken the philosophical approach that any

            17    convincing dose-dependent prolongation of cardiac

            18    repolarization is a concern, and that is extremely

            19    heightened if a concomitant interaction with other drugs

            20    that can increase the plasma concentration significantly is

            21    present.

            22                Secondly, we have taken the position because,

            23    as I said before, patients who are at risk for serious

            24    cardiac arrhythmias or the magnitude of QT prolongation

            25    that can produce arrhythmias, is very difficult to predict,

                                                                          140

             1    and perhaps there's not much consensus on that magnitude

             2    that is at risk.  We have heard before, and we will

             3    probably hear later on, that from the antihistamine

             4    experience, particularly with terfenadine and also with

             5    other drugs, that a label warning, contraindication

             6    warning, box warning and others has really not been

             7    effective.  For terfenadine, after the box warning went

             8    out, there were still cases of inappropriate use, torsade

             9    and death.

            10                So having said all of this, for an

            11    antihistamine which is really for allergic rhinitis, which

            12    is a trivial perhaps disease, not life-threatening, any

            13    risk is really an unacceptable risk.  So the bottom line

            14    here is, if you see any dose-dependent QT prolongation

            15    which is convincing in clinical studies, if there's

            16    interaction that can potentially lead into high exposure,

            17    then that risk really is unacceptable for an antihistamine. 

            18    So I just point this out for the advisory committee here to

            19    take into consideration, that our approach really depends

            20    on what the drug is, what the indication is.  Again, for

            21    allergic rhinitis, as you're aware of, there are other

            22    antihistamines available, other modalities of treatment

            23    available, and really there's no benefit of having a QT-

            24    prolonging antihistamine over existing therapies for

            25    allergic rhinitis.

                                                                          141

             1                Thank you very much.

             2                DR. TAMMINGA:  Thank you, Dr. Chowdhury.

             3                We'll now hear from Dr. Joyce Korvick from the

             4    FDA, from the Division of Special Pathogens and

             5    Immunological Drug Products.

             6                Dr. Korvick.

             7                DR. KORVICK:  Thank you.  I hope you can hear

             8    me.

             9                In the interest of time, I'll try to keep my

            10    comments brief and give the committee and advisors a simple

            11    snapshot of some of the data that was recently reviewed by

            12    the agency regarding the quinolones.  These are a class of

            13    anti-infective drug products.

            14                Next slide, please.

            15                I'm going to give you a little bit of

            16    background, the setting we find ourselves in with these

            17    drugs, different than antipsychotic drugs, some data on the

            18    drugs recently approved, comparison of selected

            19    characteristics of interest, and then go into some

            20    considerations and approach to regulatory actions.

            21                Next slide.

            22                I think that, in contrast to some of the drugs

            23    you've been talking about earlier, we have to remember that

            24    antibiotics for the most part are prescribed for 14 days or

            25    less.  Previously we have noted that there may be some

                                                                          142

             1    effects with the macrolides.  These are drugs like

             2    erythromycin, chlorithromycin and so forth.  However, you

             3    know in the postmarket experience, the effect on QT

             4    prolongation and ultimate sudden death, unexplained death

             5    does not seem to be particularly large.

             6                Finally, I think in the setting of reviewing

             7    these quinolones, sparfloxacin approved in the early 1990s

             8    was a drug, one of the first quinolones that extended the

             9    spectrum of quinolones beyond that of the Gram-negative

            10    organisms that you're familiar with that cyprofloxacin

            11    treats for urinary tract infection.  We also approved

            12    grepafloxacin in 1997.  Trying to assess the postmarketing

            13    record regarding QT abnormalities or sudden unexplained

            14    death is relatively difficult, because both of these drugs

            15    suffer from low-volume use.  So calculating the actual

            16    estimated rate is difficult.  But when that was done, it

            17    was seen that sparfloxacin, there was some suggestion that

            18    sparfloxacin may be the most potently active prolonger of

            19    QT and have some effect in the postmarketing arena.

            20                Next slide.

            21                During the time that we were reviewing

            22    moxifloxacin and gatifloxacin late last year, the Glaxo

            23    company spontaneously withdrew grepafloxacin from the

            24    market.  In the original labeling, there was some

            25    understanding based on one PK study that there may be some

                                                                          143

             1    QT prolonging effect, but that was not well understood. 

             2    Then in the postmarketing, there was additional information

             3    accrued that suggested that might be a real effect, and

             4    there were several cases that were reported that are

             5    currently under review within the agency of clinical

             6    effects.

             7                Now I'd like to turn comments to moxifloxacin. 

             8    These are only a few data that I'm going to present.  The

             9    extensive database was reviewed before our Anti-Infectives

            10    Advisory Committee, and those slides can be found at the

            11    FDA Website, if anybody is interested.

            12                Next slide.

            13                In front of the Anti-Infectives Advisory

            14    Committee, we did grapple, much as you all are doing here,

            15    with the QT issue.  We touched upon the preclinical data

            16    and the Phase I/II PK studies, of which there was a lot. 

            17    The preclinical data did suggest some prolongation in the

            18    animal models.  Because of the studies that were done in

            19    preclinical and Phase I/II, the company elected to do --

            20    which is relatively unusual for antibiotics -- paired EKGs

            21    in the Phase III studies.  So we had a lot of that data to

            22    review, and I'll show a little bit of that subsequently.

            23                We also had our postmarketing colleagues from

            24    OPDRA do a review of the postmarketing experience for

            25    approved antibiotics, and we looked at some of those

                                                                          144

             1    profiles.

             2                Next.

             3                In the preclinical animal data, it was noted

             4    that there were significant changes in the animal models,

             5    but this was related to a rapid infusion, and that was seen

             6    at extreme doses.

             7                Next slide.

             8                As I mentioned, this was their Phase III

             9    experience.  This includes moxi and the comparator drugs,

            10    and these were studies of pneumonia mostly.  But these were

            11    the patients available for safety, and they did pair the

            12    EKGs, and when they looked at the valid paired EKGs, they

            13    came down to 559 on the 400 milligram daily dose of

            14    moxifloxacin and 515 for the comparator.

            15                Next slide.

            16                Out of this experience, we saw a mean QTc of 5,

            17    and that includes a few other patients.  The numbers are a

            18    little different.  But this was compared to some of the

            19    patients who were on chlorithromycin, and we mentioned

            20    earlier that we were interested in macrolides, and it

            21    seemed that the mean change was 2 for that.  Overall, for

            22    all of the comparators, which included betalactams and some

            23    other quinolones -- levofloxacin being one -- they

            24    calculated a mean change of zero.  So this was what we saw. 

            25    This drug was being administered orally on a daily basis.

                                                                          145

             1                From a PK study, we had this dose relationship,

             2    and between the solid purple bars, that would be the

             3    concentration that you would expect.  The actual

             4    concentration was measured with the recommended dose of

             5    either 200 or 400 milligrams.  That was done in 181

             6    patients.  But you see for the most part the measurement of

             7    the delta QTc sort of is lumped into the area where we

             8    would expect the Cmax on the approved dose.  So we would

             9    like to see, as an agency, a little bit more on the

            10    extremes, as has been mentioned earlier.  We'd like to see

            11    what kind of slope we would really get if we pushed the

            12    dose, to try to understand better the dose relationship of

            13    this drug to the QT prolongation.

            14                Also to mention, this is a relatively shallow

            15    slope.

            16                Next slide.

            17                Again, when moxifloxacin was studied in IV

            18    formulation, they got a delta QTc in the PK studies of

            19    around 12.  This number probably is a little bit lower

            20    because, again, it depends on the rapidity of the infusion

            21    rate, and in some of these studies the higher numbers were

            22    seen in the 15-minute infusion.  Currently, moxifloxacin is

            23    approved in the oral dose, and there are ongoing studies

            24    and data that are looking into the IV dose.  You can see

            25    here that there were placebos in these PK studies where you

                                                                          146

             1    could see a mean prolongation of 3.5.  So I think that is

             2    of interest when we include those to see what the

             3    variability is in QTc.

             4                In summary, then, for the moxifloxacin, the IKr

             5    was blocked at three times the concentration that it took

             6    with ciprofloxacin.  There were ADP studies where, again,

             7    it was 50 micromolar compared to the prolongation caused by

             8    a lot smaller dose concentration of sparfloxacin.  As you

             9    get the feel, I think in our group we're looking at

            10    sparfloxacin as maybe the most active prolonger of QT in

            11    the quinolone class.  There were dose prolongations in

            12    animals and humans.  I mentioned the delta QTc.

            13                As far as outliers, in the large Phase III

            14    studies that we reported, they saw three patients that had

            15    QTc's measured on drug that were greater than 500.  One of

            16    those patients had hypokalemia.  Another patient had

            17    preexisting right bundle branch block.  The third patient

            18    had no associated underlying diseases.  In the control

            19    group, there was one patient that was an outlier.  Again,

            20    with additional analysis, it was noted that there were

            21    increased changes with hypokalemia.

            22                Just to mention that because of the animal

            23    experience, when they were conducting the Phase III

            24    studies, they did exclude patients that had prolonged or

            25    known cardiac problems and patients that were on

                                                                          147

             1    concomitant cardiac drugs that could prolong QT.

             2                Next slide.

             3                Gatifloxacin for comparison was reviewed at the

             4    same time.  It wasn't taken to the advisory committee. 

             5    They had preclinical and animal data which seemed to

             6    suggest there was much less of an effect on the QT.  So

             7    when they entered the Phase III studies, they did not do

             8    paired EKGs, but they also did not exclude patients with

             9    cardiac disease.  So in that Phase III experience, we were

            10    able to see -- we were looking at adverse events, et

            11    cetera, sudden unexplained death, torsade.  There was none

            12    of that seen in that experience.

            13                Next slide.

            14                Just to show you briefly another one of these

            15    dose relationship curves, the little boxes here, and you

            16    can see there are only six patients, shows delta QTc at the

            17    recommended dose.  Again, if you try to calculate what that

            18    might be, it might fall out around the minus 1.  If you

            19    look at the other studies, because there were only small

            20    numbers of patients studied, actually monitored for their

            21    QTc, it was actually hard to come up with a number to tag

            22    on that.  But it may be around 3, and we're looking into

            23    more information there.

            24                Next.

            25                So this table just summarizes some of the

                                                                          148

             1    issues that you've been talking about.  It's important to

             2    note the elimination pathway.  So for moxi, gati, grepa and

             3    spar, you see this renal-hepatic here.  It's totally renal

             4    for gati, hepatic and biliary for these two.  The only drug

             5    that has an effect on CYP450 is grepafloxacin.  As I

             6    mentioned, these were the QT changes.  All of these drugs

             7    probably do have a dose relationship as far as prolonging

             8    QT.  However, we are trying to work with the companies to

             9    establish better what that is, and again, we would like to

            10    bracket higher serum concentrations so that we can get a

            11    better handle on the slope.

            12                Again, as I mentioned, there were three

            13    outliers here.  In the 56 patients that were studied for PK

            14    for gati, there were no outliers; that is, anyone over 500

            15    milliseconds.  There were some considerations in the

            16    postmarketing database and cases reported which are

            17    currently under review, and I have a comment about that

            18    right now.  Then in the label for sparfloxacin, it was

            19    noted that there were 10 outliers out of the 14,000

            20    patients, which gave you a rate of 0.7.

            21                Going backwards, since spar was the earliest

            22    one approved, there was a contraindication written into the

            23    label, and the reason that was, even though the number is

            24    small for delta QTc, during the Phase III conduct of that

            25    study, there were cases of torsade de pointes documented. 

                                                                          149

             1    Contraindication for grepa at the time of approval was

             2    requested by the sponsor being conservative based on some

             3    small PK studies that were done showing some small changes

             4    in PK QTc relationship.

             5                Finally, we put warnings in the label for moxi

             6    and gati because when we looked at this compared to spar

             7    and grepa and took other things into consideration, we felt

             8    that the warning would be the best.  I can show you that in

             9    a moment.  We also placed an information for patients

            10    section in the package insert.  So I'll talk about that in

            11    a moment.

            12                Again, as you've heard earlier, the unique

            13    characteristics of the drug.  Does it offer an advantage

            14    over the existing drugs in some way?  The spectrum of

            15    indications.  Again, as you've heard, we would not consider

            16    using something that prolongs the QT for minor infections. 

            17    Metabolic pathways and the potential for drug-drug

            18    interaction.  Both of the drugs we recently approved seem

            19    not to have that problem.  Again, we're looking at drugs

            20    that are being approved for short-term use, not chronic

            21    administration, and the route of administration appears to

            22    perhaps also be something to consider.

            23                Next slide.

            24                Again, when we did our regulatory action, the

            25    advisory committee for moxifloxacin thought that there was

                                                                          150

             1    a unique niche for that drug, that it was approvable, that

             2    we should include a warning in the label and let people

             3    know that this thing could happen.  But we didn't know what

             4    the clinical consequences were, since in these drugs there

             5    were no torsade de pointes.  Then we included an

             6    information to patients section at the end of the package

             7    insert.

             8                This is the label, just an example, and you

             9    have a copy of this, so I won't read it to you.  But

            10    basically, we worded it in the warnings, bolded and in

            11    caps, "Gatifloxacin should be avoided in patients with

            12    known prolongation of QT interval, with uncorrected

            13    hypokalemia, and patients receiving Class IA or Class III

            14    anti-arrhythmic agents."

            15                In our Phase IV, we were asking, as I alluded

            16    to, for controlled studies, comparing not only within the

            17    quinolone class but in the same study looking at some

            18    macrolides which are of interest, as they may provide

            19    negative and positive controls and getting some ideas on

            20    the degree of the delta QTc.  Again, at least two times the

            21    recommended dose, to try to attempt to bracket that upper

            22    concentration serum level.

            23                Finally, in our postmarketing Phase IV

            24    commitments, we're not only looking at the passive kind of

            25    reporting in the past, but for both drugs we were asking

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             1    the companies to put together an active adverse event

             2    surveillance protocol, where they would go out and look for

             3    problems related to the cardiac unexpected sudden deaths,

             4    et cetera.

             5                Finally, our continuing approach to this was

             6    that we sent out labels.  We promised our advisory

             7    committee that we'd go out and look at the class issues,

             8    because again we're going back and looking at some older

             9    drugs to find out what's going on.  So at the office level,

            10    we sent letters to all current NDA holders requesting any

            11    QT data that they have.  We continue to coordinate this

            12    effort within the office.

            13                That's all I have.  Thank you.

            14                DR. TAMMINGA:  Thank you very much, Dr.

            15    Korvick.

            16                Our last speaker from the FDA will be Dr.

            17    Evelyn Rodriguez, who is the Director from the Division of

            18    Drug Risk Evaluation from the Office of Postmarketing Drug

            19    Risk Assessment, who will talk about cisapride and

            20    compliance with labeling advice.

            21                Dr. Rodriguez.

            22                DR. RODRIGUEZ:  Hi.  Can you hear me?

            23                Today I'll be talking to you about a risk

            24    intervention study that we did for cisapride.

            25                Next slide.

                                                                          152

             1                The topics for today's discussion -- I'll try

             2    to make it brief because I know I stand between you and

             3    lunch -- is to give you a regulatory overview of cisapride,

             4    to describe the risk intervention study that was performed

             5    through the cooperative agreements that we have in OPDRA,

             6    to present some summary conclusions from that, some future

             7    directions and possible next steps for this particular drug

             8    that we're discussing today.

             9                Next.

            10                This will be the regulatory history and an

            11    overview of the study that was performed.

            12                Next.

            13                Cisapride was approved in July of 1993, and we

            14    received the first reports of ventricular arrhythmia with

            15    an antifungal drug in December of 1994.  Multiple "Dear

            16    Health Care Practitioner" letters and labeling changes that

            17    described new contraindications and warnings for specific

            18    drugs and conditions were mailed by the sponsor.

            19                Next.

            20                That culminated in a black box warning, with

            21    contraindication for QT interval-prolonging drugs and

            22    cardiovascular and medical underlying conditions.  It also

            23    relegated the drug to a second-line indication and another

            24    "Dear Health Professional" letter in June of 1998.  I

            25    should point out that the only approved indication for this

                                                                          153

             1    drug was nocturnal heartburn.

             2                The study objective for the risk intervention

             3    study was to describe the impact of the labeling changes

             4    through June of 1998, which included contraindications for

             5    cytochrome 3A4 enzyme inhibitor drugs, other QT-prolonging

             6    drugs, and contraindicated comorbidities.  We looked at

             7    three separate automated databases, sites A, B, and C,

             8    which you'll see later described.  We looked at a year

             9    before the last "Dear Doctor" letter, and then a year after

            10    the "Dear Doctor" letter.

            11                Next.

            12                There were three study sites.  One of them was

            13    an IPA model with about 3.2 million persons in their

            14    overall health care setting.  One was a Medicaid managed

            15    care model, again with 1.4 million persons.  So these are

            16    very large databases.  Then Site C was an HMO, with about 2

            17    million.  These were the cohorts that we assembled before

            18    and after the labeling changes, the year before, June 1998,

            19    and the year after the labeling change.  Site A had about

            20    17,000 persons in the year before labeling, and about

            21    15,000 available for study after, and you can see Site B

            22    had about 5,000 in each period, and Site C around 8,000.

            23                Next.

            24                These are the results.  Basically, in the year

            25    before the labeling change in Site A, there were about 30

                                                                          154

             1    percent of persons who received the drug despite

             2    contraindications, in Site B about 60 percent, and in Site

             3    C about 30 percent again, and virtually no change in the

             4    year after labeling.  So there was no reduction in

             5    contraindicated use following labeling changes as of the

             6    "Dear Doctor" letter of June of 1998, and these were the

             7    investigators involved in that study.  The sites were

             8    United Health Care, Tennessee Medicaid, and the Harvard

             9    Consortium.

            10                Our summary in the Office of Postmarketing was

            11    that risk intervention studies like this are useful to

            12    assess the effects of labeling and "Dear Health Care

            13    Practitioner" letters.  With this particular drug, with the

            14    series of labeling changes that had occurred throughout its

            15    long history, it does suggest some labeling fatigue.  That

            16    is, once you make one labeling change and proceed to make

            17    yet another and another, it really doesn't seem to have

            18    much of an impact on prescribing strategies, and other risk

            19    intervention strategies such as targeted education for

            20    prescribers and patients may be useful to encourage the

            21    implementation of recommended risk management efforts.

            22                Future directions in our opinion in

            23    postmarketing would be to determine how prescribers

            24    actually interpret the information that we put in "Dear

            25    Doctor" letters and how other educational materials will

                                                                          155

             1    augment the information in labeling changes and in "Dear

             2    Doctor" letters.

             3                Also, we're in the dark, really, to ascertain

             4    the best format to really inform prescribers and patients

             5    of drug safety concerns.  Will PPIs, patient package

             6    inserts, have an impact?  What kind of information should

             7    be provided in medication guides?  Will companies' sales

             8    force materials, brochures and other kinds of materials

             9    delivered directly to physicians and instructed by sales

            10    force have an impact on reinforcing drug safety concerns? 

            11    Will CME courses, for example, as another education method,

            12    have an impact?

            13                We need to determine how information and

            14    labeling, such as contraindications, warnings, and

            15    monitoring recommendations, are actually going to be

            16    understood and implemented by prescribers.  We need to

            17    conduct risk intervention studies on multiple databases, as

            18    we did in cisapride, because you saw the variability there,

            19    although in all sites there was not much of a difference

            20    before and after the last labeling change.  But

            21    nevertheless, it should reflect the range of health care

            22    services delivery systems that we have in the U.S., and we

            23    need to validate findings in these automated databases that

            24    we use with medical record review.

            25                Possible next steps with regard to this

                                                                          156

             1    particular drug that we're discussing today is an incidence

             2    study for serious outcomes in automated databases. 

             3    However, the use of automated databases to look at QT

             4    prolongation and torsade de pointes is difficult, if not

             5    impossible, to do because the ICD-9 codes that are

             6    available to us are very non-specific and are not going to

             7    point to these disorders, and because there's likely to be

             8    under-ascertainment and underreporting even in those

             9    systems.

            10                Perhaps looking at sudden unexplained death is

            11    possible, but again, very difficult.  We would need to use

            12    an unexposed comparator group or a comparator group on a

            13    different kind of drug among the patients that we're

            14    interested in in order to really glean whether there is an

            15    increased risk of sudden death with this particular drug.

            16                Other interventions in terms of risk management

            17    would be to institute some sort of EKG monitoring, perhaps

            18    recommend that in labeling, perhaps educational

            19    interventions with prescribers and for patients, and then

            20    to evaluate whether the risk interventions used in labeling

            21    or in educational efforts would be achieving the desired

            22    goals.

            23                Thank you.  That's the end of my presentation.

            24                DR. TAMMINGA:  Thank you, Dr. Rodriguez.

            25                The company, Pfizer, has requested to have an

                                                                          157

             1    opportunity to respond to the presentations of the FDA,

             2    specifically to Dr. Moss' presentation.

             3                Excuse me, Pfizer has withdrawn their request.

             4                Therefore, the committee will have an

             5    opportunity now to ask questions to the FDA people who made

             6    their very informative presentations.  I would suggest that

             7    the committee ask pressing questions now to the FDA people

             8    and leave less pressing questions until after lunch, and I

             9    would suggest that the FDA people answer the questions

            10    directly from your seat so you don't have to go up to the

            11    podium all the time.

            12                Questions for the FDA presenters?

            13                I'll start out actually with a question for Dr.

            14    Dubitsky.  In your actions no Mellaril and your

            15    recommendations for the target of Mellaril, you said on

            16    your slide that it was restricted for an indication for

            17    schizophrenia.  Is it specifically for schizophrenia or for

            18    psychosis in general?

            19                DR. DUBITSKY:  Right now, it's for

            20    schizophrenia.  The reason it was on the slide, I don't

            21    know if I mentioned it, but previously it had been

            22    indicated for some non-psychotic conditions such as

            23    neurotic depression, things like that.  But we have

            24    eliminated those and right now it's indicated just for

            25    schizophrenia.

                                                                          158

             1                DR. TAMMINGA:  But how about for psychotic non-

             2    schizophrenic disorders?  That was my question.

             3                DR. DUBITSKY:  That is something we're looking

             4    at.  Right now there's an effort within our group to make

             5    labeling more clear as far as the specific indications, and

             6    to link those to the indications that were actually studied

             7    in the pivotal trials that led to the approval.  So if

             8    those studies were done in schizophrenic patients

             9    primarily, then we are going to label that as indicated

            10    just for schizophrenia.

            11                DR. TAMMINGA:  Dr. Laughren?

            12                DR. LAUGHREN:  This is really part of a larger

            13    effort that's underway in the Division to try to make

            14    labeling more specific to the indications that were

            15    actually studied.  It's not limited to psychosis.  It's

            16    actually been true in the anxiety disorders over the past

            17    decade.  We've gradually been shifting from the very

            18    general psychotropic claims to looking very specifically at

            19    the specific entities that were studied.  So focusing in

            20    this particular label on schizophrenia is part of that

            21    effort.  You'll be seeing more of that in the future.

            22                DR. TAMMINGA:  Other questions for the FDA

            23    presentations from the committee?

            24                Dr. Fyer?

            25                DR. FYER:  I'm not sure who to direct this to,

                                                                          159

             1    maybe to Dr. Moss.  I'm a little confused about one aspect

             2    of this QTc stuff, and I apologize for that, if I'm sort of

             3    asking the obvious.

             4                It seems that there's a definite implication

             5    from what we've heard that an interval of over 500

             6    milliseconds is associated with some of these dangerous

             7    arrhythmias and torsade de pointes.  If I'm incorrect, I

             8    hope someone will correct me about that.  The thing I'm

             9    confused about is whether or not there's any data about the

            10    impact of increases over baseline that don't lead to an

            11    individual having an interval greater than 500.  I don't

            12    know if it's just the case that nobody knows or if there

            13    have definitely been studies indicating that if somebody

            14    has a 360 and they go to 420, that is or isn't associated

            15    with some sort of risk.  I don't know who to direct this

            16    to, maybe Dr. Moss.

            17                DR. TAMMINGA:  Dr. Moss, why don't you take a

            18    first crack at it.

            19                DR. MOSS:  Well, we don't have very clear

            20    information on this, to be frank with you.  There does seem

            21    to be some increase in relative risk as you go from, say,

            22    380 to 440, even though you're still below the level.  But

            23    you're probably on a lower slope of this exponential curve. 

            24    So there is an effect there, but it's not probably as great

            25    as what you see higher up.

                                                                          160

             1                But there's really very little data on that,

             2    and in the presentation that was made earlier by Dr.

             3    Harrigan, that was an unusual graph showing that the

             4    effect, although the mean effect was quite considerable,

             5    and the range was quite considerable, it looked like the

             6    overall data was a regression to the mean, that those

             7    people who had the lowest values had the biggest increase,

             8    and those who had high values had the smaller increase. 

             9    That's most unusual in terms of mechanism, unless one wants

            10    to just say from a statistical standpoint that that is

            11    likely to happen.

            12                So I don't have a good answer for you, only to

            13    say that there's probably some gradient of risk, but it's

            14    probably too small to be measured as we understand it and

            15    with the numbers that one is dealing with.

            16                DR. TAMMINGA:  Yes, Dr. Califf?

            17                DR. CALIFF:  Maybe I'll toss something out, and

            18    also this is a question for Dr. Throckmorton I think more

            19    than anyone else.  It seems to me that one cannot

            20    generalize, because if I interpreted what you said

            21    correctly, and we were certainly there for the really

            22    interesting data, interestingly from the same company, on

            23    the drug for atrial arrhythmias, it is possible to prolong

            24    the QT interval and reduce the overall risk of sudden

            25    death, at least in one post-MI study.  So I'm not sure that

                                                                          161

             1    you can generalize a certain increase in QT interval as

             2    necessarily giving you an effect, at least on the risk of

             3    death.

             4                DR. TAMMINGA:  Except we're talking about a

             5    population here that's not primarily a cardiac population.

             6                DR. CALIFF:  Well, that's true, although

             7    there's a lot of cardiac disease, and I think what we've

             8    seen in most cases of toxicity of drugs in populations,

             9    it's the high-risk end of the spectrum.  It's not the young

            10    person who is at highest risk.  It's going to be the older

            11    person who is on multiple medications with underlying

            12    cardiac disease, a lot of which is not diagnosable based on

            13    symptoms and history.

            14                DR. TAMMINGA:  Dr. Throckmorton?

            15                DR. THROCKMORTON:  Yes, I'd agree completely. 

            16    I know of no clean data set -- Jeremy may correct me on

            17    this -- that looks at risk relative to baseline ECG.  You

            18    have a baseline that's high, you have some higher risk.  It

            19    would be interesting to have those data.  I think it's

            20    likely that it is a spectrum, like Dr. Moss said.  We have

            21    incomplete data about the effect of extreme prolongation

            22    from baseline, and again, that suggests that there is some

            23    increased risk.  But those data are difficult because they

            24    come largely from either long QT syndrome or from anti-

            25    arrhythmics, from sotalol especially.  It's difficult to

                                                                          162

             1    look at an anti-arrhythmic population and say absolutely

             2    that you can extrapolate that to a quinolone or something

             3    like that.

             4                DR. TAMMINGA:  Dr. Fyer?

             5                DR. FYER:  This is another aspect of this

             6    question.  The risk of these arrhythmias, as I understand

             7    it, this is like a repolarization process that's going on,

             8    and you have prolonged repolarization.  Is that the

             9    physiology that we're talking about?  Okay.  So how is that

            10    related to the advent of these arrhythmias?  Maybe that

            11    would help in terms of understanding whether people have

            12    lower values and just increase.

            13                DR. THROCKMORTON:  I'll let all the

            14    cardiologists arm wrestle for which one wants to answer the

            15    question.

            16                DR. FYER:  Nobody knows?

            17                DR. THROCKMORTON:  No, they do.

            18                DR. TAMMINGA:  Dr. Moss?

            19                DR. MOSS:  Well, let me just say that the

            20    lengthening of the QT interval is probably a reflection of

            21    greater what we call heterogeneity of the electrical

            22    repolarization across the myocardium, and as you look

            23    across the myocardium, the degree of repolarization varies

            24    with different sites.  The mid-myocardium seems to have the

            25    longest action potentials to begin with, and these are

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             1    cells that seem to be most vulnerable to drugs as a general

             2    rule.  When you see the lengthening of the QT interval,

             3    it's actually telling you that there is some greater

             4    heterogeneity in repolarization, and it's the heterogeneity

             5    that seems to give rise to the arrhythmic potential,

             6    allowing for certain types of either reentry or

             7    depolarizations; that is, some reflection of further degree

             8    of electrical instability.

             9                So it's a measure.  It's really a marker, and

            10    it's a marker of really some alteration in the underlying

            11    electrical activity of the heart that gives rise to these

            12    reentrant-triggered arrhythmias or after depolarization-

            13    triggered arrhythmias.  So it's simply a marker.  I

            14    wouldn't think the QT itself is the factor, but it's

            15    telling you that there's alteration in the electrical

            16    activity of the substrate of the myocardium.

            17                DR. TAMMINGA:  Could I follow this up with a

            18    question to any one of the cardiologists?  From what Dr.

            19    Califf just said, are we to understand that what you were

            20    just talking about, Dr. Moss, is primarily a risk factor in

            21    people whose cardiac function is already compromised?

            22                DR. MOSS:  Well, not necessarily.  Certainly,

            23    the people who have underlying cardiac disease seem to be

            24    at more or greater vulnerability and greater risk.  But the

            25    problem with the terfenadines and the other agents, the

                                                                          164

             1    antibiotics, have been in people with normal hearts.  It's

             2    a matter of relative risk.  Women seem to be at a little

             3    bit greater risk than men in terms of QT prolongation, and

             4    this has been well documented in the literature; older

             5    people a little bit more than younger people, and people

             6    with heart disease.  But it's heart to quantitate this

             7    information.

             8                DR. TAMMINGA:  One question from Pfizer?

             9                DR. RUSKIN:  I wondered if I could just add a

            10    response?  I'm Jeremy Ruskin.  I'm a consultant for Pfizer

            11    on this drug.  Massachusetts General Hospital, Boston.

            12                Dr. Fyer asked a question earlier about the

            13    significance of outliers beyond 500 milliseconds, which is

            14    I think a critical issue.  There are at least some data to

            15    speak to that.  The number isn't just pulled out of the

            16    air.

            17                It comes from the fact that of the reported

            18    cases of drug-induced torsade, both with cardiac and non-

            19    cardiac drugs, in which a QTc interval was measured at the

            20    time of the event, more than 95 percent of the time, those

            21    events are associated with QTc's greater than 500

            22    milliseconds, and that's where the interval comes from.  So

            23    it's not impossible, but it is unusual to see a case of

            24    drug-induced torsade with a QTc of less than 500

            25    milliseconds.

                                                                          165

             1                DR. LINDENFELD:  Dr. Ruskin, if you could

             2    clarify, that's at the time of the arrhythmia, the greater

             3    than 500?  I mean, from someone who recorded an EKG around

             4    that time?

             5                DR. RUSKIN:  Yes, around the time of the event.

             6                DR. LINDENFELD:  It is possible those patients

             7    would have a shorter QTc, or have had at other times.

             8                DR. RUSKIN:  Certainly.  There's a great deal

             9    of variability in the QTc, yes.

            10                DR. TAMMINGA:  Yes, Dr. Malone?

            11                DR. MALONE:  Many of these drugs, once they get

            12    approved, get used in children.  Are children at a greater

            13    risk -- I guess this question is for Dr. Moss -- at a

            14    greater risk for these phenomena than adults?

            15                DR. MOSS:  If you think the data for adults is

            16    incompletely, you should only know that there's virtually

            17    no data on children.  I think it would be dangerous for us

            18    to extrapolate from a long QT syndrome.  There's just very,

            19    very little data, mainly because these drugs have not been

            20    tested in children, and virtually all the pediatricians

            21    extrapolate their information from the adults.  But there's

            22    been very, very little testing, so I don't have an answer. 

            23    Maybe Dr. Califf does.

            24                DR. CALIFF:  You said it.  I think it is

            25    instructive that under the FDAMA legislation, a study was

                                                                          166

             1    finally done with sotalol, which was mentioned as one of

             2    the drugs, and there are major dosing issues in children

             3    which are not easily explainable, just treating them as

             4    small adults.  So I think it's largely unknown what the

             5    risk is in children.

             6                DR. TAMMINGA:  Yes, Dr. Oren?

             7                DR. OREN:  Dr. Rodriguez, the cisapride data

             8    that you presented are of potential immense public health

             9    significance, and I wondered if, from that study, there's

            10    been any attempt to validate the automated database on a

            11    smaller sample, and specifically to serve physicians

            12    directly.  If the decision is to prescribe, apparently

            13    contrary to labeling, was based on informed decision or

            14    based on ignorance?

            15                DR. RODRIGUEZ:  The study is as presented.  We

            16    haven't done any medical record validation or any further

            17    steps, and we didn't do a survey.  But a comment on doing

            18    surveys.  Prescribers know, I think, what we should be

            19    doing, being a prescriber myself.  I think it's worth more

            20    to see what actually is being prescribed, and then trying

            21    to find out from prescribers what is useful in

            22    communicating in labeling, what is not useful in terms of

            23    multiple contraindications to put in labeling, and then how

            24    feasible it is for them in everyday practice to

            25    thoughtfully prescribe and think about the

                                                                          167

             1    contraindications and the warnings in labeling.

             2                DR. TAMMINGA:  Dr. Fyer?

             3                DR. FYER:  Can I just ask you one question

             4    about that?  I don't know if this is possible, but did you

             5    have any ability to look and see whether -- there were no

             6    mean differences in the percent of people, but were there

             7    any prescriber-specific changes?

             8                DR. RODRIGUEZ:  I think you're asking a

             9    question about whether we can track individual prescribers. 

            10    We did not do that.  We looked at the overall percent.

            11                DR. FYER:  I understand what the data was.  I

            12    wondered if you had the capacity to do that.

            13                DR. RODRIGUEZ:  No, we did not do that.  These

            14    automated databases I don't think would be able to do that.

            15    It would be very difficult to do that.

            16                DR. FYER:  Doctors have all kinds of I.D.

            17    numbers.

            18                DR. RODRIGUEZ:  When I say "able," I think it's

            19    because these are FDA funded, and we're limited in terms of

            20    cost.  So we try to do the simplest study to address the

            21    regulatory question at hand, and frequently we have also a

            22    very short amount of time in which to do that.  So what you

            23    describe would be a very labor-intensive study that

            24    sponsors can entertain doing.

            25                DR. TAMMINGA:  Dr. Katz?

                                                                          168

             1                DR. KATZ:  Yes, I'd just like to ask Dr. Ruskin

             2    for a little more information about the data that you

             3    talked about in terms of 95 percent of patients who had a

             4    cardiogram done at the time of torsade.  Clearly, that

             5    doesn't represent the universe of patients with torsade,

             6    and obviously patients haven't been randomized to

             7    particular QT intervals to see what their incidence of

             8    torsade is.

             9                How robust was that data?  Are we talking about

            10    hundreds and hundreds of cases of torsade, or a few cases

            11    of torsade?

            12                DR. RUSKIN:  I don't have the precise number. 

            13    These are not huge numbers.  We're talking about a couple

            14    of hundred patients with cardiac drugs, and somewhere

            15    around 150 or 170 with non-cardiac drugs.  So the numbers

            16    are relatively small, you're right.  Obviously, this is

            17    data that is subject to all sorts of reporting biases and

            18    so on, because it's not gathered prospectively, and it's

            19    not controlled.

            20                I think that most clinicians, though, would

            21    agree that, while the magnitude of effect on the QTc is

            22    important, that the absolute QTc is probably more

            23    important, and going from 380 to 420 is probably

            24    significantly less worrisome than going from 460 to, say,

            25    500, or 480 to 530, based on the observations that we make

                                                                          169

             1    clinically in those patients who develop torsade.  I'd be

             2    interested in Dr. Moss' thoughts about that.

             3                These are very hard data to gather, and one is

             4    left with anecdotal reports in the literature, and that's

             5    where the data is derived from.

             6                DR. TAMMINGA:  Dr. Califf?

             7                DR. CALIFF:  I would like to pile on here to

             8    dispel any myth that these are reliable kinds of data. 

             9    Through a project with the FDA, Georgetown is putting

            10    together a prospective registry of drug-induced torsade. 

            11    It hasn't been discussed here yet, but the likelihood that

            12    the average clinician in the average setting is even going

            13    to diagnose torsade is quite small, I think, in patients

            14    who get sick and have ventricular arrhythmias.  Even at

            15    major academic centers, there can be tremendous disputes

            16    over what the nature of the rhythm disturbance actually is.

            17                DR. TAMMINGA:  Dr. Moss, would you like to

            18    weigh in?

            19                DR. MOSS:  Well, in response to Dr. Ruskin's

            20    question and comment, I would fundamentally concur.  We

            21    don't have any substantial evidence that the increment of

            22    going from 380 to 410 carries any substantial risk.  There

            23    may be a risk, but it's unmeasurable at the present time,

            24    and I don't know that anybody has data on that.  The data

            25    that's available is in the higher range.  So I think it's

                                                                          170

             1    unknown, and I would have to say that my suspicion would be

             2    that if there is a risk, it's got to be so small that you

             3    would need hundreds of thousands to millions of patients to

             4    detect anything.

             5                DR. TAMMINGA:  Dr. Throckmorton?

             6                DR. THROCKMORTON:  The only place that we have

             7    any large data does come from the sotalol database.  The

             8    sponsor for sotalol did do an analysis of torsade related

             9    to both extreme prolongation of QT -- that is, incidence

            10    over 500 to 550 or 600 milliseconds -- and by change from

            11    their baseline.  In both those cases, for sotalol, they

            12    described a relationship that the longer the extreme

            13    prolongation or the larger the change from baseline for an

            14    individual patient, the higher the risk for torsade.  The

            15    problem was that those ECGs were taken at the time of

            16    torsade, and we don't know what their normal QT would have

            17    been.  We also don't know what the incidence of QT over 500

            18    was for patients who did not suffer torsade.  So we lack

            19    two pieces of information.

            20                But to the extent you could extrapolate, I

            21    think that's the only place like that.  Now, again, like

            22    Dr. Califf said, the dofetilide database might be open to

            23    some analysis along those lines and could give some answers

            24    maybe.

            25                DR. TAMMINGA:  We'll have one last question

                                                                          171

             1    from Dr. Hamer before lunch.

             2                DR. HAMER:  This question is also to Dr. Moss. 

             3    I just want to make sure I understand the risk estimates

             4    that were presented, where you had a risk at 440, a

             5    relative risk of 1, 500 at 1.4, 640 at 2.8.  These are

             6    absolute or baseline QTc intervals; is that right?  So in

             7    some sense, they really don't say anything about what

             8    happens to a given person or individual if you increase the

             9    QTc interval from 440 to 500, or 500 to 640?

            10                DR. MOSS:  Well, there seem to be two questions

            11    in that.  We used the QTc of 440 milliseconds as simply a

            12    reference.  So we just arbitrarily took that as a

            13    reference.  The risks that we reported were relative to

            14    whatever the risk is at 400.  So we use that as a reference

            15    of 1.0 so that we can measure the risks above that.  So

            16    it's not that there's zero risk at 440.  We know that there

            17    is some risk, but we took that as the arbitrary reference

            18    point.

            19                DR. HAMER:  No, but I guess the question I'm

            20    asking is, these are subjects or patients who, in a sense,

            21    walked in the door.  You didn't watch them increase their

            22    QTc interval from 440 to 500 or 420 to 500 or anything like

            23    that.  So all this tells you, in a sense, is if a patient

            24    walks in the door with this particular QTc interval, then

            25    perhaps this is what his risk or risk relative to 440 is,

                                                                          172

             1    not what happens if a patient has increased his or her

             2    particular QTc interval from one number to another.

             3                DR. MOSS:  Yes, our data was cross-sectional. 

             4    It was not in terms of individual changes.

             5                DR. HAMER:  And also, I assume that these risks

             6    came from some sort of a logistic regression or some model

             7    like that?

             8                DR. MOSS:  That is correct.  It was actually a

             9    Cox model for time-dependent events.

            10                DR. HAMER:  Were there confidence intervals

            11    associated with them?

            12                DR. MOSS:  We did have confidence intervals. 

            13    What I provided was just the point estimates.

            14                DR. HAMER:  If you look at the confidence

            15    intervals, do they overlap or do they differ from a

            16    relative risk of 1 for the QTc intervals that are higher

            17    than 440?

            18                DR. MOSS:  The answer is yes, to a degree. 

            19    That is, the ones that are closest to 440 definitely

            20    overlap, and the ones that are higher do not.  So it's a

            21    continuum, and because of the limited numbers, the

            22    confidence intervals do overlap, of course, as you are

            23    closer to the 440.

            24                DR. HAMER:  Thanks.

            25                DR. TAMMINGA:  I think with this question and

                                                                          173

             1    this set of answers, we'll adjourn for lunch.  It's 1:00,

             2    and we'll start promptly at 2:00 with the open public

             3    hearing.  Thank you very much.

             4                (Whereupon, at 1:00 p.m., the meeting was

             5    recessed for lunch, to reconvene at 2:00 p.m.)

             6

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             1                         AFTERNOON SESSION          (2:04 p.m.)

             2                DR. TAMMINGA:  If people could take seats,

             3    please, we'd like the meeting to come to order.

             4                I'd like to open up the afternoon session of

             5    this Psychopharmacological Advisory Committee Meeting, and

             6    to open up the afternoon session, we'll have the open

             7    public hearing, and we have three speakers for our open

             8    public hearing.

             9                The first of our three speakers is Ms.

            10    Jacqueline Shannon, who is President of the Board of

            11    Directors of the National Alliance for the Mentally Ill.

            12                Ms. Shannon.

            13                MS. SHANNON:  Am I in the right place here?

            14                Thank you for this opportunity to present at

            15    this public hearing of this committee, and as she said, I'm

            16    Jacqueline Shannon.  I live in San Angelo, Texas, and I'm

            17    President of the Board of Directors of NAMI, the National

            18    Alliance for the Mentally Ill.

            19                As the nation's largest organization,

            20    representing individuals with serious mental illnesses and

            21    their families, in fact, we have over 220,000 members now

            22    and 1,200 affiliates nationwide.

            23                We know firsthand and how critical it is to

            24    have effective treatment for these brain disorders.  In

            25    addition to serving as NAMI's president, I'm also the

                                                                          175

             1    mother of Greg Shannon.  Greg was first diagnosed with

             2    schizophrenia 15 years ago, when he was a college senior,

             3    and for the past 15 years, Greg and our entire family have

             4    struggled through his illness.

             5                But for the last eight years, we've had new

             6    hope due to his treatment with the first of the new

             7    generation of antipsychotic medications, Clozaril.  Since

             8    Clozaril or clozapine has arrived on the scene, only a few

             9    more of the new atypical new generation medications have

            10    been developed and passed the scrutiny of the FDA.

            11                However, with the advent of these ground-

            12    breaking advances in psychopharmacology, recovery is now a

            13    very real possibility for people with mental illnesses and

            14    for increasing numbers of people with schizophrenia.  These

            15    new medications offer new possibilities for full and

            16    productive lives.  These treatments can make the difference

            17    between hope and despair, recovery and struggle, and even

            18    life and death.

            19                For example, Clozaril has made a real

            20    difference in my son's life.  Where previously he had been

            21    hospitalized, in and out of hospitals, for a number of

            22    years, in the last eight years, he has not been back in the

            23    hospital at all.  In fact, he now works two part-time jobs. 

            24    He lives in his own apartment, drives his own pick-up and

            25    is resuming his own life.

                                                                          176

             1                Well, not everyone is a candidate for clozapine

             2    or Clozaril.  In fact, in most states, that particular

             3    medication is reserved for kind of a second tier after

             4    people don't do very well on a couple of the other new

             5    antipsychotic medications that have come on the market, and

             6    although these new atypicals often produce superior

             7    outcomes by treating a broader range of schizophrenia

             8    symptoms, they're different from one another, and people

             9    don't react the same to those medications.

            10                Side effect profiles, which differ among the

            11    medications, have a significant effect on adherence, and

            12    non-adherence, as we all know, has major risks, even

            13    sometimes death.

            14                Unfortunately, the new atypical antipsychotic

            15    medications that are on the market presently all have one

            16    serious side effect in common, and that is of weight gain. 

            17    Now, weight gain, and I'm not talking just about a little

            18    bit, is a real serious problem.  It certainly affects

            19    adherence, morbidity and quality of life.

            20                Because of its different characteristics,

            21    ziprasidone is likely to be an important new addition in

            22    the small arsenal of effective new generation medications

            23    for schizophrenia and other psychotic disorders.

            24                NAMI members strongly believe that professional

            25    judgment and informed consumer choice should be the

                                                                          177

             1    determinants in making decisions about what medications to

             2    take.

             3                However, it's essential that we have more

             4    choices, and NAMI fully supports the research that makes

             5    those choices and those decisions possible.

             6                We understand that you have judgments to make

             7    today about the risks and benefits of medications in

             8    reaching a decision about approval.  We would ask that you

             9    be sure to consider the full range of risks and benefits in

            10    making that judgment.

            11                Absent clear evidence of substantial risk, we

            12    would ask that you make information about benefits and

            13    risks available and allow professional judgment and

            14    consumer choice to weigh these very different drugs in

            15    making their decisions and their choices about treatment.

            16                I also would like to make this disclaimer about

            17    NAMI.  The National Alliance for the Mentally Ill is a non-

            18    profit, grassroots, self-help, support and advocacy

            19    organization composed of consumers, family members and

            20    caring professionals and friends of people with severe

            21    mental illnesses, including schizophrenia, bipolar

            22    disorder, depression, and the other serious mental

            23    illnesses, anxiety disorders and childhood mental

            24    illnesses.

            25                We were founded in 1979.  We have, as I said,

                                                                          178

             1    more than 220,000 members.  In addition to support from our

             2    membership dues and contributions, NAMI is supported

             3    indirectly through the NAMI Anti-Stigma Foundation by

             4    unrestricted educational grants from companies in both the

             5    pharmaceutical and managed care industries.

             6                But NAMI has a strict policy in not endorsing

             7    specific products.  Neither Pfizer nor any of its

             8    competitors have had input into our testimony, and I'd also

             9    like to say that none of the three presenters today,

            10    including me, have had any remuneration nor consulting fees

            11    from Pfizer.

            12                Thank you.

            13                DR. TAMMINGA:  Thank you very much, Mrs.

            14    Shannon.

            15                The next speaker will be Ms. Shannon Flynn, who

            16    is a consumer member of the National Alliance for the

            17    Mentally Ill.

            18                Ms. Flynn.

            19                MS. FLYNN:  Good afternoon.  My name is Shannon

            20    Flynn.  I am here today speaking on behalf of the consumer

            21    members of NAMI, the National Alliance for the Mentally

            22    Ill.  I serve as the Chairperson of the Research Committee

            23    of NAMI's Consumer Council.

            24                I have been diagnosed with schizoaffective

            25    disorder, bipolar type and have been taking atypical

                                                                          179

             1    antipsychotics along with medicines to treat mood for the

             2    past nine years.

             3                During this time, I have gained an average of

             4    about 10 pounds a year, which has accumulated to an

             5    unhealthy level.  Atypical antipsychotic medications seem

             6    to have the mechanism of either increasing appetite or

             7    decreasing metabolism, an effect I have observed in myself

             8    as well as in the many people with schizophrenia and

             9    schizoaffective disorders that I encounter through my

            10    support groups and my work.

            11                In fact, it is very unusual for me to meet

            12    someone with psychotic illness who is treated with

            13    medications that is not overweight, often to a significant

            14    degree.

            15                Weight gain caused by atypical antipsychotics

            16    increases risks for serious physical illnesses, such as

            17    heart disease and diabetes, both of which can have fatal

            18    consequences, and it can be just as risky to decide to stop

            19    taking these medications and possibly face severe

            20    decompensation since weight gain is also a prominent reason

            21    for non-compliance.

            22                The atypical antipsychotics, I have found and

            23    so have others, are tremendously efficacious drugs in terms

            24    of symptom relief, both positive and negative symptoms,

            25    and, in general, they have a much better side effect

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             1    profile, except for the greater incidence and amount of

             2    weight gain as compared to the typical antipsychotics.

             3                I have managed to live successfully with my

             4    schizoaffective disorder, thanks to my own efforts, the

             5    care of a superb psychiatrist, the support of my family and

             6    friends, and, of course, extremely affective medications. 

             7    I have a full-time job and a Master's degree in Art

             8    Therapy.

             9                I facilitate two support groups and serve on

            10    the NAMI Consumer Council in an executive position.  I have

            11    warm relationships with my family, close friends, and a

            12    significant other.  I would like to continue enjoying these

            13    aspects of a full life, but without treatment with atypical

            14    antipsychotics, I may not be able to do this.

            15                I am not a doctor.  I can't weigh the details

            16    of the medical risks, but I encourage you to consider the

            17    changes in metabolism and the weight gain as a common and

            18    significant problem of many current medications involving

            19    both long-term medical risks and shorter-term risks of

            20    stopping treatment.

            21                I would like to e able to consider an option to

            22    live an enriching life at a normal, healthy weight, as I

            23    did before the onset of my illness, although that option

            24    might involve other side effects or risks.  Together with

            25    my doctor, I would want to assess the benefits and the

                                                                          181

             1    risks of these different alternatives.

             2                If the risk associated with a novel drug is

             3    rare and can be decreased with appropriate screening, I

             4    would want to have that choice and so would the many other

             5    people with these illnesses.

             6                Thank you for the opportunity to speak with you

             7    on behalf of NAMI's consumer members.

             8                DR. TAMMINGA:  Thank you, Ms. Flynn.  We

             9    appreciate hearing your thoughts.

            10                Our next and final public speaker will be Dr.

            11    Rex Cowdry, who's the Medical Director of NAMI.

            12                Dr. Cowdry.

            13                DR. COWDRY:  Thank you very much, Dr. Tamminga,

            14    members of the committee.

            15                I'll be very brief.  A lot of what I say just

            16    has a slightly different spin from the other presenters. 

            17    I'd like to speak about three issues very briefly.  One is

            18    risk assessment, a second is benefits, and a third is the

            19    issue of patient information.

            20                On risk assessment, first, I think it is clear

            21    that it's understandable, it's human nature to be

            22    particularly concerned about severe adverse events, even

            23    very rare ones, but I think in weighing this risk, such as

            24    it is, and I think from what we heard, it's proven to be a

            25    rather illusive and difficult-to-quantify risk,

                                                                          182

             1    particularly with this agent, it's also important to take

             2    into account the range of other adverse consequences of

             3    this illness.

             4                Schizophrenia is not allergic rhinitis. 

             5    Schizophrenia is one of the major causes of disability in

             6    the United States and worldwide.  It's a major cause

             7    particularly of long-term disability in our younger

             8    population.

             9                So one of the questions is what are the full

            10    range of risks that may be involved with this disorder, and

            11    I would just ask that you not dismiss the impact of problem

            12    chronic side effects on issues of adherence, on the one

            13    hand, for example, the issues of substantial weight gain,

            14    which in our clinical practice, we know is a deterrent to

            15    people starting treatment, and it's a deterrent to people

            16    continuing treatment, and if I had to identify the one

            17    biggest risk to someone with schizophrenia and the biggest

            18    public health risk, it's stopping treatment.

            19                The second issue has to do with benefits, and

            20    here, we don't have the data we would like.  I hope we'll

            21    get more data from some of the NIMH research that's

            22    starting on a large scale with effectiveness trials with

            23    relatively unselected populations to address the question

            24    of the relative benefits of different medications and their

            25    relative costs, but we know from clinical experience, and

                                                                          183

             1    we hear it every day from clinicians who are associated

             2    with NAMI, that people who don't respond to one medication,

             3    the one atypical medication, may well respond to another. 

             4    That is very hard to predict.

             5                There's no easy hierarchy of it, and what it

             6    means is that the broader our armamentarium, the better

             7    position we're in to treat these individuals and make a

             8    range of options available to them.

             9                The third comment.  The question came up about

            10    providing patient guides, and I think NAMI would stand

            11    four-square behind the idea of providing patient guides,

            12    not just where there's this kind of a discreet risk, but in

            13    a much broader way, because I think for many of the

            14    medications that we have, there are specific things that an

            15    informed consumer ought to know, and that ought to be there

            16    in lay language.

            17                It ought to be simple.  It ought to be

            18    concrete.  For example, if tardive dyskinesia is a risk of

            19    a medication, there ought to be a little line that says

            20    your doctor, you know, at least every six months to a year,

            21    ought to look at your mouth and limbs to see if there are

            22    any abnormal movements.  It ought to outline what people

            23    ought to call their doctor about immediately or go to an

            24    emergency room about, and this ought to be used much more

            25    broadly in marketing and in actually dispensing

                                                                          184

             1    pharmaceutical agents.

             2                We've been very actively involved in this.  We

             3    think one of the ways, given how hard it's proven to change

             4    provider behavior through continuing medical education or

             5    through labeling or through these other techniques, we

             6    think one of the things that is underused and is probably

             7    ultimately going to be more effective is providing the

             8    information to consumers, who can go in in an

             9    individualized way with information that's specific to

            10    their drug they're on, and it says, oh, well, for example,

            11    with this drug, if an EKG at some point were made part of

            12    the labeling, it says I should have gotten an EKG, and I

            13    didn't.

            14                I think that kind of input actually, and the

            15    Consumer Guide from the FDA may be one approach to that,

            16    and we'll be pursuing some of our own approaches, may

            17    provide a very hopefully more effective way of changing

            18    provider behavior and improving quality of care.

            19                Thank you.

            20                DR. TAMMINGA:  Thank you, Dr. Cowdry, and thank

            21    you to all of the public speakers for their remarks.

            22                Now I'd like to open the topic directly for the

            23    committee's consideration, the consideration of the safety

            24    and efficacy of ziprasidone for the treatment of

            25    schizophrenia.

                                                                          185

             1                Dr. Laughren has made our job a little bit

             2    easier in that we have several areas in which some

             3    discussion from the committee is requested.  I guess that

             4    would be a good way to say it.

             5                We've had some discussion this morning, before

             6    lunch, about the observed QTc effect, the difference

             7    between what's the significance of a change in QTc or leap

             8    over a threshold.  I wonder if any of the committee has

             9    additional comments or questions or whether any of the

            10    committee has questions for our cardiology consultants.

            11                (No response.)

            12                DR. TAMMINGA:  I could start with actually a

            13    question from the committee, from a non-expert, any one of

            14    our cardiology consultants on the committee.

            15                Clearly, as the FDA people made, especially Dr.

            16    Chowdhury made, emphasized this morning, when he was

            17    talking about allergic rhinitis as sniffles, and I'm sure

            18    that people have sniffles, don't consider them

            19    inconsequential for sure, but schizophrenia for sure is not

            20    an illness that that would be in that class.  It's an

            21    illness with a high mortality, a very, very high morbidity,

            22    that lasts a lifetime, for which we don't have any

            23    effective treatments.

            24                How do people, how do psychiatrists and

            25    physicians and then consumers who consult the physicians,

                                                                          186

             1    think about this kind of a risk in that sort of a context?

             2                DR. CALIFF:  You know, I thought we had some

             3    good discussion about this this morning, that, you know,

             4    there's some 50 drugs that have this particular QT

             5    prolongation issue, and we certainly on the Cardiorenal

             6    Committee had to consider risk-benefit ratio in populations

             7    with regard to some other drugs.

             8                The problem that we have here really is that

             9    we're considering a real benefit, that is, a demonstration

            10    of reduction in symptoms for the mental illness with a

            11    somewhat hypothetical risk, because the data just are not

            12    there to know what the risk is, and I think this is what

            13    makes it so difficult.

            14                I think we felt on the Cardiorenal Panel that

            15    where we could quantify the risk and quantify the benefit,

            16    that at least you're able to come to a judgment that you

            17    may have differences of opinion about, but then you have

            18    some substance to discuss.

            19                In this case, we really don't know how to

            20    quantify what the risk side of the equation is, but

            21    specifically with regard to your question, where there's a

            22    demonstrated benefit for a serious illness, I think there's

            23    a lot of data to show that patients and doctors are willing

            24    to accept an increase in the risk of a rare adverse event,

            25    and there are plenty of precedents for that in

                                                                          187

             1    cardiovascular drugs.

             2                DR. TAMMINGA:  Dr. Fyer.

             3                DR. FYER:  Maybe starting a little from where

             4    we left off, I guess the difficulty for me in addressing

             5    this is -- I mean, I agree with the statement of what the

             6    situation is.  My concern is that, in reference to what Dr.

             7    Cowdry just said, I think there has to be created, if this

             8    drug is approved, a situation in which consumers and

             9    physicians can really accurately assess what the risk is,

            10    and I think the difficulty is, is that as far as I can

            11    tell, we can't really tell what the risk for this sudden

            12    death is, given the current data, and the structure of drug

            13    approval, et cetera, in our particular country right now is

            14    such that it's not clear as to how to set up a situation

            15    that will simultaneously make the drug available to people

            16    who may want to take it, given the unquantifiability of the

            17    risks now at the same time as we provide for people who

            18    might want more knowledge of the risks, that eventual

            19    availability of that data.

            20                I think that for me, that's an issue.  I mean,

            21    can we set up a mechanism for doing both of those things?

            22                DR. TAMMINGA:  I'm not sure that's correct. 

            23    Maybe Dr. Laughren or Dr. Katz, you could comment on that.

            24                DR. KATZ:  Well, there's a couple of things,

            25    yes.  First of all, there are mechanisms that exist prior

                                                                          188

             1    to approval, if you wanted to make the drug available under

             2    certain circumstances and yet still continue to accrue data

             3    that you think would be necessary to allow you to make a

             4    decision about approval.

             5                For example, something like the treatment IND,

             6    which would allow you to give the drug out to people who

             7    might want it or would be qualified for it, but yet still

             8    continue to accrue data.

             9                The other thing is that you can do that post-

            10    approval.  You can approve it based on the judgment that

            11    the risk-benefit ratio, if there really is such a thing, is

            12    acceptable with appropriate labeling, but then require

            13    studies in Phase IV, whether they're registry-type of

            14    studies or whether they're comparative studies.  Tom talked

            15    a little bit about that.

            16                So I think there are ways.  We never have all

            17    the information we absolutely want when we decide to

            18    approve a drug.  So there are ways to do it.

            19                DR. FYER:  I understand some of those things,

            20    except I guess what concerns me is that in a situation

            21    where a drug causes, you know, more weight gain or some

            22    discomfort or it might be a little less effective than the

            23    next drug, one has a different level of concern in that

            24    people might be in the situation that people who died

            25    taking Seldane and antibiotics were, where they have no

                                                                          189

             1    choice until after the fact, and it seems to me that there

             2    needs to be a little more certainty that these studies will

             3    actually take place, that information will actually be made

             4    available, and that the current state of affairs will be

             5    made very, very clear to everybody, which is that, given

             6    experience with other drugs, there may or may not be a

             7    risk, and we do not know what it is right now.

             8                I mean, you know, Dr. Cowdry talked about

             9    having a black box in the thing.  I mean, I would

            10    anticipate something to that effect, where it's really

            11    clear to people that it may be nothing, and it may be

            12    something, and we just don't know.

            13                DR. KATZ:  Well, again, there are ways to do

            14    that.  Obviously the reason we're coming to you is to find

            15    out whether or not you would recommend that given the

            16    amount of data that we have at the moment, the drug is

            17    approvable with appropriate labeling.

            18                But there's all sorts of things we can do in

            19    labeling.  We're very used to expressing and labeling our

            20    uncertainty of what information we would like to have is

            21    not available, and, you know, then if it's approved, it's

            22    up to the prescriber and the patient, but it can be done, I

            23    believe.

            24                DR. WINOKUR:  I guess I have a little kind of

            25    context to place my questions, and then a few questions for

                                                                          190

             1    the cardiologists.

             2                I guess for those of us on the committee who

             3    are psychiatrists, we're kind of used to not having as much

             4    information as we would like to have to address very

             5    reasonable questions that other people are posing to us. 

             6    So maybe it's reassuring that some of our colleagues in

             7    other medical disciplines sometimes face that same

             8    situation.

             9                But, clearly, what we're thinking through as

            10    committee members in part is, on one hand, some laboratory

            11    data that shows some different numbers and different

            12    circumstances, but then trying to understand how that

            13    extrapolates to, you know, meaningful experiences or

            14    problems in real patients, and I think Dr. Califf, if I

            15    remember, raised an important point/question this morning

            16    that I'd like to kind of steer discussion back to, which is

            17    what happens when this drug gets out into larger

            18    populations, and that would be a -- I mean, I think I can

            19    sort of think through for myself kind of how I feel about

            20    that 20 millisecond, you know, and what I've heard from the 

            21    discussion, but there are a few issues that I'd be

            22    interested in getting comments, because these are

            23    circumstances that, from my psychiatric experience and

            24    perspective, I can see coming up that may relate in whether

            25    it adds to our expectation about problems or reassures us

                                                                          191

             1    that it's not that likely to be an issue.

             2                So let me mention three, and I'm sure there

             3    would be others that might be worth discussing.  One is the

             4    issue of multiple drug use.  We've heard, I think, very

             5    important data about the metabolic inhibition to drug

             6    interaction issue, and I think that was very interesting

             7    and important data.

             8                But another type of issue would be drugs that

             9    people are likely in this population to be on that would

            10    interact, I guess the word would be "pharmacodynamically"

            11    or both potentially exerting effects at the site.

            12                You know, from experience, we know that many of

            13    these patients will end up on antidepressants, some of

            14    which can also have effects, and, you know, many of our

            15    colleagues or perhaps ourselves will add in a second

            16    antipsychotic drug because people do tend to do, you know,

            17    multiple drug-prescribing.

            18                So if any of the cardiologists would have

            19    opinions about how a drug with this profile might be viewed

            20    in the context of real world use, that would involve other

            21    drugs, not so much from the drug interaction issue at the

            22    metabolic level, but at the pharmacodynamic level, that

            23    would -- I'll mention my three questions, and then I'd

            24    raised the question about obstructive sleep apnea before

            25    with Dr. Casey, and I agree with his assessment that, you

                                                                          192

             1    know, that's not likely to be higher in the schizophrenia

             2    population, other than related to weight gain, but we also

             3    heard from him impressive data about, I think, 42 percent

             4    being significantly obese, and I think we can appreciate

             5    that that will often be a specific reason why patients on

             6    another atypical antipsychotic would choose to switch to

             7    ziprasidone.

             8                So I guess my question is, would a drug with

             9    this profile, would that population, obstructive sleep

            10    apnea, since, to my understanding, that's a population

            11    that's more susceptible to cardiovascular and especially

            12    arrhythmia problems, and the third question, which again we

            13    just slightly got into, bradycardia, I think Dr. Lindenfeld

            14    mentioned as an important issue, and one predictable time

            15    of a slowing down of heart is during sleep, especially in

            16    slow-wave sleep, and since this drug, I guess, will be

            17    dosed twice a day and with meals and has a Cmax about six

            18    hours, I can imagine it peaking at a time when people would

            19    be falling asleep.

            20                So these are some of the kind of, you know,

            21    real-life practical situations that I can easily envision,

            22    you know, a lot of patients being exposed to, and I'd just

            23    be interested in how our cardiology experts feel about any

            24    or several of these.

            25                DR. LINDENFELD:  Well, I think there will be

                                                                          193

             1    several opinions.  I think I would guess that as you add

             2    more of these drugs, some of which have independent effects

             3    on the QT interval, you're going to see substantially more

             4    problems, and I'm still a little bit concerned, as I was

             5    this morning, that although I understand the reason that

             6    people were withdrawn from their other drugs, as we've

             7    heard, these patients are apparently on a number of other

             8    drugs, many of which independently affect the QT interval,

             9    even to a small degree, but I don't think in these studies,

            10    we have any idea what that's likely to be in a large

            11    population.  So that concerns me.

            12                We heard that sleep apnea is not common in this

            13    population.  So I can't comment on that, and I think that

            14    the bradycardia issue is a separate issue, and I'd have to

            15    let Dr. Califf or Moss describe that.

            16                But I am a little bit concerned about, as we

            17    get into more discussion, the variability in QTc intervals

            18    that we see with multiple measurements, and how we see a

            19    large number, and how many is enough to actually check the

            20    safety of these drugs?  That would be something to come

            21    back to, I think.

            22                DR. TAMMINGA:  Could you be more specific about

            23    your last comment?  The variability in QTc measurements?

            24                DR. LINDENFELD:  Well, we saw some data that

            25    the more times you measure it, the larger difference there

                                                                          194

             1    is in inter-individual difference, and so the question

             2    would be, if it goes from if you measure it 20 times, it

             3    goes from 68 up to a 98 difference among people, how many

             4    times is enough to be sure that you have reached some cut-

             5    off that's reasonably safe?  That's an issue, a safety

             6    issue, I think, when we come back to that.

             7                DR. TAMMINGA:  Dr. Hamer.

             8                DR. HAMER:  As the pedantic statistician, may I

             9    comment on the fact that the larger the sample size gets,

            10    the larger the range gets, because the higher the

            11    probability is that you'll encounter some extreme value on

            12    one end or the other?

            13                So it's not surprising that the more times we

            14    measure it, the more extreme values we find, just in a

            15    purely statistical sense.

            16                DR. LINDENFELD:  But I don't think that was the

            17    extreme value.  Wasn't that the mean value that went up? 

            18    Maybe I misinterpreted that slide, but I think it was the

            19    mean value that went up, not the range.  Was it the range?

            20                DR. HARRIGAN:  No.

            21                DR. TAMMINGA:  Dr. Harrigan.

            22                DR. HARRIGAN:  The three values for those three

            23    studies were the means of that collection of individuals. 

            24    So the various sample sizes, the mean of each individual's

            25    range.  Does that make sense?  No?

                                                                          195

             1                Each individual had a range, 20 individuals

             2    with a range, added those up and divided by 20, I believe,

             3    would be a reasonable summary of how those three studies

             4    did it.

             5                DR. TAMMINGA:  Dr. Marder.

             6                DR. MARDER:  While Dr. Harrigan's up, I'm

             7    wondering if I could ask him a question, and then perhaps

             8    the cardiologists would have an answer as well.

             9                What about the experience of ziprasidone in the

            10    elderly?  What kind of experience have you had, and did you

            11    measure QTc, and then I'd also like to hear from the

            12    cardiologists about what the risk is likely to be in an

            13    elderly population, and the drug is likely to be, if it's

            14    approved, to be used in some elderly individuals.

            15                DR. HARRIGAN:  Can we look at G4?  Look at the

            16    distribution of patients in the Phase II/III database by 

            17    decade.

            18                So here we have basically a distribution, each

            19    row representing a decade, the age distribution of patients

            20    in the ziprasidone database.  It's about 5 percent of

            21    patients over age 60, 217 people over age 60.  This is

            22    fairly comparable with the Antipsychotic Drug Development

            23    Database, as I mentioned earlier.  Patients tend to enroll

            24    at a slightly younger age, and there's very little specific

            25    dementia development in this program.

                                                                          196

             1                Now, let's look at M65 for QTc change by age. 

             2    Taking the individuals who are age 65 and older, here's the

             3    mean change in each of the four treatment groups, and, of

             4    course, the sample sizes are directly underneath the mean

             5    with the confidence intervals.

             6                So 76 individuals with a baseline/post-baseline

             7    ECG who are over age 65 years.  As you can see, no

             8    particular suggestion in the mean of increased

             9    susceptibility to QTc prolongation in the elderly.

            10                DR. TAMMINGA:  Dr. Califf.

            11                DR. CALIFF:  Well, I mean, of course, one of

            12    the difficulties with the elderly -- I want to press Dr.

            13    Lindenfeld a little bit on this because she was wise enough

            14    with another drug, mebaformil, to look into this and see a

            15    problem down the road, which did occur.

            16                One of the problems with the elderly, of

            17    course, is they're on a lot of other drugs, and the average

            18    person over age 65 is on 11, I think.  Commonly, 15 percent

            19    of these people have atrial fibrillation, and they're

            20    likely to be treated with some of the other drugs we've

            21    talked about that also cause significant QT prolongation.

            22                So unfortunately, a lot of this is all tied

            23    together.  I think if we could be assured that people would

            24    take drugs or the doctors would prescribe the drugs purely

            25    by what the label says, you could potentially write

                                                                          197

             1    labeling that would prevent these interactions, but,

             2    unfortunately, our national track record here is not

             3    looking very good.

             4                I think we have very good documentation now

             5    from a different studies that "Dear Doctor" letters don't

             6    work, and that writing labeling doesn't necessarily work. 

             7    So I'm concerned about this, but again we're talking about

             8    a hypothetical risk, you know.

             9                At least my judgment right now, based on the

            10    data we've seen, is that the risk is relatively low

            11    compared to some other drugs in the absence of

            12    interactions, but I'm also a little -- I just want to check

            13    out one thing, which is that it seemed from the

            14    measurements that were made in this most recent study, that

            15    the older atypical antipsychotics also cause QT

            16    prolongation, is that correct?

            17                It seemed like there might have even been a

            18    little disagreement about the interpretation of the

            19    comparative data.

            20                DR. TAMMINGA:  Would you like Dr. Harrigan to

            21    put up that slide again with all the data on it?  Maybe the

            22    one with the multiple different ways of calculating it with

            23    and without the inhibitors?

            24                DR. CALIFF:  It seemed that the Haldol didn't,

            25    but that the others may have.

                                                                          198

             1                So one thing we want to avoid here, I think, is

             2    excluding a new drug when the old drugs have the same

             3    problem.

             4                DR. TAMMINGA:  Well, the oldest of the drugs,

             5    of course, is thioridazine.

             6                DR. HARRIGAN:  The slide that Dr. Tamminga

             7    requested, we're putting up right now.

             8                We'll look at mean change from baseline.  So

             9    this has both its steady state and the presence of

            10    metabolic inhibitor.  Again, the Bazett correction formula

            11    here on the left, baseline correction formula, derived from

            12    the Study 054 population at baseline, and the Framingham

            13    correction formula.

            14                Your interpretation of the effects of other

            15    drugs depends partly on your selection of correction

            16    formula.  With the Bazett formula, as I mentioned before,

            17    all of these drugs, with the exception of haloperidol, 

            18    have changes from baseline with confidence intervals that

            19    do not overlap zero.

            20                Now, if you flee from the Bazett formula to a

            21    formula which uses a different calculation for heart rate,

            22    then some of the drugs that cause more profound tachycardia

            23    will reduce their QTc effect over here.  Ziprasidone is

            24    reduced a bit as well.

            25                On the other hand, haloperidol, which did not

                                                                          199

             1    appear to have an effect potentially, its steady state with

             2    the Bazett formula, seems pretty clearly to have an effect

             3    over here, particularly with metabolic inhibitor.

             4                DR. TAMMINGA:  So the old drugs in that slide,

             5    Dr. Harrigan, are red for thioridazine and blue for Haldol,

             6    and all of the yellow to greenish dots would be the new

             7    antipsychotics, relatively recently approved?

             8                DR. HARRIGAN:  Yes, and white.

             9                DR. TAMMINGA:  And white.  Excuse me.  White.

            10                DR. CALIFF:  So it looks like we can be

            11    relatively certain from the confidence intervals there that

            12    ziprasidone prolongs the QT more than risperidone, but

            13    risperidone may also prolong the QT, just not as much.

            14                DR. HARRIGAN:  Well, the confidence intervals

            15    with the Bazett formula overlap between ziprasidone and

            16    risperidone and quetiapine.  Now, I'm not sure what you

            17    mean by "more," but the point estimate for ziprasidone was

            18    20 with the Bazett, and for risperidone, I think it was

            19    11.6.  Of course, then you have your choice of other

            20    formula.

            21                DR. TAMMINGA:  Dr. Hamer.

            22                DR. HAMER:  Again, as the pedantic

            23    statistician, there are 42 confidence intervals on there. 

            24    If you attempted to correct those for multiple comparisons,

            25    the number that overlapped zero and overlapped with each

                                                                          200

             1    other would change a great deal.

             2                So you know, at best, we can look at those and

             3    have some kind of a gestalt interpretation, but I'm not

             4    sure what also to make of 42 confidence intervals.

             5                DR. TAMMINGA:  From a statistician's point of

             6    view, do you want to comment on Dr. Califf's observation

             7    that perhaps the new antipsychotics look more like each

             8    other than not?

             9                DR. HAMER:  No.

            10                (Laughter.)

            11                DR. CALIFF:  Could we ask Dr. Moss' opinion? 

            12    He's probably looked at as much of this data as anyone.

            13                DR. MOSS:  Well, I think that you're dealing

            14    with such a small sample size on this study, there's 30

            15    patients with some drop-outs or 33 patients with some drop-

            16    outs, and the problem of multiplicity further compounds it.

            17                So I think you could come to any conclusion you

            18    want, that they look similar, they look different, because

            19    of the very small sample size.

            20                What strikes me is that the magnitude of the QT

            21    interval change of 20 milliseconds in 30 patients or 33

            22    patients is quite considerable as just a baseline value,

            23    and that was the peak effect from this study, and that's

            24    just more than one ordinarily sees with drugs that are

            25    given in this manner.

                                                                          201

             1                So in the order of the hierarchy, we saw that

             2    this came in second in terms of QT prolongation.  To draw

             3    any significant conclusion from the difference is

             4    impossible because of the sample size and the range of the

             5    confidence intervals, and with a larger sample size, the

             6    confidence intervals would shrink, and you might be able to

             7    make some statement, but I don't think you can claim that

             8    there's an overlap of these drugs because of the limited

             9    number of patients that have been studied.

            10                When I have a chance, I'd like to address the

            11    issue of the multiple drugs because I think that's a very

            12    central and critical issue.

            13                DR. TAMMINGA:  I have one more question that

            14    I'd like to ask about this slide, then we can let Dr.

            15    Harrigan sit down.

            16                This study was done at peak plasma levels, and

            17    so these are the only data we have for ziprasidone and

            18    these drugs at their maximal plasma levels.

            19                From your Phase II/III studies, what was the QT

            20    prolongation in the more ordinary way where we would have

            21    more of our numbers?  Was it around 20?

            22                DR. HARRIGAN:  No.  In the ziprasidone program?

            23                DR. TAMMINGA:  Yes.

            24                DR. HARRIGAN:  No.  In a short-term fixed-dose

            25    dataset, where you had patients who stayed at those fixed

                                                                          202

             1    doses they're in, the range was 6 to 10 milliseconds, being

             2    10 milliseconds at the highest recommended dose of a 160.

             3                If you look at the entire Phase II/III

             4    database, with patients being treated with flexible doses,

             5    and ECGs obtained at random times of day, reflecting, you

             6    know, the wide patient population taking the doses as

             7    prescribed by the investigator, the change is about 4

             8    milliseconds.

             9                DR. TAMMINGA:  So it seems to me, Dr. Moss, I

            10    don't know -- and I'd like you to comment on this, that the

            11    number that we should use, that we might compare to other

            12    numbers, would be randomly selected QTc intervals, which

            13    would be more in the range of 10, and this QTc interval in

            14    the range of 20 would be more of a maximal drug

            15    concentration interval.

            16                DR. MOSS:  That is correct, but it also has the

            17    implication that there's a dose-response effect, and that

            18    is, if you're talking about random doses and random

            19    concentrations with a QT interval that's 4 to 6

            20    milliseconds, and now you're talking about a peak

            21    concentration, even though they didn't show a concentration

            22    effect, that would suggest that there is a dose-response

            23    effect, and I'd be interested in Dr. Harrigan's response to

            24    that.

            25                DR. HARRIGAN:  Well, there certainly seem to be

                                                                          203

             1    in the short-term fixed-dose dataset an increase in QTc

             2    with increasing dose.

             3                If one looks at the highest dose in that short-

             4    term fixe-dose dataset, the mean QTc effect did not

             5    increase further.

             6                If one looks at the highest concentration, the

             7    individuals at the highest concentrations in the Phase

             8    II/III database, there does not seem to be a signal that

             9    the QTc effect has increased in proportion to their serum

            10    concentrations.

            11                Nonetheless, the data out there is sparse

            12    enough that a mathematical demonstration of that as a fact

            13    is certainly not possible.

            14                DR. LINDENFELD:  Dr. Harrigan, while you're

            15    there, I have one slightly off-the-subject topic.

            16                You told us that the M9 metabolite is an L-type

            17    calcium channel blocker.  So that would be expected to slow

            18    the heart rate if you shifted more of the metabolism to

            19    that side by blocking cytochrome 3A4.

            20                With ketoconazole, was there a change in heart

            21    rate between the groups that got the metabolic inhibitor

            22    and those that didn't?  Because if there is a difference in

            23    heart rate of bradycardia, we might view that as a problem

            24    or possible --

            25                DR. HARRIGAN:  Let me take a few steps.  It's

                                                                          204

             1    in the briefing document in one of the tables.  If it is,

             2    it's not more than a one or two beat per minute.  The

             3    ziprasidone increased the heart rate in both the presence

             4    and absence of a metabolic inhibitor.  It was four and a

             5    half beats in the presence, and I think Dr. Brater's

             6    looking it up, it wasn't more than one or two beats

             7    different from that.

             8                DR. TAMMINGA:  If you need a few minutes, we

             9    can go on to some other questions.  Dr. Hamer has a

            10    pressing question.

            11                DR. HAMER:  Actually, I want to follow up on

            12    something that you said, Dr. Tamminga, and it's something

            13    I've wondered about at many of these meetings.

            14                From what little I know about pharmacokinetics,

            15    population pharmacokinetics has only relatively recently

            16    become more extensively developed and extensively used, and

            17    traditional pharmacokinetics seems to pretend that

            18    basically all of us individuals have the same

            19    pharmacokinetics.

            20                So when you've talked about, well, we've taken

            21    these EKGs at "peak levels," i.e. however long after the

            22    dose for a given particular drug, that's really pretending

            23    that all the people that took the dose are absorbing and

            24    metabolizing this drug at the same rate, and it could well

            25    be very, very different.

                                                                          205

             1                So we really have no idea how close -- I mean,

             2    it's probably closer than just taking them randomly, but we

             3    really do have no idea how close to peak in any given

             4    individual these measurements actually occurred, is that

             5    correct?

             6                Could someone who knows a lot more about

             7    pharmacokinetics than I do talk about that?

             8                DR. TAMMINGA:  Certainly one would expect these

             9    EKGs to be closer to the peak than random EKGs throughout

            10    the data, and I think that was the point of the study.

            11                Dr. Laughren.

            12                DR. LAUGHREN:  Actually, I wanted to comment on

            13    the overall design of the study and a problem in knowing,

            14    you know, what the change from baseline means for the other

            15    drugs.

            16                There was no placebo group here.  So I don't

            17    know what the smaller change means for the other drugs, but

            18    I do know that in studies that have included a placebo, and

            19    I believe that you showed a slide, Ed, earlier, having both

            20    haloperidol and placebo along with ziprasidone, that

            21    basically showed no difference between haloperidol and

            22    placebo in QTc effect.

            23                We have data from multiple other trials,

            24    including the seven-arm trial that Dr. Dubitsky presented,

            25    that looks at three different doses of haloperidol, 4A and

                                                                          206

             1    16, against placebo, again showing completely flat curves,

             2    an absence of any apparent QTc effect.

             3                So I think you have to factor all of those

             4    other data, you know, into this interpretation of this

             5    study that doesn't have a placebo control.

             6                DR. HARRIGAN:  Can we follow up on that?  I

             7    mean, I agree that the therapeutic trials with haloperidol

             8    have not shown a QTc effect with haloperidol in our program

             9    or in the programs you've seen obviously.

            10                We do have some concentration QTc data from

            11    Study 054 with haloperidol, and I wondered if Dr. Thomas

            12    Ludden would be available and allowed to present that just

            13    very briefly.

            14                DR. LUDDEN:  Can we have Slide M134?

            15                This is a graph of the QTc change from

            16    baseline, using a baseline correction, versus the

            17    haloperidol serum concentration.  The two-day values, which

            18    was during a titration phase, the lowest levels shown to

            19    the left there in yellow.

            20                The next set of levels are in white which

            21    represent at steady state, and then the orange levels are

            22    with the metabolic inhibitor, and the large squares

            23    represent the means of those data, both in regard to

            24    concentration and to response.

            25                Could I have Figure 236, please?  This is

                                                                          207

             1    PK236.

             2                Okay.  Now, that's the same data essentially

             3    with a regression line shown through it, and that is a

             4    significant regression line for that dataset.  It's

             5    performed using a mixed effect modeling approach, the

             6    population approach that was referred to a few minutes ago,

             7    in trying to keep the correlation or the identity of an

             8    individual intact in the data analysis.  It's not like

             9    treating those data points as being completely independent

            10    because some of them arise in the same individuals.  But

            11    one can get a significant regression from that.

            12                Now, I would point out that the interaction

            13    study worked quite well for Haldol, that it actually moves

            14    the concentration nicely to the right in this study, and so

            15    it did stress Haldol fairly well in changing the exposure.

            16                DR. TAMMINGA:  Dr. Winokur.

            17                DR. WINOKUR:  I wanted to try to come back and

            18    pick up on the discussion that Dr. Hamer started with the

            19    design of that study because I think it's -- I'm sorry.

            20                DR. TAMMINGA:  Let's finish first with Haldol

            21    discussions, if you don't mind.

            22                DR. WINOKUR:  Sure.

            23                DR. TAMMINGA:  Dr. Laughren, do you have

            24    another comment in response to this?

            25                DR. LAUGHREN:  I don't know how to interpret

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             1    that graph.  I mean, again, all I'm doing is falling back

             2    on our very extensive database in which, you know,

             3    haloperidol is used as a control, and studies that include

             4    placebo, where you never see any difference.

             5                It's puzzling, you know, why that should show

             6    up here.  I don't know what it means.

             7                DR. TAMMINGA:  Dr. Katz.

             8                DR. KATZ:  The variability around those means

             9    are rather large, at least for the greater concentration,

            10    it's not up any more, and, of course, patients weren't

            11    randomized to particular concentrations, those that fell

            12    out of the dose they were on.

            13                So I'm inclined to agree with Tom.  It's hard

            14    to know exactly what that means against the backdrop of

            15    empirical evidence, which suggests it really isn't very

            16    different from placebo.

            17                The point being that if it's really not

            18    different from placebo, I don't know if that slide, Ed,

            19    that you had about Study 54, if you put those back up, if

            20    that's possible.

            21                If you accept as an assumption that Haldol's

            22    equivalent to placebo in that study, and you subtract the

            23    other measurements for the other drugs, the other QTc

            24    measurements, you see that ziprasidone does sort of stand

            25    out.

                                                                          209

             1                I think if you look at the steady state in the

             2    baseline correction, in the Framingham correction, without

             3    metabolic inhibitor, you see there really isn't any overlap

             4    with the confidence intervals between ziprasidone and the

             5    other drugs.  Thioridazine, of course, is a separate issue,

             6    but Haldol's higher than the others.

             7                So if you consider that as sort of a placebo

             8    or, you know, a surrogate for placebo response, you really

             9    see that ziprasidone does sort of distinguish itself, and

            10    we've tried to make the case that we don't think that the

            11    Bazett is the appropriate correction.  Obviously things

            12    look a little different on the Bazett side of things, but

            13    if you believe that that doesn't correct appropriately for

            14    heart rate, if you look at the other two, which sort of

            15    probably we believe are a little bit more accurate as far

            16    as correcting for heart rate, you see that ziprasidone

            17    really does sort of stand out, again if you consider as

            18    Haldol as sort of a placebo, even if you don't.

            19                DR. HARRIGAN:  We have a little bit of

            20    frustration probably with the analyses.

            21                The Bazett formula was the prospectively-

            22    declared formula in the protocol for analysis of QTc, and

            23    with the Bazett formula, as we pointed out earlier, there

            24    are a large number of drugs that appear to have an effect.

            25                Now, if you move to another correction formula,

                                                                          210

             1    and there are good reasons to consider doing that, then it

             2    seems to us that haloperidol pretty clearly has an effect. 

             3    If you dissect that data further, then there's a

             4    concentration effect relationship with haloperidol and QTc.

             5                So it seems from our point of view that if you

             6    pick one correction formula or the other, one correction

             7    approach or the other, and either way, there are certainly

             8    other antipsychotics which cause a QTc prolongation and

             9    actually fairly close to the neighborhood of ziprasidone.

            10                DR. TAMMINGA:  From a cardiologist's point of

            11    view, what do these differences make?  Well, what do these

            12    differences look like?

            13                DR. LINDENFELD:  I think we've been having

            14    trouble answering that all day.

            15                In any individual patient, I think -- and

            16    please, everybody, add to this -- a 20 millisecond increase

            17    would not be a huge increase, and I don't think if it was

            18    in the normal range of EKG of QT interval, I don't know

            19    that it would make any of us stop a drug.  If it went from

            20    400 to 420, I doubt that any of us would stop the drug at

            21    that point.

            22                But I think that's a difference in what it

            23    means in large populations where there will be some people

            24    who will prolong substantially more.

            25                DR. TAMMINGA:  Could you comment also on the

                                                                          211

             1    differences between the medications that were just up?

             2                DR. LINDENFELD:  Do I think there are real

             3    differences?  I guess I think ziprasidone stands out a

             4    little bit as to have more QT prolongation than the others,

             5    yes.

             6                DR. CALIFF:  I think JoAnn said it quite well. 

             7    I would just add just the point of frustration that the

             8    numbers studied are small.  We're talking about three

             9    million patients.  It would seem worthwhile to get little

            10    bit bigger sample sizes so we could potentially distinguish

            11    one drug from another.

            12                The other point I'd just make here is one

            13    reason we're all so much in the dark, there's no empirical

            14    base of research.  I think as Dr. Throckmorton pointed out,

            15    despite all 50 drugs having this QT prolongation problem,

            16    there's very little data that relates the QT prolongation

            17    to the risk of arrhythmias across the different classes of

            18    drugs.  It's really quite remarkable.

            19                DR. LINDENFELD:  Maybe if I could, I'd like to

            20    ask Dr. Moss a question.

            21                In terms of risk, Dr. Moss, do you think we're

            22    picking out a highly-susceptible population?  So is the

            23    risk the greatest in the first several months or is it an

            24    on-going cumulative risk per year, do you think?

            25                DR. MOSS:  Well, let me answer a couple of

                                                                          212

             1    questions.

             2                The first one of does 20 milliseconds make a

             3    difference, well, in a given individual patient, no.  The

             4    question is, does this represent a signal?  That's the real

             5    question that's out there.  That is, does a 20 millisecond

             6    change, which is a substantial change, a highly-significant

             7    change, does that represent a signal that there's going to

             8    be some group of patients out there that are going to have

             9    a much larger change?

            10                So that, I think, is an issue, and so you can't

            11    really interpret the 20 millisecond per se interval.

            12                Now, your other question related to?

            13                DR. LINDENFELD:  Are we picking out susceptible

            14    patients whose risks would be primarily in the first few

            15    months of this therapy or is this likely to be a cumulative

            16    risk year after year?

            17                DR. MOSS:  I don't think we know, but I believe

            18    that the risk is just short-term, unless they have evidence

            19    that the QT interval resolves or accommodates over time.  I

            20    haven't seen any evidence to that effect.

            21                DR. TAMMINGA:  Dr. Moss, what do you make of

            22    the rest of the data that Pfizer reported to us, that, say,

            23    with the metabolic inhibitor, the QT interval did not go

            24    up, and that with the overdose cases, there weren't

            25    substantial or gigantic QT interval changes, and then the

                                                                          213

             1    lack of syncopal episodes, that at least Pfizer put those

             2    together for us in a bundle to kind of look at, it seemed

             3    to me, to answer the question or to provide some data to

             4    the question that you posed?

             5                DR. MOSS:  They're very reassuring.  I mean,

             6    the fact that although the number of overdose cases is

             7    relatively small, they didn't see any clear pattern of QT

             8    prolongation.  That's very, very useful information, and

             9    every case becomes extremely important.

            10                So that this information that they've shown has

            11    been reassuring in that regard.

            12                DR. TAMMINGA:  We'll get back to Dr. Winokur's

            13    questions.

            14                DR. WINOKUR:  Well, it was initially stimulated

            15    by Dr. Hamer's comment, but it may also fit in with the

            16    discussion that Dr. Katz and Dr. Laughren brought up as

            17    well.

            18                I wanted to remind myself and mention to the

            19    committee and others that, as I understand it, this study

            20    was done in a way that is actually quite different than

            21    most previous study for which we have such data, and this

            22    was something that came out of the discussions with the

            23    division after the initial review, and I guess I would see

            24    it differently than the point that Dr. Hamer was making.

            25                You know, certainly there's inter-individual

                                                                          214

             1    variability, but a way to reduce variance and to get a more

             2    accurate signal is to have a study done in as consistent a

             3    manner as possible, and the time selected for doing the EKG

             4    was geared to the time of Cmax, and actually they did three

             5    EKGs an hour apart.

             6                So they really bracketed the time that would be

             7    expected.  I think that's a significant change from what I

             8    understand to be the usual approach.  So to me, that would

             9    be an important step in making a statistician happy.

            10                The other thing is it concerns me as to whether

            11    the concerns about the data with haloperidol being

            12    different might also relate to this being a very different

            13    paradigm that was used, and therefore, you know, instead of

            14    falling back into going with numbers that we're familiar

            15    with, but those numbers were really derived from a quite

            16    different experimental protocol, then, you know, that might

            17    be a reason for things looking different.

            18                We actually heard about rather different

            19    numbers as a function of the usual way of collecting such

            20    data in the larger studies, you know, where they got a

            21    quite different estimate as opposed to doing it in this

            22    specified way to specifically tie into the Cmax.

            23                DR. TAMMINGA:  What I would add, Dr. Winokur,

            24    about that, about placebo periods and previous studies, is

            25    that oftentimes in antipsychotic drug trials, placebo is

                                                                          215

             1    not as drug-free as you would wish because placebo periods

             2    are oftentimes aborted, and EPS as a side effect usually

             3    continues on through the placebo period.

             4                I think it's as drug-free as we can probably

             5    provide, but it isn't fully drug-free.  I don't know how

             6    that pertains to the present discussion.

             7                Dr. Moss had said that he wanted to come back

             8    to the study of drug-drug interactions, which I think is an

             9    important topic.

            10                DR. MOSS:  Well, it has to do with the question

            11    that was raised about multiple drugs, and these patients

            12    are likely to be on multiple drugs.

            13                Now, within the psychiatric drugs, I would

            14    suspect the possible overlap with other antipsychotic drugs

            15    as well as antidepressants, and although there is a table

            16    here that relates to their experience in really, I suspect,

            17    what is the earlier Phase II/Phase III trials, it was

            18    really observational data, never clear trial data.  It's

            19    just what they happened to be on.

            20                It would seem to me that there's also, as one

            21    is getting into the age 40+ age group, that generally the

            22    four most frequently-used non-psychiatric drugs are ACE

            23    inhibitors, diuretics, beta blockers, and calcium channel

            24    blockers, and it would seem to me that it would be

            25    worthwhile to have some information on this in some

                                                                          216

             1    appropriate way.

             2                So that's the one issue that was raised about

             3    drugs, and I think that we just don't really have

             4    substantial data to properly interpret that.  It's

             5    conceivable that could also be accrued post-approval, but

             6    I'm just saying that that information really is not

             7    interpretable at the present time.

             8                Then, the other issue that was raised, which

             9    is, I think, an important one, is the bradycardia issue,

            10    because bradycardia is really known to be a significant

            11    trigger in patients with QT prolongation, that this is what

            12    seems to enhance the abnormality of the repolarization, and

            13    so we don't really have any information during sleep or

            14    during other times where, say, Holter information would be

            15    helpful to see if there is some type of change later,

            16    during a bradycardic rate or what have you.

            17                So these are two issues.  I think they're

            18    relevant issues.  I don't think we can answer them on the

            19    basis of the data that's available, but it would seem to me

            20    this is something that is relevant from the clinical use of

            21    this medication, particularly in drug combinations, and

            22    some of the drugs themselves slow the heart rate, like beta

            23    blockers, et cetera.

            24                So these issues are open.  I wish we could

            25    answer them.  I cannot give you specific information, but

                                                                          217

             1    they're out there.

             2                DR. HARRIGAN:  Dr. Tamminga?  Sorry.  Snuck in

             3    behind you.

             4                Just two things to address Dr. Lindenfeld's

             5    question.  The heart rate, mean heart rate, went from --

             6    with ziprasidone in the absence of metabolic inhibitor 4.6b

             7    per minute increase, with ketoconazole 3.6b per minute

             8    increase in the mean.

             9                Another point is in response to Dr. Moss

            10    raising the issue of drug interactions, we probably

            11    haven't, I think, surveyed sufficiently the drug

            12    interaction data available on ziprasidone.

            13                I wonder if Dr. Craig Brater from Indiana

            14    University would be able to just provide a brief summary of

            15    that?

            16                DR. TAMMINGA:  Do you think that would be

            17    helpful, Dr. Moss?

            18                DR. MOSS:  Couldn't hurt.

            19                DR. HARRIGAN:  Thank you.

            20                DR. BRATER:  As you heard, I'm Craig Brater. 

            21    I'm from Indiana University.

            22                I can't speak, I don't think, to

            23    pharmacodynamic interactions, but if you're thinking about

            24    them, you've also got to have some corner of your brain

            25    that must also be thinking about pharmacokinetic

                                                                          218

             1    interactions, and so let me say a few words about that.

             2                As you saw and as has been inferred, there have

             3    been a number of interaction studies that have been

             4    performed to look at that, and if you stand way back and

             5    look at this, and I can show you the specific data if you

             6    want to delve into that, one of the things that strikes you

             7    is that the kinetic interactions, disease effects, et

             8    cetera, are not very great in terms of their magnitude.

             9                I think it's important to keep a frame of

            10    reference that the bioavailability of this drug is 60

            11    percent, and so when you see drug-drug interactions that

            12    cause big increases in serum concentrations, it's usually

            13    because they have low bioavailability.  They're being

            14    metabolized by the intestinal epithelium.

            15                You block that with an interacting drug, and

            16    all of a sudden, you get a greatly-enhanced

            17    bioavailability, in addition to a decreased ability to

            18    eliminate the drug once it's in the system.  Typical

            19    example of that is terfenadine, typical example of that.

            20                But if you have a 60 percent bioavailability to

            21    start with, the most you can go is to a 100, and so you're

            22    not going to see a big delta in that fashion.

            23                But if you look at these data, and you ask

            24    yourselves what are the ways that you can permute the

            25    system, ketoconazole has already been mentioned, and

                                                                          219

             1    remember what ketoconazole does.  It's the most potent

             2    inhibitor of 3A4.  So it's going to shunt everything down

             3    that other pathway.  It's going to shunt things to M9, and

             4    it's going to shunt things to ziprasidone.

             5                Another aspect of ketoconazole is if there is

             6    any secretory elimination of the drug or M9 through biliary

             7    secretion, if part of that is by peak glucoprotein, it will

             8    also block that.

             9                So again, ketoconazole serves as a very good

            10    tool to really stress the metabolic system to its capacity,

            11    and you see about at most a 40 percent increase in

            12    exposure.  So it's not very much.

            13                If you look at liver disease, the patients with

            14    the most severe liver disease, it's about a 35 percent

            15    increase in exposure.

            16                If you look at elderly, it's about a 20

            17    percent, and actually if you take the extremes and look at

            18    exposure in an elderly female compared to a young male,

            19    it's about a 40 percent increase.  I think if you turn it

            20    around and you say what happens if I use an inducer like

            21    carbamazepine, it's about a 40 percent decrease in

            22    exposure.

            23                So the numbers that you keep coming up with is

            24    that if you stress the system to its max, either by age,

            25    demographics, disease or drug interaction, you get about a

                                                                          220

             1    40 percent change in exposure, and I think that's an

             2    important frame of reference for you to keep in your

             3    deliberations in terms of polypharmacy.

             4                What might happen with multiple drugs?  What if

             5    you have a patient with liver disease, and then, all of a

             6    sudden, you put them on ketoconazole?  Does that mean that

             7    you get 40 percent plus 40 percent?  So now there's an 80

             8    percent exposure?  No.

             9                There's a lot of internal consistency in these

            10    data in that if you -- as you heard, about a quarter to a

            11    third of the metabolic elimination of this drug is through

            12    CYP pathways.  That would allow you to predict that if you

            13    completely shut off those pathways, you would get about --

            14    guess the number -- a 40 percent increase in exposure, and

            15    indeed that's what you see with ketoconazole.

            16                So you would not have additivity in a situation

            17    like that, if you got essentially the maximal effect by

            18    either an interacting drug or by disease or what have you. 

            19    If you layered something else on top of that, you would not

            20    expect to see additional exposure.

            21                So again I think that paints sort of a frame of

            22    reference in terms of what you're going to see in terms of

            23    kinetics, is this magic 40 percent number.  How that

            24    affects, again I have to say I can't get into the business

            25    about dynamics.

                                                                          221

             1                I'm not sure if the data can be looked at in

             2    that fashion.  I don't know if there's any population

             3    information, but in terms of pure kinetics, the boundaries

             4    are reasonably narrow.

             5                DR. CALIFF:  Craig, I'm just trying to

             6    understand the overdose information.

             7                If you have a dose-response effect, and you

             8    have an overdose, I mean, from other data about QT

             9    prolonging drugs and IKr channels, is there some

            10    theoretical threshold or leveling off?  How would you

            11    explain someone with an overdose not having a substantial

            12    prolongation of the QT?

            13                DR. BRATER:  I'm not an expert on IKr channels

            14    and that kind of thing, but I guess you have to basically

            15    presume that the slope of the concentration response

            16    relationship is very shallow or you've got a -- you do have

            17    an upper asymptote that has been essentially defined within

            18    this database, though statistically you can't fit the curve

            19    and meet the technical criteria to say that it does have an

            20    upper asymptote.

            21                But, I mean, you've got more than the overdose

            22    data.  You've also got those outliers that were out there. 

            23    The only way I can explain that is that there's some

            24    plateauing that goes on.

            25                DR. CALIFF:  And then, just to reiterate one

                                                                          222

             1    more time, I heard you say it, and I just wanted to check,

             2    if we have no knowledge of what would happen if someone

             3    took quinidine or sotalol or dofetilide on top of this

             4    drug?

             5                DR. BRATER:  I don't personally.  I don't know

             6    if others here do.  People are shaking their heads no.

             7                DR. MOSS:  Could I ask a question?  If one goes

             8    higher in the dose to patients in studying dose-response

             9    effect, do adverse side effects prohibit one from going to

            10    higher doses?

            11                That is, as I understand it, the highest dose

            12    is the 200 milligrams a day.  If one went to 400 milligrams

            13    a day, in terms of testing, is that precluded by side

            14    effects?  Maybe that's already been done in earlier phases

            15    of the trial.

            16                DR. BRATER:  I'll have to turn that back over

            17    to Dr. Harrigan.

            18                DR. HARRIGAN:  No.  The 200 milligram per day

            19    dose was associated with increased side effects, and in

            20    clinical trials, we did not exceed that dose.  We really

            21    haven't exceeded that dose in the clinical development

            22    program or experimentally.

            23                There are increased adverse effects of various

            24    sorts, including some extra-prandial symptoms, at doses in

            25    that range.

                                                                          223

             1                DR. MOSS:  Could I get a comment from

             2    Regulatory on that point?

             3                DR. LAUGHREN:  You mean about whether or not

             4    we'd like to see a full exploration of the dose-response

             5    curve even in normals?

             6                I mean, clearly, we would, and I think that's

             7    sort of, you know, what we're reaching here.  Because of

             8    the remarkable stability of the pharmacokinetics of this

             9    compound, you're not learning about that by trying to block

            10    the clearance, and so the fact is that we don't have any

            11    good data, any systematic data, on what the QT effect is

            12    at, say, a doubling of the therapeutic dose, and that's

            13    sort of an unknown.

            14                DR. HARRIGAN:  Normal volunteers would not

            15    tolerate really even therapeutic doses of this atypical

            16    antipsychotic or any of the atypical antipsychotics that

            17    people are using that are prescribed, and we have not

            18    deliberately run a patient study at overdose at those high

            19    dose range.

            20                DR. CALIFF:  Why wouldn't they tolerate it?  If

            21    someone with psychosis could tolerate it, why couldn't a

            22    normal volunteer?

            23                DR. TAMMINGA:  It's quite common that normal

            24    volunteers don't tolerate any of the dose levels for any of

            25    the antipsychotics that people with schizophrenia do.

                                                                          224

             1                DR. HARRIGAN:  I agree.  I mean, some of it is

             2    the Alpha 1 effect, which normal volunteers don't tolerate

             3    that patients who become acclimated to and tolerate fairly

             4    well.

             5                There's one other point, if I can digress just

             6    a little bit, that's another perspective on the haloperidol

             7    effect.  If one were to treat the haloperidol as a placebo,

             8    with the non-Bazett correction formula, then that would

             9    reduce the mean effect of the ziprasidone and QTc to

            10    something south of 10 milliseconds, be somewhere between 5

            11    and 10 milliseconds, in order to subtract that out as a

            12    placebo effect which I think Dr. Katz was suggesting you

            13    consider doing for some of the other agents in Study 054.

            14                DR. TAMMINGA:  Dr. Katz.

            15                DR. KATZ:  Well, yes, it does decrease.  I

            16    mean, people have been talking about 20 millisecond

            17    prolongation, and we agree that if you use the maneuver

            18    that you just mentioned, it brings it down.

            19                I think we brought it to around 10 or something

            20    in that ball park in general.

            21                DR. TAMMINGA:  Dr. Throckmorton.

            22                DR. THROCKMORTON:  Yes, just a comment about

            23    the Number 10 milliseconds.

            24                Given the absence of information about as much

            25    of an effect of a doubling of the drug dose, I'd be a

                                                                          225

             1    little cautious about extrapolating to exactly what would

             2    happen at 300 or a doubling of the dose, something like

             3    that.

             4                I mean, we imagine that it would be linear or

             5    something like that.  That is, that you'd have some smaller

             6    higher number.  I don't know, 14 or whatever.  We don't

             7    have a lot of drugs to really base that sort of inference

             8    on.

             9                DR. TAMMINGA:  Dr. Marder.

            10                DR. MARDER:  I'm wondering if it would be all

            11    right to change the topic just a little bit.  I wanted to

            12    address something that was brought up in the consultation

            13    that we got from the Division of Cardiorenal Drug Products.

            14                There was suggested that evaluating the risk of

            15    QT prolongation against the risk of, you know, factors,

            16    such as lipids and weight, was not valid because increases

            17    in weight and lipids could be detected by a clinician, and

            18    then a change in the pharmacotherapy could be made to

            19    reduce that risk.

            20                I question whether that's relevant in the real

            21    world for a couple of reasons.  First, even in the setting

            22    of optimal care, where clinicians are, you know, weighing

            23    their patients and monitoring lipids closely, still

            24    patients are gaining weight, and it still remains -- I

            25    mean, in most clinics where patients are on the newer

                                                                          226

             1    drugs, they're not being changed, which is the reality of

             2    practice.

             3                Secondly, the reason that they're not is

             4    because what does the clinician change to in order to

             5    reduce the risk?

             6                The drugs that appear to have the least risk of

             7    QTc prolongation seem to be a group of, from what I gather,

             8    high potency, older antipsychotics, but if one looks at

             9    treatment guidelines that have been developed by some

            10    individuals in the Texas guidelines and other consensus

            11    statements, those drugs are also considered second-line

            12    agents.

            13                I know FDA doesn't consider them, but many

            14    clinicians have come to think of them as second-line agents

            15    because they may be associated with a higher risk of

            16    tardive dyskinesia or other risks.

            17                So the clinician is left with the group of

            18    agents which we've been talking about, the three drugs

            19    which are first-line agents, and all of those cause

            20    substantial weight gain.

            21                Even if one accepts that quetiapine may cause

            22    or risperidone may cause slightly less weight gain, the

            23    amount in some individuals is substantial, and given that

            24    this is such a common problem, I think that there are very

            25    few alternatives for clinicians.

                                                                          227

             1                So I'm just addressing that argument, which I

             2    don't really consider invalid.  I still think that the risk

             3    of these other factors needs to be weighed against the risk

             4    of the QTc prolongation.

             5                DR. THROCKMORTON:  I guess I win.  I don't

             6    think the consultation was making any regards judgment as

             7    regards to which of those was a thing to be concerned about

             8    or even the relative concern that should, you know, sort of

             9    burden of concern for the two things.

            10                I think the consult was raising an issue of

            11    which of the two groups of adverse events are manageable

            12    through relatively easy mechanisms, and which of the

            13    adverse events is one for which we have a difficult time

            14    predicting individuals that are at risk and identifying

            15    that risk before an adverse event.

            16                So you have a significant concern, weight gain,

            17    lipid change and those sorts of things.  Yes, you're right. 

            18    We may have a hard time intervening in those if they occur,

            19    but we don't have any difficulties identifying them through

            20    things that we do all of the time.

            21                On the other hand, QT prolongation, as we've

            22    all heard today, trying to identify an individual at risk

            23    is extraordinarily difficult, and the consequences of

            24    failing to identify that risk in an individual is

            25    irreversible, and so the concern was that you're trading a

                                                                          228

             1    potentially irreversible adverse event that you have a

             2    difficult time predicting will occur for an equally serious

             3    or an alternate significant adverse event but one that is

             4    amenable perhaps to other therapies and is readily

             5    identifiable.

             6                I hope I'm not putting into words --

             7                DR. TAMMINGA:  I would add actually another

             8    feature to this that may be important in that I suppose

             9    what we're talking about is theoretical risk or

            10    hypothetical risk in that this is a risk that we all assume

            11    is there, but we don't see any signal for it, except the 20

            12    millisecond signal.

            13                Dr. Califf is going to correct me.

            14                DR. CALIFF:  No, I'm not, actually.  I'm just

            15    going to pile on and say that although not gaining weight

            16    is a very important thing, and I think an important issue

            17    to consider, we also cannot jump to the conclusion that

            18    drug-induced changes in weight or lipids or diabetes

            19    control necessarily impact on the down-the-road events

            20    we're trying to prevent.

            21                I mean, we don't care what our lipids are,

            22    unless we have a vascular event, which is what lipids

            23    predict, but, you know, I would just point out the lesson

            24    we learned from hormone replacement therapy in the last

            25    five years.

                                                                          229

             1                Beautiful effects on lipids, not so much on

             2    triglycerides as here, and yet, you know, no prevention of

             3    cardiac events in one secondary prevention trial and an

             4    increase in thrombosis.

             5                So the risks on both sides of that equation are

             6    hypothetical, except for weight in and of itself as

             7    something that's personally important and may affect

             8    adherence.

             9                DR. TAMMINGA:  And there's a far different

            10    incidence of risk, I guess you'd call it, between cardiac

            11    event and between weight gain in that weight gain is very

            12    common.

            13                DR. THROCKMORTON:  Are you arguing for outcome

            14    trials now in this population?

            15                DR. CALIFF:  I don't know how you can listen to

            16    this and not -- I mean, you know, this is all resolvable by

            17    randomizing a few thousand patients in each group, and if

            18    I, you know, was a person that had this problem, I would

            19    want to know.  I wouldn't want hypothetical risks and

            20    benefits.  I would want truly measured risks and benefits,

            21    and I know the NIMH is beginning to fund some studies that

            22    are looking at this, but, you know, we're all talking about

            23    hypothetical things here based on surrogates that we can't

            24    presume accurately predict what's going to happen to

            25    patients.

                                                                          230

             1                DR. TAMMINGA:  Dr. Oren.

             2                DR. OREN:  Just in the last couple of minutes,

             3    the discussion has introduced again what the ziprasidone

             4    may do as far as lowering lipids.

             5                I think that we don't have an adequate database

             6    to address that potential benefit.  Again, the sponsor this

             7    morning was not able to provide us with data showing what

             8    happens to people with different baseline lipid levels.

             9                So that unless we knew, for example, that

            10    people with the high baseline lipid levels have lowering of

            11    their lipid levels, it would be hard to make direct

            12    comments on that specific point.

            13                DR. TAMMINGA:  Dr. Cook.

            14                DR. COOK:  Actually, I wanted to follow up on

            15    where this was headed, and I don't want to debate the

            16    completeness of it, and that's what concerns us all, but we

            17    focused appropriately on the QTc, and in some ways, there's

            18    some concern, but then I want to actually ask, particularly

            19    the cardiologist review of the -- I think there are about

            20    4,500 exposures to this over about 1,700 patient years,

            21    with mortality that's lower than placebo, which is

            22    relevant, and equal to comparators.

            23                Now, the problem, of course, is the sample

            24    size, and in direct comparison to ziprasidone, it's not so

            25    high, but I'd just like your comments, and perhaps Dr.

                                                                          231

             1    Hamer's comments on how much we can take from that.

             2                The one thing we obviously don't have is

             3    particularly the fact that even if we have people only on

             4    one drug, they're probably not going to be washed out from

             5    another antipsychotic.

             6                So aside from the fact that we have almost no

             7    data on concomitant psychotropic use, there do seem to be a

             8    lot of patient exposures here in patient years.  So I'd be

             9    curious about those as outcomes.  I mean, that's the

            10    outcome we care about, not the QTc.

            11                DR. TAMMINGA:  Dr. Laughren.

            12                DR. LAUGHREN:  Before Dr. Califf comments, let

            13    me just add one additional piece of information about what

            14    reassurance, if any, one can draw from the fact that the

            15    overall mortality in the NDA database for ziprasidone is no

            16    different than other recent antipsychotic NDAs.

            17                For this drug sertindole that we talked about a

            18    little earlier, the overall mortality in the NDA database

            19    was also right in that ball park, and that drug turned out

            20    to be a problem in terms of sudden death.

            21                So I'm not sure how much reassurance one can

            22    draw from this overall mortality figure from a relatively

            23    small NDA database.

            24                DR. COOK:  Okay.  I know that's a problem,

            25    particularly with the sample size, but was it the same size

                                                                          232

             1    database?

             2                And Number 2, when sertindole was pulled, was

             3    it clear that it had a higher mortality or was it pulled

             4    because of some cases -- I mean, this is the issue.  The

             5    issue is overall mortality.

             6                Are patients that you put on this medication

             7    more likely to die?  I recognize a single event or a set of

             8    events can sort of captivate people emotionally, but the

             9    issue is are patients dying or not in many ways?

            10                DR. LAUGHREN:  The overall person-time

            11    experience was in the same ball park as what we're seeing

            12    for the others, and in terms of the decision-making about

            13    sertindole, I really can't comment on that, but Dr.

            14    Dubitsky showed you earlier the reasoning, the public

            15    reasoning on the part of other regulatory agencies, and it

            16    was based on cases of torsade and sudden death in the

            17    public experience.

            18                DR. COOK:  I don't want to minimize those, but

            19    if we're -- I mean, many of these questions are public

            20    health-related questions, and overall mortality seems to be

            21    the big concern to me at least.

            22                DR. TAMMINGA:  Dr. Fyer.

            23                DR. FYER:  I'd like to disagree a little bit

            24    with Ed about this, in that, I mean, this is probably a big

            25    leap, but it does seem to me that what we're talking about

                                                                          233

             1    with the QTc is a relatively rare event, and, so that the

             2    kinds of sample sizes that you're going to need whereby

             3    it's going to affect mean values in terms of risk factors,

             4    et cetera, are going to be huge, and I think way beyond

             5    anything that anybody's going to do.

             6                I do a lot of, as Ed does, complex disorder

             7    genetics in that similar problems arise, and you sort of

             8    get used to dealing with it, but for me, on the advisory

             9    board, the issue really is that I sort of feel like it's

            10    our job to protect that particular subgroup of people who

            11    may have a very low chance of having gotten into these, you

            12    know, samples, but for whom there is possibly in the data

            13    we've seen today about QTc prolongation evidence that they

            14    do exist.

            15                What concerns me is that the drug will be

            16    approved and go on the market, and another incident like

            17    Seldane and antibiotics will occur, and it's easy to say,

            18    well, that's a very low percentage of people, but for the

            19    people involved, you know, that's the end, and I'm not sort

            20    of taking the position that we shouldn't approve the drug

            21    under this kind of situation, but again what I said earlier

            22    is that I take very seriously the responsibility for, you

            23    know, protecting in a very rigorous way, you know, any

            24    possibility that that will occur, and that we have to

            25    accept that mean data is not going to really address that

                                                                          234

             1    issue at this point.

             2                DR. COOK:  I just have to respond that I share

             3    your concern and think about my own patients as potential

             4    fatalities and thinking about this, and then, I guess, the

             5    only other question to follow up is, could the

             6    cardiologists tell us what the effect of screening would

             7    be, and if this is approved, what level of screening they

             8    would recommend, and would that at all reassure us or not

             9    about this hypothetical risk?

            10                DR. TAMMINGA:  We're going to take Dr. Califf's

            11    response to Dr. Fyer's question first before that question.

            12                DR. CALIFF:  I think, Dr. Cook, I tend to side

            13    with him a little bit on the original point he made on this

            14    issue, and it's one reason in cardiorenal we try to look at

            15    all cause mortality, because I think the case has been made

            16    here that it's possible that you might even have an

            17    increase in risk of death due to long QT, and you might

            18    have a decrease in risk of death due to lowering of lipids

            19    and better weight and better diabetes control, and, you

            20    know, in the end, people don't care what the cause of death

            21    is, they care what their overall risk of death is, and so

            22    it's very conceivable you could have offsetting issues

            23    here, one favorable, one detrimental, and the question is

            24    which outweighs the other?

            25                On the other point of the degree of exposure, I

                                                                          235

             1    think there are two issues here.  One is sample size and

             2    years of exposure.  The other is the representativeness of

             3    the population, and there's been a tendency in FDA-related

             4    clinical trials to enroll patient populations which are not

             5    as sick or complicated as the patients who are eventually

             6    going to be treated when the drug gets on the market. 

             7    That's where a lot of problems have occurred.

             8                I think the sponsor made a pretty good case

             9    that these were reasonably representative patients,

            10    although we don't have all the data in front of us to come

            11    to our own conclusion on that, but I would argue strongly

            12    that looking at total mortality is really the best way to

            13    look at it.

            14                DR. TAMMINGA:  Dr. Harrigan?

            15                DR. HARRIGAN:  Can I just take one moment to

            16    try to address a point that Dr. Califf made earlier, and

            17    that I think may be a point of confusion?

            18                We wouldn't be trying to suggest that

            19    ziprasidone saves lives by lowering cholesterol and

            20    lowering body weight.  It's not a cholesterol-lowering

            21    agent or a weight-loss drug.  It's a drug that doesn't

            22    share the risks of treatment alternatives which aggravate

            23    those cardiovascular risk factors, which exacerbate those

            24    cardiovascular risk factors.

            25                So to the extent that we have some

                                                                          236

             1    understanding of what aggravation of those risk factors,

             2    increasing body weight, increasing cholesterol, increasing

             3    triglycerides, to the extent that we have some idea of what

             4    risks those changes carry, then it's avoidance of those

             5    risks that we think is the key property for ziprasidone.

             6                DR. CALIFF:  I mean, again, they're somewhat

             7    hypothetical.  For example, most drugs that improve

             8    diabetes control also result in an increase in weight.

             9                So the problem is when you deal with surrogates

            10    for cardiovascular disease, there's so many unknowns and

            11    confounding influences of different surrogates, that it's

            12    very hard to be sure what you're going to get without

            13    measuring it.

            14                I mean, we've been through this so many times. 

            15    Still, I think hypothetically, the case that's being made

            16    is pretty strong as hypothetical things go.

            17                DR. TAMMINGA:  And what do you think is very

            18    strong, if you could be clear about that?

            19                DR. CALIFF:  Well, if you believe that drugs

            20    that cause an increase in LDL cholesterol and an increase

            21    in weight lead to an increase in the risk of future

            22    cardiovascular events, and that this drug doesn't do that,

            23    the connection is very plausible.

            24                I'm just making a case that we've seen a lot of

            25    plausible things that turned out not to be right when we

                                                                          237

             1    actually measured them.

             2                DR. THROCKMORTON:  Yes.  I'd echo that, just to

             3    remind the audience that there's another compound that

             4    Pfizer has, of course, that has had similarly-lowered

             5    lipids, that is Doxazocin, but had a reported adverse

             6    outcome as regards to some cardiovascular events.

             7                I'm certainly not saying that we know that

             8    those things are in fact true or connected or anything

             9    else.  I think your point about being very careful of

            10    accepting non-prespecified surrogates as evidence of

            11    benefit is warranted.

            12                DR. TAMMINGA:  Dr. Rudorfer.

            13                DR. RUDORFER:  Yes.  I just wanted to make a

            14    slight paradigm shift just to put in a couple words that

            15    some of the risk factors that we've been talking about

            16    related to weight and lipids also apply to the other side

            17    of the equation, namely the benefit side, because, I mean,

            18    I found the public testimony very moving this afternoon,

            19    that in fact factors that might increase treatment

            20    adherence should not be discounted, and I think the

            21    question of whether effect of weight and lipids reduce

            22    cardiac risk, I agree with Dr. Oren's comment that these

            23    studies were not designed to ask that question, and we

            24    really can't answer it, but I think independent of that,

            25    the fact that those data add to the benefit side of the

                                                                          238

             1    equation, we should keep in mind.

             2                DR. TAMMINGA:  Dr. Laughren.

             3                DR. LAUGHREN:  In line with Dr. Califf's

             4    earlier comments, do you think that there ought to be an

             5    actual demonstration of improved treatment adherence?

             6                DR. TAMMINGA:  Do you mean by Pfizer or in the

             7    real world, in some other place?

             8                DR. LAUGHREN:  Well, again, you know, we've

             9    been talking a lot about theoretical risks and theoretical

            10    benefits.  It seems to me that that's perhaps another one

            11    that hasn't actually been empirically demonstrated, and,

            12    you know, if that were proposed as a theoretical benefit to

            13    offset the theoretical risk of increased sudden death,

            14    should that be subjected to empirical testing rather than

            15    making the assumption that the patients will adhere better

            16    because of less weight gain and so forth?

            17                I mean, it seems to me that it's another

            18    theoretical advantage that perhaps has not been empirically

            19    demonstrated.

            20                DR. CALIFF:  Yes.  I'm not sure I understood

            21    when you say about Pfizer or are in the real world.  I

            22    think Pfizer sells its drugs in the real world.  So I would

            23    assume that one could pretty easily do a study that would

            24    show improved adherence, if in fact the way the lack of

            25    weight gain results in better adherence.

                                                                          239

             1                DR. TAMMINGA:  I didn't mean to exclude Pfizer

             2    from the real world.  The NIMH is currently doing a study,

             3    and I suspect that ziprasidone would be included in that

             4    study, were it approved, where this kind of data might be

             5    collected, although I don't know for sure.

             6                DR. MARDER:  My recollection of the protocol is

             7    that it will be included, if it's approved.

             8                DR. TAMMINGA:  And compliance data will be

             9    collected?

            10                DR. MARDER:  Yes.  That study will measure

            11    treatment adherence.  It will also measure a lot of the

            12    cardiovascular factors as well.

            13                DR. TAMMINGA:  Dr. Winokur.

            14                DR. WINOKUR:  Dr. Cook raised a question before

            15    which to me was a pretty important pragmatic one, which I'd

            16    like to come back to, again putting it into context.

            17                I think we currently use a fair number of

            18    medications that have a lot of complexities and initially

            19    had some major safety and health concerns, and we're kind

            20    of accustomed to having to do a lot of monitoring. 

            21    Depakote might be one good example of that, which -- I'm

            22    sorry?  Many.  Right.  I mean, we can go on and on about

            23    that.

            24                But Dr. Cook raised a question about screening

            25    and monitoring with respect to, you know, EKG, and I don't

                                                                          240

             1    know if there would be any other measures, but to what

             2    extent would that, just from a strictly pragmatic point of

             3    view, be something that we could use constructively on

             4    clinical grounds or is this something that would not be

             5    aided that much in terms of safety issues by good clinical

             6    management of cases?

             7                DR. MOSS:  Well, certainly screening would be

             8    of interest.  The question is, are you talking about

             9    screening in terms of entry of patients in starting the

            10    drug or monitor screening as occurring during periodic

            11    follow-up?

            12                I suspect probably more the latter from --

            13                DR. WINOKUR:  Well, really, when we use

            14    Depakote now, we do baseline liver function tests because

            15    we don't want to start somebody on that drug without

            16    knowing that their liver function is okay, and then, once

            17    they're on it, we repeat it periodically.

            18                So I mean, that's a paradigm we're pretty

            19    familiar with, and I would think of both determining that

            20    it would be a reasonable agent to select initially, not

            21    take somebody, you know, that had a QTc of 500 at baseline,

            22    but also for those people that might be especially

            23    responsive to that drug.

            24                In other words, I'm not talking about a

            25    research study.  I'm just talking about in terms of good

                                                                          241

             1    clinical practice, what we would do or teach our residents. 

             2    Would these kind of measures in your opinion be helpful in

             3    really actually addressing the kind of concern that Dr.

             4    Fyer raised about, you know, our responsibility to protect

             5    our patients?

             6                DR. MOSS:  I think it would be very reasonable,

             7    particularly in the start-up, as one gets a large amount of

             8    experience to see what the pattern of the follow-up

             9    electrocardiograms are.

            10                I think that over a period of six months or so

            11    of a goodly number of patients, one would have an idea that

            12    this drug is safe.  I think that would be very useful as

            13    certainly a screening for the start-up, but the follow-up,

            14    what we're looking for is is this signal really

            15    representative of something that one's going to see when

            16    one's treating thousands of patients, and that would be

            17    useful, extremely useful information.

            18                DR. CALIFF:  Just out of interest, I wonder

            19    what the actual adherence to your LFTs is in practice.  If

            20    their adherence is good, it would be quite unusual compared

            21    to other things we're looking at, but measuring QT interval

            22    is not necessarily easy for the average person to do but

            23    could be done, and I think Pfizer is getting a lot of

            24    experience with dofetilide.  It's just coming on the market

            25    now with measuring a lot of QT intervals.  So it can be

                                                                          242

             1    done.

             2                DR. TAMMINGA:  But it would be useful to add

             3    after this comment that most people with schizophrenia are

             4    actually treated in the public sector, so that the common

             5    place for them to get their medications would be in

             6    community mental health centers, places that may not even

             7    have an EKG machine, let alone a physician that might be

             8    able to be qualified to read an EKG.

             9                Dr. Laughren.

            10                DR. LAUGHREN:  Can I just add a comment?  Based

            11    on the data that Pfizer showed earlier, looking at baseline

            12    EKG versus change in QTc, it looked like patients with

            13    relatively high baseline QTcs had the least change, and

            14    perhaps it's regression to the mean, but I guess that

            15    raises a question of what the value is of getting a

            16    baseline EKG here?

            17                DR. CALIFF:  Yes.  I would think that if there

            18    was going to be screening, it would be on a steady state

            19    dose, would probably be a more valuable time to look for

            20    those who developed a lot of QT prolongation on treatment.

            21                DR. MOSS:  I'd be a little bit hesitant on the

            22    basis of 33 patients to make some of that interpretation. 

            23    That is, it may well be valid that the higher baseline QTc

            24    in fact have the least increment.  It's just atypical of

            25    what we've generally seen, and so it's a question mark in

                                                                          243

             1    my mind.

             2                DR. TAMMINGA:  I think progression to the mean

             3    data was not on the 33.  I could be wrong.  What I think

             4    was on the total Phase II/III dataset.  I don't know if we

             5    want to see that again.

             6                Dr. Katz, you may want to make a remark while

             7    we're waiting for Pfizer to get that slide up.

             8                DR. KATZ:  I think it was in the total dataset. 

             9    We monitor a lot of things.  Clinically, lots of things are

            10    monitored.  For example, LFTs are monitored in Depakote and

            11    many other drugs.

            12                DR. HARRIGAN:  That's true.

            13                DR. KATZ:  The problem is we don't really know

            14    necessarily what to do with the results or whether or not

            15    they actually predict what you're worried about or whether

            16    or not when you see something, by that time it's

            17    irreversible.  So people do these things, and you've asked

            18    this sort of analogous question with monitoring EKGs here,

            19    that I think we still don't know if you see a 30

            20    millisecond increase in somebody that started out at 420,

            21    what does it mean?

            22                I still don't think we've heard an answer. 

            23    Maybe we can't get an answer to that question, but I don't

            24    think we've heard an answer about whether or not we think

            25    that sort of change matters to anybody, and what would you

                                                                          244

             1    do if you saw it?

             2                Dr. Moss, you said that if smaller changes in

             3    the QTc might be a risk, but the risk is probably

             4    extraordinarily small.  I wonder what that statement is

             5    based on.

             6                DR. MOSS:  It's not based on good science. 

             7    That, I can tell you.

             8                (Laughter.)

             9                DR. MOSS:  It's based more on just a large

            10    amount of non-specific observational information of

            11    clinicians who've treated patients, that the patients who

            12    have minimal change in QTc, by minimal change.

            13                If you start at 420 and go to 450 or so,

            14    there's just been remarkably few events in cardiologists'

            15    experience or anybody else's experience that's been

            16    reported.  So that, as Dr. Ruskin said earlier, virtually

            17    the vast majority of events have been in those patients

            18    over 500.  We don't think that that's an absolute

            19    threshold, but the risk seems to progressively increase,

            20    and that's where it becomes clinically evident.

            21                I don't know that one has better information

            22    than that.

            23                DR. TAMMINGA:  Dr. Katz.

            24                DR. KATZ:  Yes.  I'd just like to ask Doug, I

            25    think on the sotalol data you presented, you showed that

                                                                          245

             1    there was a relationship between torsade, the incidence of

             2    torsade, and change in QTc, but I don't recall whether or

             3    not that was linked to any threshold or, you know,

             4    approximate threshold or whether or not it was really -- I

             5    mean, I think there are other problems with that sort of

             6    data.  It wasn't randomized, you know, or that sort of

             7    thing.  But it seemed to be linked to change.

             8                DR. THROCKMORTON:  They did look at that, and

             9    in fact, in the sotalol label, there are two tables that

            10    report the sponsor's analysis of extent of QT prolongation

            11    from baseline by, I don't know, tens of milliseconds, and

            12    then another by the incidence of torsade for patients whose

            13    QT goes over 500, the incidence of of torsade for people

            14    who go over 550, and the incidence of torsade for people

            15    who go over, I think, 600, something like that, and in both

            16    of those analysis, there is a relationship.  That is, the

            17    people who go over 500 had a certain incidence, 550 a

            18    higher incidence still, and 600 was even higher than 550.

            19                The problem is that, as you say, those data

            20    were collected for patients who had torsade events.  We

            21    don't know how many people did not have torsade events but

            22    still had QTs of 550 or 600.

            23                But I think that -- I mean, correct me, I

            24    believe that is the only place where that's actually sort

            25    of been looked at, and in that one case, there was a

                                                                          246

             1    relationship between how many people went way far over 500

             2    and the incidence of torsade.

             3                DR. KATZ:  Of course, that's confounded, too,

             4    because probably the people who went over 500 or 600 are

             5    the people that had the biggest change, too.

             6                DR. THROCKMORTON:  Right.

             7                DR. KATZ:  So one wonders what happens if you

             8    see that sort of change, if you start out at, I don't know,

             9    380, and you go to 460.  I don't know.

            10                DR. THROCKMORTON:  Yes.  There's one other

            11    point, if I could, just from a regulatory standpoint.  I

            12    think there are three labels that say if you go too long,

            13    you should stop the drug or sort of recommend that. 

            14    Sotalol, bepridil and dofetilide all have sort of

            15    recommendations, saying, you know, if you measure the QTc

            16    on ECG, and it's greater than 500, or in the case of

            17    bepridil, it's 520, for reasons that I haven't been with

            18    the agency long enough to know why it's 520 instead of 500,

            19    you should stop the drug.

            20                But other than those -- and I'm not sure what

            21    data that was based on.  Those are the only three that -- I

            22    believe maybe moxi.  That could be the other one.  Has

            23    explicit instructions for recommending discontinuation for

            24    an extreme prolongation of QT.

            25                DR. TAMMINGA:  And it's not the case in other

                                                                          247

             1    drugs, other non-psychiatric drugs, that are known to

             2    prolong QT?

             3                DR. THROCKMORTON:  Not that I'm aware of.

             4                DR. KORVICK:  For the moxifloxacin, we advise

             5    to not start patients that have prolonged QT.

             6                DR. TAMMINGA:  Of course, in the database that

             7    we heard today, no one, I believe, had a QT over 500 at

             8    baseline in the whole II/III dataset.  So that the

             9    incidence of people with schizophrenia, who require

            10    treatment, who have prolonged QT, is quite low.

            11                Yes, Dr. Oren.

            12                DR. OREN:  A question for Dr. Moss.  I realize

            13    we're still at best at the beginning of the dawn of the era

            14    of pharmacogenomics, but in reference to your presentation,

            15    if we knew more about HERG polymorphisms, would we be

            16    better able to quantify or qualify the cardiac risks of

            17    this drug?

            18                DR. MOSS:  Yes, to a degree, but it's going to

            19    be at an immense -- one's going to need an immense number

            20    of patients to understand the association with

            21    polymorphisms, and one's going to also have to relate each

            22    of the polymorphisms to expression studies to see what

            23    effects they actually have, even to a minor degree, on the

            24    potassium current.

            25                There's already known about a 130 different

                                                                          248

             1    mutations in the HERG gene to date, and that's not counting

             2    the polymorphisms.  So it becomes a question of enormous

             3    numbers.  The Genome Project's not going to make life

             4    simpler.

             5                DR. TAMMINGA:  Well, we've done an awful lot of

             6    discussing this afternoon.  We may have even exhausted our

             7    questions for our consultant cardiologists but I'm not

             8    sure.

             9                Dr. Katz.

            10                DR. KATZ:  I have another question.  Something

            11    has been made of the terfenadine data which suggests that

            12    in the absence of metabolic inhibition, the prolongation of

            13    the QTc is somewhere on the order of 18 milliseconds or

            14    something like that, and the fact that there have been no

            15    reports of arrhythmias in the absence of metabolic

            16    inhibition with terfenadine is put forth as evidence that

            17    you can tolerate that sort of a change in QTc, and it

            18    really doesn't pose a risk.

            19                For the moment, forgetting about the vagaries

            20    of postmarketing reporting and whether or not you really

            21    are hearing about cases that they occur, the question I had

            22    had to do with the duration of the QTc prolongation.

            23                My understanding with terfenadine is that it

            24    reaches Cmax, and it comes down rapidly, and so I'm

            25    wondering, do we have any evidence about the duration of

                                                                          249

             1    the effect on the QTc with ziprasidone, maybe with any

             2    drugs, but specifically with ziprasidone?

             3                Study 054 measured at Cmax, and the attempt was

             4    made to measure Cmax.  Do we know anything about that?  By

             5    the way, do we think that that might even be important? 

             6    I'll direct the latter to the cardiologists since we're in

             7    the realm of the hypothetical for most of the afternoon.

             8                DR. HARRIGAN:  We concentrated the ECG

             9    measurements around that predicted time of Cmax.  We did

            10    not collect serum measurements or ECGs around the clock in

            11    those patients during that period, nor did we plot out a

            12    time concentration curve, such as I think you're

            13    describing.

            14                DR. KATZ:  And let me just ask the second part

            15    again directly to the cardiologists.  Is that something

            16    that you think would matter?

            17                DR. MOSS:  Well, if I understand your question,

            18    does the increase of 20 milliseconds matter?

            19                DR. KATZ:  What I'm asking is, if you're

            20    increased to 20 milliseconds for an hour or if you're

            21    increased to 20 milliseconds for seven hours or for 10

            22    minutes, does the --

            23                DR. MOSS:  I think one's dealing with a

            24    probability of an event, and the minute you increase the

            25    exposure, you would think that there would be some increase

                                                                          250

             1    in the likelihood and the probability of an event.  So the

             2    duration of exposure would certainly be important.

             3                DR. KATZ:  Well, just to follow up, do people

             4    think that would be an important bit of information to

             5    obtain, let's say, with this drug?  Add that to the list of

             6    questions yet to be answered.

             7                DR. TAMMINGA:  As I recall from some of the

             8    other drugs that we saw in our preparation material, would

             9    it be reasonable to assume that the QT prolongation change

            10    might follow the kinetics of the drug?  Might follow the

            11    blood levels?  That was my question.

            12                DR. MOSS:  The answer is yes, they would

            13    certainly be related to the blood level.  That was one of

            14    the peculiarities, that as one got higher, it didn't seem

            15    to keep going up.  There seemed to be a plateau, but at

            16    least in the lower range, there did seem to be a dose-

            17    response effect.

            18                Bob?

            19                DR. CALIFF:  That would make a lot of sense,

            20    but it would seem to be a fairly straightforward thing to

            21    measure, also, to be sure about, and it is an important

            22    part of the consideration of some of the drugs used to

            23    treat atrial fibrillation, to know the time course of the

            24    prolongation.  For example, if you need to treat with other

            25    drugs due to an emergency situation.

                                                                          251

             1                DR. TAMMINGA:  Dr. Cook.

             2                DR. COOK:  I'm sorry.  I'm jumping back to the

             3    discussion of pharmacogenomics and concern and really, I

             4    guess, this is a question for clarification.

             5                One of the ways that we have of knowing about

             6    variation is that based on population history, various

             7    groups differ in drug response, sort of the basis of

             8    pharmacogenetics, and my question, I suppose, is one I

             9    should have asked earlier this morning, but I did want to

            10    ask it before we go further.

            11                It's what evidence do we have that more than

            12    Caucasians, we have safety data for this drug, considering

            13    variability across populations, efficacy as well?

            14                DR. TAMMINGA:  So you'd like the company to

            15    show us some race data?

            16                DR. COOK:  Yes.  Ethnicity.  I don't think race

            17    exists.

            18                DR. HARRIGAN:  The efficacy data has been

            19    analyzed with a number of cofactors, covariates, and race,

            20    gender or age were not factors.

            21                In terms of the QTc, Slide M83 --

            22                DR. COOK:  Let me just take them as they come.

            23                DR. HARRIGAN:  Sure.

            24                DR. COOK:  But I need to know what

            25    representation you had of different ethnic groups.

                                                                          252

             1                DR. HARRIGAN:  Yes.

             2                DR. COOK:  Did you have sufficient numbers to

             3    demonstrate efficacy by those different groups?

             4                DR. HARRIGAN:  Sure.  G2.  So here's the Phase

             5    II/III program.  We set this alongside the comparator

             6    groups.  So for ziprasidone, 4,571 patients in the Phase

             7    II/III program.  This is cumulative up to 5 February this

             8    year.

             9                You can see 3,200 of those patients were

            10    Caucasian, approximately 700 or about 16 percent of the

            11    total black, and 16 percent other.

            12                DR. TAMMINGA:  What would the other be mainly?

            13                DR. HARRIGAN:  Well, the other would include

            14    Asian, Hispanic.  That would probably be most.  I don't

            15    have it precisely.

            16                DR. MOSS:  Is the pharmacokinetics similar in

            17    various racial groups?

            18                DR. HARRIGAN:  Yes.  We looked at that with

            19    population pharmacokinetics.  I think, Dr. Brater, you wish

            20    to address that?

            21                DR. BRATER:  Yes.  That was looked at with the

            22    population pharmacokinetics, which had what, 2,000 -- Tom,

            23    what was the number?  Pardon me?  453 subjects, and there's

            24    no gender, no race, no ethnicity effect.

            25                DR. COOK:  Did I interrupt you from showing

                                                                          253

             1    something else?

             2                DR. HARRIGAN:  Whatever else you would like to

             3    see.  We --

             4                DR. COOK:  You were hopefully going to show QTc

             5    by ethnicity.

             6                DR. HARRIGAN:  Sure.  That would be M83 to

             7    start, yes, by dose.  Thank you.

             8                Similar to the graph we looked at earlier by

             9    gender, we're looking at the short-term fixed-dose placebo-

            10    control trials, with each dose group represented, with

            11    white being in green, the blue black, and the red other.

            12                As you can see the numbers, at less than 40

            13    milligrams, then 40, 80, 120, 160, and 200 milligrams or

            14    more.  There seemed to be no systematic differences there. 

            15    Some variability in the data, of course, but no suggestion

            16    that there's a greater mean effect in either of the other

            17    racial groups compared to Caucasian.

            18                Dr. Brater.

            19                DR. BRATER:  I'll just insert myself one more

            20    time.  Another issue here potentially is whether or not

            21    there are any ethnic differences in any of the drug-

            22    metabolizing enzymes.  3A4, the aldehyde oxidase, and one

            23    that we really haven't talked about that adds the methyl

            24    group on there, TMT it's called, and all three of those

            25    enzymes do not, do not have polymorphisms.  So they all

                                                                          254

             1    have sort of a Gaussian distribution.  So there are no

             2    ethnic-related differences in those, in contrast to, say,

             3    2D6 and some of the others.

             4                DR. TAMMINGA:  Well, the committee has two

             5    specific questions to vote on, and then three additional

             6    questions to discuss.  The discussions that we've had this

             7    afternoon so far have been very productive about the

             8    voting.  I'm not sure they've prepared us to vote in one

             9    way or the other.

            10                Have we discussed pretty much the items that

            11    you had indicated, Dr. Laughren, or do you see big holes in

            12    what we've discussed?

            13                DR. LAUGHREN:  I think most of the issues have

            14    been discussed.  There hasn't been quite as much discussion

            15    of potential studies perhaps.  Some discussion of that but

            16    not a lot.

            17                DR. TAMMINGA:  Would you suggest to us what the

            18    committee can suggest about potential studies?  For

            19    instance, that potential studies be done before or after or

            20    what would we be suggesting to you?

            21                DR. LAUGHREN:  Well, you know, you could

            22    suggest both the timing, and it could be before, it could

            23    be before, and the general nature of the kinds of studies

            24    that you would propose.

            25                Dr. Califf, for example, was proposing, as I

                                                                          255

             1    understood it, fairly large comparative outcome studies,

             2    looking at things like, you know, perhaps overall

             3    mortality.  Another outcome one might look at is sudden

             4    unexplained death, but you also might look at things like

             5    treatment adherence as a potential benefit in a large

             6    outcome study.

             7                So those kinds of issues, and then, the other

             8    type of study that I had suggested earlier on to think

             9    about would be a study to show benefits on the efficacy

            10    side.  In other words, the kind of trial that was done with

            11    Clozapine.

            12                DR. MARDER:  I mean, to me, there are some

            13    obvious studies that need to be done, and whether they're

            14    pre or post I think depends upon other discussions.

            15                But I do think by having such a limitation of

            16    dose and not knowing the -- if this drug is approved, it

            17    would likely be administered by some individuals at a

            18    higher dose than recommended.

            19                So I think we should have some idea about what

            20    happens at higher doses or higher plasma concentrations. 

            21    The drug will be taken by -- the number of elderly

            22    patients, particularly those over 70, was relatively small. 

            23    So I think knowing about cardiovascular factors in the

            24    elderly seems obvious.

            25                You know, there may be others I don't know

                                                                          256

             1    about, cardiac monitoring and things like that.  Those

             2    would be things for the cardiologists to recommend.

             3                DR. TAMMINGA:  Dr. Winokur.

             4                DR. WINOKUR:  While we're on the topic of

             5    studies, I do believe that there are going to be almost

             6    immediately studies in the larger effectiveness program, as

             7    I understand it, that will involve ziprasidone, if it's

             8    available.

             9                The issue from our discussions that seems

            10    crucial to me, that we would have more information -- I

            11    mean, I could certainly accept it being -- you know, Phase

            12    IV post-marketing relates to the issue of in the context of

            13    using other drugs, because that clearly is going to happen.

            14                We just know that's going to happen.  We've

            15    heard from the cardiologist experts that that's an issue of

            16    potential importance and health importance, which they

            17    can't really advise us on further without any information,

            18    and I think that's not going to be the kind of data that

            19    will come in a systematic scientifically-rigorous way that

            20    will also be clinically applicable from the other kinds of

            21    more naturalistic studies that are in the process of being

            22    formed up.

            23                So that would be one area that I would -- and

            24    again, I'm not talking about the drug-drug interaction

            25    issue.  I'm talking specifically about two different drugs

                                                                          257

             1    that will be used, that both in theory could affect QTc,

             2    and we need to know how in combination they affect things,

             3    and what kind of additional health concerns they raise.

             4                DR. LINDENFELD:  Yes.  I think we'd certainly,

             5    as Rob mentioned earlier, would like to see some data on

             6    beta blockers and at least the rate-lowering calcium

             7    blockers and diuretics that was on a slide but wasn't

             8    really mentioned, that hypokalemia is an important

             9    predisposing risk for torsade, and I think that makes

            10    diuretics very important here, too.

            11                So you'd like to see a group of patients with

            12    those commonly-used drugs evaluated.

            13                DR. TAMMINGA:  I'm not exactly sure if Dr.

            14    Califf is coming back, but his study, of course, was the

            15    large study that would be large enough to evaluate the

            16    sudden death risk.

            17                Would either one of you like to speak to that?

            18                DR. MOSS:  I don't think he was proposing that

            19    as a precondition for approval.  I don't think that was his

            20    intent at all.  He, I think, was just saying it would be

            21    wonderful to have that type of data, but I don't think he

            22    was proposing that as a preapproval.

            23                I think just the comment about the medicines,

            24    what one's really talking about is are the additive effects

            25    of the medications on the QT, not the interaction effects,

                                                                          258

             1    and these are really important considerations.

             2                The studies that have been done have been the

             3    interaction effects, seeing if there's alteration in the

             4    metabolism of the drug, et cetera, but what one is talking

             5    about is the potential additive effects.

             6                What percentage of these patients are also on

             7    tricyclic antidepressants, for example?  Small number?

             8                DR. TAMMINGA:  Not small.  It would be 20 to 30

             9    to 40, 20 to 40 percent, 20 to 35 percent, plus many of

            10    them are on mood stabilizers.

            11                I bet that Dr. Marder would have a more

            12    accurate estimate than me.  What percentage of

            13    schizophrenic patients are on, for instance, mood

            14    stabilizers and antidepressants?

            15                DR. MARDER:  I'd say probably at least half.

            16                DR. TAMMINGA:  Dr. Casey.

            17                DR. CASEY:  The antidepressant medicines are

            18    now much more likely to be SSRIs rather than tricyclics, as

            19    we are not using those as first- or even second-line

            20    treatments for depression.

            21                So we've taken some of that risk out of the

            22    equation by using SSRIs.  I'd agree with Dr. Marder.  In

            23    general, probably half of the patients with schizophrenia

            24    may be taking another psychotropic drug.

            25                DR. TAMMINGA:  Dr. Malone.

                                                                          259

             1                DR. MALONE:  You had mentioned various age

             2    groups.  The other age group would be to study children,

             3    especially the effect on QTc, because they probably will be

             4    administered these medications if they're approved.

             5                DR. TAMMINGA:  Have there been any studies at

             6    all in the under-18 age group?

             7                DR. HARRIGAN:  I'd like to ask Dr. Craig Brater

             8    to discuss that.

             9                DR. BRATER:  There have been two, and those

            10    have been kinetic dynamic studies, and most particularly to

            11    get to the QT question, the heart of the batting order,

            12    that's Slide Number 66, where you will see -- and these go

            13    down to average age in the youngest group was 7, and you

            14    see the colored symbols in here, and then on the background

            15    is all of the other data that you've already seen.

            16                We were given information that one of your

            17    panel members who couldn't be here today wanted

            18    specifically to know about QTs that went above 480.  Here's

            19    your 480 line.  You notice there are no colors that go up

            20    there.  The biggest QT is about 440 in these children.

            21                DR. TAMMINGA:  And what is the age of the pink,

            22    and what's the age of the blue?

            23                DR. BRATER:  Well, the age range here, there

            24    were three groups, and they were dosed according to body

            25    weight, and the lowest body weight for the youngest age,

                                                                          260

             1    that group, the average age was 7.6.  The middle group was

             2    average age of 11, and the oldest group was average age of

             3    14.

             4                DR. MALONE:  What was the sample size?

             5                DR. BRATER:  I'm sorry?

             6                DR. MALONE:  What was the N for those groups?

             7                DR. BRATER:  In the group with the age of 14,

             8    8, the middle group, 7, and the youngest and lightest

             9    weight 8 years, N of 8.  So there should be 23 dots on

            10    there.

            11                DR. COOK:  And to clarify, this is not done at

            12    peak levels.  This was determined more at trough, like the

            13    other Phase II/III?

            14                DR. BRATER:  I don't know if I can answer that. 

            15    It was all collected within one hour of an ECG, but I don't

            16    know if it was collected -- an attempt to make it at peak. 

            17    That would imply to me that they were random.

            18                DR. TAMMINGA:  Thank you.

            19                While there aren't many data in children, it

            20    may be more than anybody else has.

            21                I wonder if there's any additional discussion

            22    or additional points for discussion that people would like

            23    to bring up before we start to consider the questions we

            24    have to vote on, which would first be the efficacy question

            25    and would secondly be the safety question.

                                                                          261

             1                (No response.)

             2                DR. TAMMINGA:  If there aren't any additional

             3    areas of comment, then I could just review that we would

             4    really be voting on the adequacy of the database that we've

             5    heard presented to us.

             6                That would speak to both the efficacy and the

             7    safety of this drug to be used for the treatment of

             8    schizophrenia, and the first question that we would want to

             9    vote on would be, has the sponsor provided evidence from

            10    more than one adequate and well-controlled clinical

            11    investigation that supports the conclusion that ziprasidone

            12    is effective for the treatment of schizophrenia?

            13                Now, I think we'll probably be prepared to go

            14    around the table and vote on that, and we could start with

            15    Dr. Moss.  Dr. Moss is not voting.  I think we'll start

            16    with Dr. Grady-Weliky.  If you could turn on your

            17    microphone.

            18                DR. GRADY-WELIKY:  I would say yes.

            19                DR. TAMMINGA:  Dr. Oren?

            20                DR. OREN:  Yes.

            21                DR. TAMMINGA:  Dr. Ortiz?

            22                DR. ORTIZ:  I agree that efficacy's been

            23    demonstrated.

            24                DR. TAMMINGA:  Dr. Hamer?

            25                DR. HAMER:  Yes.

                                                                          262

             1                DR. TAMMINGA:  Dr. Marder?

             2                DR. MARDER:  Yes.

             3                DR. TAMMINGA:  Dr. Lindenfeld?

             4                DR. LINDENFELD:  Yes.

             5                DR. TAMMINGA:  Dr. Rudorfer?

             6                DR. RUDORFER:  Yes.

             7                DR. TAMMINGA:  Dr. Cook?

             8                DR. COOK:  Sorry, more than a yes.  Yes, but

             9    only 18 and above, and only for this specific indication of

            10    several that the medication would be considered for.

            11                DR. TAMMINGA:  I think that's what we're voting

            12    for, isn't it, Dr. Laughren?  We're voting for the adult

            13    population, and we're voting for schizophrenia?

            14                DR. LAUGHREN:  Right.

            15                DR. COOK:  I'm sorry.  I just had to comment

            16    because this is probably the only time this committee is

            17    likely to vote on indications for this medication, and

            18    absent a similar effort for other indications, including

            19    those that are psychotic but not schizophrenia, the

            20    question is limited, and off-label use is likely to exceed

            21    that of the on-label use.  So that's a concern.

            22                DR. TAMMINGA:  Dr. Winokur?

            23                DR. WINOKUR:  Yes.

            24                DR. TAMMINGA:  Dr. Malone?

            25                DR. MALONE:  Yes.

                                                                          263

             1                DR. TAMMINGA:  Well, that was a pretty clear

             2    sweep, but it also was not the more thorny of the

             3    questions.  Oh, yes.  I'm yes, also.

             4                DR. TITUS:  There are 11 yeses.

             5                DR. TAMMINGA:  Now, the next question that we

             6    have to vote on, has the sponsor provided evidence that

             7    ziprasidone is safe when used in the treatment of

             8    schizophrenia?

             9                Included in the answer to this question, of

            10    course, is really the topic that we've been discussing all

            11    afternoon, and after we get done voting for this question,

            12    we'll still have a chance to address, although not vote on,

            13    the other issues that Dr. Laughren laid out for us.

            14                If you'd like to start again around the table?

            15                DR. GRADY-WELIKY:  I was actually hoping we

            16    could start on the other side.

            17                (Laughter.)

            18                DR. GRADY-WELIKY:  It's a harder question.  I

            19    guess my thought is that I'm going to say yes, with a

            20    caveat that I think there needs to be more work after this. 

            21    I think that there's a lot of question that was raised

            22    around, you know, what the QTc interval really means, if

            23    there's a way to screen for it.

            24                I think Dr. Fyer's question about how much, you

            25    know, what's the difference, if it's 60 milliseconds or 20

                                                                          264

             1    milliseconds, starting at a baseline of 320 milliseconds,

             2    or if it's 20 starting at 440.

             3                So I think we certainly need to have more data,

             4    but I think outside of that, my vote would be yes.

             5                DR. TAMMINGA:  Dr. Oren?

             6                DR. OREN:  My vote would be yes, with the

             7    encouragement that the FDA use all of its powers to ensure

             8    that safety is fully assured in the practice and the use of

             9    the drug, and that the public hears the message that the

            10    FDA provides with the labeling.

            11                DR. ORTIZ:  I think I'm going with a qualified

            12    yes.  I think following Dr. Cook, my concern would be the

            13    elderly and what is lacking in information about the

            14    elderly, and what Dr. Lindenfeld has suggested about

            15    interactions with beta blockers and calcium channel

            16    blockers, which are so commonly used in the elderly, and as

            17    a geriatric psychiatrist, I'm particularly concerned about

            18    that, but my vote is yes.

            19                DR. TAMMINGA:  Dr. Hamer?

            20                DR. HAMER:  I'm going to do something I don't

            21    think I've ever done before at one of these meetings, which

            22    is I'm going to abstain because I just don't feel that I'm

            23    comfortable enough with or know enough about the

            24    relationship of the lengthened QTc intervals to the risk of

            25    arrhythmias and related illnesses, and I haven't gathered

                                                                          265

             1    enough information at this meeting to really enable me to

             2    interpret that correctly.

             3                DR. MARDER:  Yes.

             4                DR. LINDENFELD:  This is a difficult question

             5    for me because I think it involves what is safe, and that's

             6    a relative, what is safe.  So do I think this drug is

             7    perfectly safe?  No.  My suspicion is that there will be an

             8    excess of torsade with this drug, particularly when more

             9    drugs are added as you see the drug used in the real world.

            10                So is it perfectly safe?  Again, you know, I

            11    guess this gets down to will there be an excess risk of

            12    torsade?  I think from the data we have, we would guess

            13    that there will be.  I think that the risk will be

            14    relatively low.

            15                So I don't know quite how to answer that safe,

            16    unless you want to define it for me more precisely.

            17                DR. TAMMINGA:  The safe is qualified by has the

            18    sponsor provided evidence that ziprasidone is safe when

            19    used in the treatment of schizophrenia?

            20                DR. LINDENFELD:  I would say no.

            21                DR. TAMMINGA:  Dr. Katz?

            22                DR. KATZ:  Well, I think it's a fair question

            23    for sure.  I think when we say safe, I think we mean in

            24    this question placed here whether or not you think there is

            25    sufficient information available at the moment about the

                                                                          266

             1    toxicity, so that we could write adequate labeling, so that

             2    the drug could be used, so that it's appropriate that the

             3    drug could be used with appropriately-written labeling at

             4    this moment, given the information we have.

             5                DR. LINDENFELD:  Again, I don't want to be

             6    difficult, but I think it's a difficult question.  I think

             7    that labeling could be written to minimize the risk, but I

             8    think there will be a small but excess risk probably with

             9    this drug, based on what we know about other drugs that

            10    prolong the QT interval.

            11                DR. KATZ:  Fair enough, but I think we're

            12    asking you, given your belief about what you think the risk

            13    is or will be, whether or not you think it's appropriate to

            14    market it at this time.

            15                DR. LINDENFELD:  Not without other data about

            16    use of additional drugs with this drug.

            17                DR. TAMMINGA:  Dr. Rudorfer?

            18                DR. RUDORFER:  I would say yes.  My concerns, I

            19    think, can be addressed with labeling and post-marketing

            20    issues that we'll talk about.

            21                DR. TAMMINGA:  Dr. Cook?

            22                DR. COOK:  Yes.  I would say yes, and again

            23    we're going to have to have a discussion about how strong

            24    the labeling would be, and in my sense, it's going to be

            25    quite strong and is going to exclude use of concomitant

                                                                          267

             1    medications that may cause a problem.

             2                DR. WINOKUR:  Yes.

             3                DR. MALONE:  I'm not sure -- we had evidence

             4    that labeling doesn't -- well, at least the "Dear Doctor"

             5    letter doesn't seem to be paid much attention to.

             6                Does the FDA have post-marketing things they

             7    can do different from one drug than another or is

             8    everything the same?  I guess that's a question I'm asking.

             9                What could be done post-marketing to assure

            10    that there is clear follow-up about these cardiac risks?

            11                DR. KATZ:  Well, there are things that can be

            12    done.  There are things called Phase IV commitments.  In

            13    other words, where we require a sponsor to perform

            14    additional studies once the drug is approved.  There are

            15    mechanisms by which we could restrict the distribution of

            16    the drug once it's approved, so that only certain

            17    physicians or only certain centers, you know, could have

            18    the drug available.

            19                There are registries that we could talk about

            20    possibly setting up so that the first X numbers of patients

            21    or some reasonable sample are followed prospectively.  So

            22    there are things that can be done once the drug is

            23    approved.

            24                DR. MALONE:  I would say yes, if there are some

            25    specific things that are set up to do follow-up that are

                                                                          268

             1    somewhat different than most medications.

             2                DR. TAMMINGA:  My vote is yes.

             3                DR. TITUS:  So we have one abstention, one no,

             4    and nine yeses.

             5                DR. TAMMINGA:  This particular vote on safety

             6    came along with a lot of caveats, and I wonder if it might

             7    be useful to the FDA to have from us the most specific

             8    ideas about those caveats.

             9                DR. LAUGHREN:  Yes.  Anything you can say along

            10    those lines would be helpful.

            11                DR. TAMMINGA:  Dr. Grady?

            12                DR. GRADY-WELIKY:  I think there are two things

            13    that I think are critical, and I think the first relates to

            14    the drug-drug interaction with the concomitant medications,

            15    and whether or not there's going to be a labeling issue

            16    there we can talk about.

            17                But I think given the patient population that

            18    we're dealing with, it will be on multiple medications.  So

            19    I think that risk needs to be looked at in the form of a

            20    study.

            21                The other is the labeling question that was

            22    raised by a number of people.  I think like Dr. Malone, I

            23    have concerns about whether or not physicians will follow

            24    that, based on the data that Dr. Rodriguez, I believe,

            25    presented.

                                                                          269

             1                So those are the two things that I think really

             2    need to get looked at and talked about.  Perhaps the

             3    labeling -- since this is my first meeting, I don't know

             4    all the details about the labeling, but that's something

             5    that maybe we can get addressed here.

             6                DR. TAMMINGA:  Dr. Marder.

             7                DR. MARDER:  Well, in the labeling, I would

             8    make it very clear that there is very little experience

             9    with doses over a 160 milligrams a day, and that just

            10    strong language to discourage that because that's unknown

            11    territory, and there could be serious problems.

            12                Also, it could very well be that the

            13    maintenance data showed that a dose of 40 milligrams -- I

            14    mean, 40 was as good as 80 as good as 160, and for

            15    physicians to reduce the dose as quickly as possible over

            16    the long run might increase the safety of the drug.  Those

            17    kinds of statements might be helpful.

            18                DR. TAMMINGA:  I would add a recommendation for

            19    a dose escalation study above a 160 milligrams.

            20                Dr. Hamer.

            21                DR. HAMER:  As long as we're talking about

            22    labeling and notwithstanding the fact that I abstained on

            23    the safety vote, Dr. Rodriguez used the phrase "label

            24    fatigue."  That was you, right?

            25                DR. RODRIGUEZ:  Yes.

                                                                          270

             1                DR. HAMER:  Which I actually thought was a

             2    wonderful phrase.  I wonder if there's any evidence,

             3    though, that the initial language in a label, when a drug

             4    is first approved, is somehow intended to better than these

             5    repeated changes, "Dear Doctor" letters, and so on, so that

             6    notwithstanding label fatigue, if the label is sort of

             7    written strongly in the first place, that will shape the

             8    behavior on the part of the physician to prescribe it.

             9                DR. RODRIGUEZ:  We don't have information on

            10    that, but it's certainly something that the sponsor can be

            11    encouraged to look at.

            12                DR. TAMMINGA:  Dr. Cook.

            13                DR. KORVICK:  Well, I think, just to follow,

            14    just to make another statement, I agree with Dr. Rodriguez,

            15    but I think it also impacts the kind of marketing that the

            16    company can do, because that's based on the language that's

            17    in the label, which may turn --

            18                DR. COOK:  I'm sorry.  I want to make a very

            19    strong plea for patient package inserts and any other

            20    approaches.  Obviously, I know that NAMI and other groups

            21    will be effective in this way and would encourage the FDA

            22    to work with groups like NAMI.

            23                The more we educate the patients and their

            24    families, the more that we'll have another safeguard in

            25    place there.

                                                                          271

             1                DR. WINOKUR:  Just to repeat the same theme

             2    that we've been talking about, but now we're talking about

             3    labeling, I think the fact that it's been clearly

             4    acknowledged that we don't have information about additive

             5    effects with other drugs that could affect QTc, we just

             6    don't have information about that, and that totally changes

             7    how we would feel about, you know, the safety potential

             8    needs to be clearly communicated.

             9                DR. TAMMINGA:  Dr. Malone, have all of your

            10    caveats been attended to in what people have been saying or

            11    would you like to add something?

            12                DR. MALONE:  Well, I'm a child psychiatrist, so

            13    clinically, I see drugs given to children a lot.  What I

            14    see happening is as soon as a drug hits the market, a lot

            15    of children end up on the drug, and I think that's a

            16    particular concern with ziprasidone.

            17                So if somehow the insert or the advertising

            18    would strongly indicate that it hadn't been tested in

            19    children very well, and that we don't know what the QTc

            20    effects will be in children.

            21                DR. TAMMINGA:  We might want to recommend

            22    studies in children.

            23                DR. MALONE:  Yes.  I would also want to

            24    recommend studies in children, but that could take awhile

            25    to get done, and by the time that gets done, if the drug's

                                                                          272

             1    on the market, it could have been prescribed many times.

             2                DR. HAMER:  I do think the labeling ought to

             3    strongly indicate the potential risks associated with

             4    prolonged QTc intervals, regardless of how well that's

             5    quantified and how well you all understand them.

             6                We haven't yet talked about one of the other

             7    questions, which is, what prominence should the risk be

             8    given in the labeling, and I'm not at all sure that this

             9    really requires a black box warning, but the warnings

            10    certainly needs to be there.

            11                DR. TAMMINGA:  What other recommendations would

            12    people give about a black box or a warning statement?

            13                Dr. Moss.

            14                DR. MOSS:  Well, it's not addressing exactly

            15    that question, but I do feel it's important to get higher

            16    doses.  I think it's really critical.  It's surely going to

            17    be used in higher doses, above a 160 milligrams, and so

            18    they have some data on 200 milligrams, and it would seem to

            19    me that they ought to look at some higher doses just to

            20    make sure that there in fact is a plateau.  That would be

            21    extremely reassuring with regard to the QT interval

            22    question.

            23                DR. TAMMINGA:  Dr. Malone.

            24                DR. MALONE:  How does a black box affect how

            25    the drug is advertised?  I mean, what patients or

                                                                          273

             1    physicians are often influenced by is by drug reps coming

             2    around and leaving advertisements.

             3                I don't think very many people read the drug

             4    inserts or the PDR.  So that the most influential thing is

             5    the advertising, and I'm not sure how any of these things

             6    influence what is written in the advertisement.

             7                DR. TAMMINGA:  Dr. Laughren or Dr. Katz.

             8                DR. KATZ:  Unfortunately, I don't know exactly

             9    either, but I know that if there's a black box, it

            10    certainly has an effect.  It's got to be in the ads.  It's,

            11    I think, got to be on anything that is handed out that's

            12    imprinted with the name, this sort of thing.

            13                There are definitely more requirements for a

            14    drug vis a vis advertising and promotion if it has a box

            15    warning.

            16                DR. LINDENFELD:  I would think at least you'd

            17    want to have a strong warning that the drug right now

            18    should not be used with other drugs that are known to

            19    prolong the QT interval with what we know now. I  would

            20    think that would be a very important and strong warning to

            21    make.

            22                DR. HAMER:  And as Dr. Laughren originally

            23    mentioned perhaps and others, also used with other drugs

            24    that inhibit the cytochrome P450, was it, 1A4, was it?  I

            25    don't know.  But, you know, other drugs that potentially

                                                                          274

             1    could interact with it in terms of inhibition.

             2                DR. OREN:  Dr. Laughren specifically asked if a

             3    compliance study should be required.  I think it would be

             4    to the company's marketing advantage if they sponsored such

             5    a study.  I'm not sure if that needs to be a preapproval

             6    requirement, especially because in many ways, the proof of

             7    the pudding with the drug will be if people in fact are

             8    compliant with it.

             9                Obviously there are problems with labeling

            10    issues, and people have been buying boxes of cigarettes for

            11    30 years that say right out on the box, this will kill you

            12    if you use it, and people still use it.  So labeling is

            13    difficult, but maybe one innovation could be -- and I don't

            14    know if this is currently within the FDA's purview, if

            15    marketing representatives, when talking about the drug,

            16    whether at conventions or in meetings with physicians,

            17    could emphasize the known or the potential risks with QTcs

            18    because certainly hearing a negative from a marketing

            19    representative is a novel feature that might attract

            20    people's attention.

            21                DR. LAUGHREN:  Well, promotion directly follows

            22    from labeling.  So we have a lot of control in what we put

            23    in labeling, and that does influence the promotion.

            24                DR. TAMMINGA:  Dr. Laughren.

            25                DR. LAUGHREN:  Could we have some more

                                                                          275

             1    discussion about some of the other items under Question 4,

             2    first-line versus second-line, and then, there's already

             3    been some comment on a patient medication guide, but I

             4    don't think everyone here's had a chance to comment on

             5    that?  Maybe there's universal agreement on that.  I can't

             6    tell.

             7                DR. TAMMINGA:  The medication guide for

             8    patients was something that Dr. Cowdry in his public

             9    remarks actually recommended, and I don't think that --

            10    there may not be a single physician who wouldn't really

            11    concur with that.

            12                I don't know how much of an innovation that

            13    would be.  Is that common to have patient guides written by

            14    the FDA?

            15                DR. LAUGHREN:  It's more common.  I mean, we're

            16    using them more and more, and again the idea is to provide

            17    key information to patients and their families, to guide

            18    them in their use of the drug, and what they should be

            19    telling their physicians about, you know, their other

            20    medications and perhaps other conditions they may have that

            21    may be influenced, you know, by interacting with the drug

            22    in some way.

            23                So more and more, we're using those when

            24    there's something useful that can be conveyed that would

            25    impact on their care.

                                                                          276

             1                DR. TAMMINGA:  I think what's particularly

             2    fortunate about that now is that the National NAMI has

             3    actually initiated a program to have consumers and families

             4    become more informed and become more active in these kinds

             5    of issues.

             6                Dr. Cook.

             7                DR. COOK:  There's a particular point to

             8    educate about in this case, and this comes back to what Dr.

             9    Cowdry said.  There are some things patients need to know

            10    to call the physician immediately or head to the ER right

            11    away, and others that they need to know, well, that's

            12    tough, kind of stick it out.

            13                One of my concerns is by the history of these

            14    medications, patients may have actually gotten used to the

            15    idea that lightheadedness is okay and actually counseled,

            16    oh, you're going to feel lightheaded from this medication,

            17    but in this setting, obviously not all lightheadedness is a

            18    severe event, but it may be a prelude to a fatal

            19    arrhythmia.  Education of what it is and how to describe it

            20    to your physician would be helpful.

            21                DR. TAMMINGA:  Dr. Marder.

            22                DR. MARDER:  What would be most useful would be

            23    a patient information which wasn't specific to ziprasidone,

            24    but that related to antipsychotic drugs, and that had the

            25    advantage, you know, the advantages and disadvantages of

                                                                          277

             1    the different drugs rather than a specific one for

             2    ziprasidone.

             3                Now, that may be difficult to do, and it's a

             4    big leap forward to start with ziprasidone, but I think in

             5    the long run, it would be most useful to have it for this

             6    group of compounds.

             7                DR. LAUGHREN:  If we had head-to-head

             8    comparisons of all the drugs that generated good data, then

             9    we could write those kinds of inserts.  I'm not sure that

            10    we're at that point.

            11                DR. TAMMINGA:  Dr. Katz.

            12                DR. KATZ:  Yes.  Not to beat it into the

            13    ground, but before the committee discusses these other

            14    subsections of Question 4, first-line versus second-line,

            15    we've had some discussion about box warning, but I don't

            16    really have a good feel from the committee as to whether or

            17    not people think a box warning specifically is necessary or

            18    not necessary, and Dr. Hamer was pretty clear.  You said

            19    you didn't think it needed to be a box warning.

            20                But I just don't have a sense of the committee

            21    on that specific question.

            22                DR. TAMMINGA:  Dr. Malone.

            23                DR. MALONE:  I was thinking it was necessary. 

            24    I was thinking that a box warning with some of this was

            25    necessary at this point in time at least.

                                                                          278

             1                DR. TAMMINGA:  Would any of the other committee

             2    like to weigh in?  It's really a box warning of a

             3    hypothetical risk?

             4                DR. MALONE:  Well, in my box warning, I would

             5    also put that the effect of QTc in children and adolescents

             6    is fairly unknown, and it is known that it does have a

             7    definite effect in adults, so that there should be extra

             8    caution.

             9                DR. LAUGHREN:  Maybe it would be helpful to

            10    give a little bit of discussion and background on what the

            11    general policy is about when we use the box as opposed to

            12    not using the box.

            13                It's generally for a very serious event, an

            14    event that, you know, we feel very strongly is related to

            15    taking the drug.  Generally, in my experience, it's when

            16    the events, you know, have actually been realized, and

            17    you're more likely to include a box if there's some

            18    important information you can convey in the box that might

            19    prevent the event from happening, if there's some kind of

            20    monitoring or screening or something or some kind of advice

            21    you can give that might help to detect or predict, you

            22    know, prevent the event from happening.

            23                So it's sort of some general background about

            24    when we use boxes.  I mean, just as an example, in this

            25    recent labeling change for thioridazine, we did use the

                                                                          279

             1    black box, but, of course, there, you know, that decision

             2    was in part based on the fact that there have been a number

             3    of post-marketing reports and other literature reports of

             4    actual cases of torsade occurring with thioridazine.

             5                DR. TAMMINGA:  Dr. Katz.

             6                DR. KATZ:  I would just add one other aspect,

             7    which is that not only do we necessarily only restrict it

             8    to cases where we think there's something you can do to

             9    prevent it, but also if we think it's a serious and a

            10    significant enough risk that it might affect your decision

            11    as to whether or not to use the drug in the first place.

            12                DR. TAMMINGA:  One might wonder whether you

            13    could have something like an invisible box that you could

            14    activate whenever there was an event that became apparent.

            15                DR. GRADY-WELIKY:  With the better

            16    understanding of what a black box means, I guess my sense

            17    would be I don't think we know enough right now to make it

            18    a black box warning, that the company hasn't shown us data

            19    that shows any torsade or any significant clinical event

            20    based on the QTc interval change.  So I would say no to the

            21    black box.

            22                DR. LINDENFELD:  They also haven't shown you

            23    any data on any other drugs, and I would just be cautious

            24    about -- at least somewhere in there, it would be my strong

            25    feeling that they ought to say something in a very strong

                                                                          280

             1    way about using other drugs that are known to prolong the

             2    QT interval when combined with this, and I think we're also

             3    talking about using this drug by physicians who don't

             4    usually think about prolonging the QT interval, and who

             5    might not be aware of the very large number of drugs or the

             6    fairly large number of drugs that do prolong the QT

             7    interval.

             8                I think while we don't know the precise risk,

             9    and it may be very low with this drug alone, most of us

            10    would guess that the risk would go up substantially when

            11    combined with other drugs that are known to prolong the QT

            12    interval.

            13                DR. OREN:  This comment is directed

            14    specifically and only to the black box question.  I think

            15    that the only places we see black boxes are in the obituary

            16    sections of the newspaper as well as in the PDR, and I

            17    think that without that level or near that level of danger,

            18    we would be risking the situation of crying wolf and

            19    causing label fatigue if we used a black box prematurely.

            20                I think all of the warnings and all of the

            21    concerns that have been expressed here should be in the

            22    labeling and in the education, but I would personally

            23    encourage holding off on the black box at this point.

            24                DR. COOK:  Okay.  I'm not that strongly in

            25    support of the black box, but I moved in that direction

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             1    with the idea that basically relates to what's happened

             2    with thioridazine.  It's going to be a lot harder, I think,

             3    to make an impression with the black box after years of not

             4    having it and then moving toward having it.

             5                It also shows that perhaps the only difference

             6    between -- and I know there's some other quantitative

             7    differences, but they're not sufficiently reassuring to me. 

             8    The biggest difference between sertindole, thioridazine and

             9    this medication is that we have post-marketing data that

            10    showed the deaths.

            11                So I'm coming back to your comment that

            12    although we could be reassured by the mortality data, that

            13    without the post-marketing data, we have a drug that

            14    prolongs QT, which may be a severe risk, and we should tell

            15    people that up front.

            16                Now, if it turns out to be unwarranted, I'd be

            17    much more feeling like people's behavior could change in

            18    the easing-up side than the tightening-up.  I'm not a 100

            19    percent on this, but that's sort of how I lean on it.

            20                DR. TAMMINGA:  Dr. Katz.

            21                DR. KATZ:  Well, there are, I think, other

            22    differences between this drug and sertindole, other than

            23    the post-marketing reports, which is that about 7 or 8

            24    percent of patients in that development program had QTcs

            25    greater than 500 milliseconds, and the mean increase in QTc

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             1    was greater on certain as it is here.  But, right, there

             2    were no other cases.

             3                DR. WINOKUR:  Just to weigh in, since we're

             4    kind of informally polling, I'm not in favor of the black

             5    box.  I agree with the gist of the comment that you made

             6    before, that we've seen actually quite a bit of data on the

             7    population that's been studied, and then we've also

             8    discussed the importance of the QTc findings and the

             9    vagaries of interpreting that and extrapolating that.

            10                So we certainly need to be attentive to that

            11    and need more data, and again many of us have addressed the

            12    concerns about when other drugs are on the scene, but I

            13    think that's a different type of labeling and advising at

            14    this point than what would be implicated with the black

            15    box.

            16                DR. TAMMINGA:  Dr. Marder.

            17                DR. MARDER:  Well, I'm going to be very

            18    ambiguous in this answer, but I think guiding clinicians to

            19    make sure that patients aren't taking other drugs that

            20    prolong the QT interval and making sure that they're not

            21    using excessive doses, if it takes a black box to save

            22    lives in that particular -- if it does work that way

            23    insofar as the labeling and the advertising, and it would

            24    really save lives by preventing clinicians from doing that,

            25    I could be convinced to support it, and if there was

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             1    something in between, like bold print or something like

             2    that, that would guide clinicians to do that, and that that

             3    had to be part of the marketing of the compound, that would

             4    make me feel better.

             5                DR. KATZ:  There are bolded warnings as opposed

             6    to boxed warnings, which are usually bolded, also.  How

             7    they actually influence anybody's behavior is another

             8    question.

             9                DR. TAMMINGA:  Does the FDA have any ability to

            10    influence something like a company's activity in educating

            11    the physicians during the post-marketing period?

            12                DR. KATZ:  Yes, I think we do.  I think that's

            13    something that could probably be worked out between the

            14    agency and the sponsor.

            15                DR. TAMMINGA:  In this particular situation,

            16    especially as Dr. Lindenfeld pointed out, that this drug

            17    will be used by people not characteristically used to

            18    looking for cardiac abnormalities or changes in cardiac

            19    parameters, it may be that Pfizer could take a lead in

            20    doing some educational work amongst psychiatrists.

            21                DR. ORTIZ:  I think I'm the last one to vote on

            22    the black box, and my feeling is that the incidence of

            23    torsade de pointes and the overdose data don't suggest to

            24    me that a black box is necessary.  But I think a strong

            25    warning is.

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             1                DR. TAMMINGA:  We haven't yet addressed Dr.

             2    Laughren's question about first-line versus second-line

             3    status, and I don't want to really end before we address

             4    that to some degree.

             5                Dr. Marder may be the one amongst us who has a

             6    lot of experience in this area, and you might want to lead

             7    off the discussion.

             8                DR. MARDER:  Well, I was going to ask a

             9    question.  Does first-line versus second-line mean that the

            10    drug should -- one way to interpret it, that the drug

            11    should only be considered after other drugs have been

            12    considered, the other is that this drug should only be used

            13    after other drugs have been shown to have problems.

            14                What's your interpretation of first-line versus

            15    second-line?

            16                DR. KATZ:  Well, I think you can write labeling

            17    any way you want.  So I don't think there is a specific

            18    definition.  I would say in most cases, in my experience,

            19    when we talk about second-line, the labeling says something

            20    along the lines of where other appropriate drugs have

            21    failed, but you could easily say or when the patient's not

            22    a candidate for other available treatments.  So it could be

            23    both.

            24                Usually I think in practice, it's when other

            25    drugs have failed, but you could do it any way you want.

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             1                DR. LAUGHREN:  Very often, the language

             2    includes both failures and patients who can't tolerate

             3    other appropriate drugs.  So if that's what you meant by

             4    it.

             5                DR. KATZ:  Well, that's one way to fail on a

             6    drug, is to not be able to tolerate it, but if you're

             7    asking whether or not you can call second-line, you can

             8    call usage second-line when other drugs haven't been tried,

             9    but you think they're not going to work.  Usually we ask

            10    that the other drugs be tried, if there's no compelling

            11    reason not to.

            12                DR. LAUGHREN:  Actually, if I could just add

            13    another comment, another issue along these lines, when we

            14    make a drug a second-line drug, is the question of whether

            15    or not you actually have evidence that the drug works in

            16    patients who are in some sense refractoried to other drugs.

            17                You know, we have not been, you know, uniform

            18    about requiring that.  For example, the change that we've

            19    just made with the drug thioridazine, we've made it a

            20    second-line drug, but that's clearly in the absence of any

            21    systematically-collected data that it's superior in

            22    patients who've failed in other drugs.

            23                So we could go either way with that, and again

            24    one of the questions that I posed is whether or not you

            25    think, you know, there should be data here on the efficacy

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             1    side to suggest some benefits, you know, over other drugs

             2    in the class.

             3                DR. MARDER:  Let me just put out, it would seem

             4    to me that in healthy individuals, treated at a dose of

             5    about 80 milligrams a day, it hasn't reached the threshold

             6    for me that would make it a second-line drug.

             7                On the other hand, in some settings where

             8    clinicians are treating vulnerable populations and are

             9    escalating the dose, it might not be, but based on that, my

            10    tendency would not be to add the term "second line" but

            11    just make it sure that clinicians as they prescribe it

            12    consider these other problems with the drug.

            13                DR. TAMMINGA:  Dr. Winokur.

            14                DR. WINOKUR:  I feel strongly, based on what

            15    we've had presented and heard, that it should be in the

            16    first line, and I think there are at least a couple of

            17    reasons for that opinion.

            18                First of all, I think that the notion of

            19    showing that a new drug in our field is better than what's

            20    currently out there is a really tough standard, and I would

            21    take almost any therapeutic category and wonder, except for

            22    very selected cases, when and how it's been possible to

            23    show that.

            24                What we've had is a lot of drugs that have been

            25    shown to be comparably effective, but once they're out

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             1    there, as we know clinically, we often find they have great

             2    utility in selected niches, but it's kind of at a different

             3    phase.

             4                The drug and our understanding of how to use it

             5    appropriately will be greatly disadvantaged if it's

             6    immediately relegated to second-line status, especially

             7    when we've seen data to at least equate it to standard

             8    accepted first-line drugs.  We have no reason to feel that

             9    from an efficacy perspective, it's inferior, and I think we

            10    may learn over time about ways that it's particularly

            11    clinically valuable, and so the only additional reason to

            12    put it in the second-line status is, in my understanding of

            13    that, if there were health concerns that ought to cause it

            14    to be really held back, and we've already kind of had that

            15    discussion.

            16                DR. TAMMINGA:  Dr. Rudorfer.

            17                DR. RUDORFER:  Yes, I agree.  I think it would

            18    be a mistake to force people to start off on the wrong

            19    foot, to have an unfortunate experience with a different

            20    drug first, but I think our efforts should be directed at

            21    alerting clinicians that thoughtfulness is required to use

            22    this drug, that it just shouldn't be casually introduced

            23    because it's the newest thing around.

            24                DR. TAMMINGA:  Anybody else want to weigh in on

            25    the first- or second-line question?  Dr. Ortiz.

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             1                DR. ORTIZ:  Yes.  I think I'd agree that the

             2    data that we've been presented and the information

             3    certainly makes it a very reasonable first-line choice.

             4                DR. TAMMINGA:  I wonder if there might be

             5    additional comments on the other topic that Dr. Laughren

             6    brought up about whether or not we would recommend that the

             7    company look for a special niche or a special treatment

             8    group where efficacy was superior.

             9                When I was looking through some of the initial

            10    material, it really wasn't in the neuroleptic refractory

            11    group that it seemed to me there was some indication that

            12    ziprasidone might be superior but rather in cognitive

            13    dysfunction, and one might wonder whether a recommendation

            14    to look for superiority in the area of the treatment of

            15    cognitive dysfunction.

            16                I don't know why one -- the company's probably

            17    in the process of doing it, but whether something like that

            18    might be useful.

            19                DR. GRADY-WELIKY:  It's not exactly a comment

            20    on what you just asked, but in terms of recommendations for

            21    additional studies, post-approval, if that's the decision,

            22    one would be to look more closely at women receiving

            23    ziprasidone.

            24                I think Dr. Lindenfeld brought up the idea, and

            25    it's in the back of the material, that women are more

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             1    likely to have prolonged QTcs, and the numbers were fairly

             2    small, at least in the 054 study.  So that would be one

             3    suggestion.

             4                I think the other thought would be to look at a

             5    broader group, as Dr. Cook raised, in terms of the ethnic

             6    groups.  I think the company did a great job at having a

             7    large number of non-Caucasian subjects, but it's not clear

             8    who's in that other category, and we do know that there's a

             9    lot of differences across ethnic groups, particularly in

            10    Asian and Hispanic populations.

            11                DR. TAMMINGA:  Dr. Winokur.

            12                DR. WINOKUR:  I think early in his

            13    presentation, Dr. Harrigan did a very nice job of pointing

            14    out that as is true with other of the atypicals, this drug

            15    has a very unique pharmacology that may lend itself to

            16    notions about specific utility and efficacy, and I'm sure

            17    between the company's efforts and very capable clinicians

            18    out there in the field working with the populations, there

            19    will be a lot of ideas about how to apply that.

            20                But, you know, again the point is that I think

            21    we can really think about looking at the match of clinical

            22    needs and opportunities and pharmacological distinctiveness

            23    that may help to get past the sort of broader studies that

            24    have to be done to bring things to this point, so we can

            25    vote on the first question that we had to vote on but can't

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             1    really get to the point of kind of dissecting out the kinds

             2    of questions that that agenda would raise.

             3                DR. TAMMINGA:  Do you think that those studies

             4    might be driven by the field, indeed not be required by the

             5    FDA?  I would ask Dr. Laughren and Dr. Katz if they have

             6    any more questions that they'd like the committee to

             7    address or if you think that we've covered our pink sheets.

             8                DR. LAUGHREN:  I guess my final question would

             9    be again on the first study that was proposed here, whether

            10    or not the committee thinks that there should be strong

            11    encouragement or requirement that some kind of study be

            12    done to try and come up with an estimate of what the risk

            13    might be, some kind of quantitative estimate, recognizing

            14    that that's perhaps a very difficult study to do, but it's

            15    an unknown here, and it's possible that we may never or not

            16    for a long time know the answer to that question, if we

            17    were to rely solely on post-marketing reporting, because

            18    unless a drug that has some marginally greater effect on

            19    the QT results in a lot of cases of torsade, we're not

            20    likely to pick up a small differential increase in post-

            21    marketing reporting of sudden deaths.

            22                So that's just sort of, you know, one remaining

            23    question.  How strongly should we push for that kind of

            24    study, again recognizing it's a difficult study to do?

            25                DR. TAMMINGA:  Dr. Califf, who was one of the

                                                                          291

             1    people who seemed a strong supporter of that, is not here. 

             2    Maybe Dr. Moss or Dr. Lindenfeld would like to lead off on

             3    this question.

             4                DR. LINDENFELD:  I'd be interested in Dr. Moss'

             5    comments, too, but I think it would be important to have

             6    additional data on people who are on a substantial number

             7    of other medications, particularly some of those ones that

             8    increase the QT interval a small amount but do affect the

             9    QT interval.

            10                DR. MOSS:  I would agree with that.  I

            11    personally think the most important thing is to do just

            12    simply a very simple higher dose there.  I would be very

            13    reassured if higher dose did not increase the QT interval. 

            14    I think that this would bode very, very well.

            15                I think to require outcome events, that's going

            16    to get reported anyway.  They should be encouraged to, but

            17    I don't know how you can actually make that a requirement.

            18                DR. LAUGHREN:  So you would be reassured by

            19    just a better exploration of the dose-response for QT,

            20    basically?

            21                DR. MOSS:  I would, indeed.  That would be very

            22    reassuring.  I think the data they've presented has been

            23    very, very solid, but the one area that we don't know, we

            24    just have really a small dose above what is the 160

            25    milligram dose, and to have a 240 or 300 milligram dose in

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             1    a relatively small number of patients, just to see if there

             2    is a dose effect, if in fact there's not, that would be

             3    reassuring.

             4                DR. TAMMINGA:  If there aren't any more

             5    comments from the committee or questions from the FDA, I'll

             6    take the prerogative to thank the committee for working

             7    hard all day, to thank Pfizer for presenting, and for the

             8    FDA for inviting us all.

             9                Thank you.

            10                (Whereupon, at 4:56 p.m., the meeting was

            11    adjourned.)

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