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                   UNITED STATES OF AMERICA

            DEPARTMENT OF HEALTH AND HUMAN SERVICES

                 FOOD AND DRUG ADMINISTRATION

            CENTER FOR DRUG EVALUATION AND RESEARCH

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   CARDIOVASCULAR AND RENAL DRUGS ADVISORY COMMITTEE

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                           92nd MEETING

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                             THURSDAY
                           MAY 24, 2001

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             The Committee met at 8:30 a.m. in the Jack
Masur Auditorium, Building 10, Clinical Center, National
Institutes of Health, 9000 Rockville Pike, Bethesda,
Maryland, Dr. Jeffrey Borer, Acting Chairman, presiding.

PRESENT:

JEFFREY BORER, M.D.                    Acting Chairman
MICHAEL F. ARTMAN, M.D.                Member
RALPH D'AGOSTINO, PhD                  Temporary Voting Member
ROBERT FENICHEL, M.D.                  Temporary Voting Member
THOMAS FLEMING, PhD                    Member
THOMAS GRABOYS, M.D.                   Member
ALAN T. HIRSCH, M.D.                   Member
MARVIN KONSTAM, M.D.                   Temporary Voting Member
JOANN LINDENFELD, M.D.                 Member
STEVEN NISSEN, M.D., FACC              Member
ILEANA PINA, M.D.                      Member
JOAN C. STANDAERT                      Executive Secretary




                            NEAL R. GROSS
                    COURT REPORTERS AND TRANSCRIBERS
                        1323 RHODE ISLAND AVE., N.W.
(202) 234-4433         WASHINGTON, D.C. 20005-3701     www.nealrgross.com
                                                                         2
                          I-N-D-E-X

                                                              Page

Open Public Hearing:

Sidney M. Wolfe, M.D.                                               7
Director, Public Citizen's Health Research Group

Edward J. Parr, Jr., Esq: Comments Franz H.                       20
Messerli, M.D.

Response to Citizen's petition regarding
NDA 19.668, Cardura, Pfizer Inc.:

PRESENTATIONS:

Introduction: Salvatore J. Graziano                               28

Dr. L. Krakoff, Englewood Hospital and                            29
Mt. Sinai School of Medicine

Jeffrey A. Cutler, M.D., M.Ph, Director                           53
Clinical Application and Prevention Program,
NHLBI, NIH

Pfizer's Response to ALLHAT:         Introduction               109

Doxazosin Data Review, Dr. Patricia Walmsley                    112

Non-Clinical Trial Post-Approval, Dr. Dieck                     131

Pfizer Comments on ALLHAT                                       135

Committee Questions, Discussion and                             161
Recommendations:
Committee Reviewer: Dr. Thomas Fleming, PhD

FDA Invited Guests:

Dr. R. D'Agostino, Boston University

Dr. R. Fenichel, Washington, D.C.

Dr. M. Konstam, New England Medical Center

NIH Guest: Dr. B. Davis, University of Texas,
Director of ALLHAT Clinical Trials Center



                         NEAL R. GROSS
                 COURT REPORTERS AND TRANSCRIBERS
                     1323 RHODE ISLAND AVE., N.W.
(202) 234-4433      WASHINGTON, D.C. 20005-3701     www.nealrgross.com
                                                                                  3
1                         P-R-O-C-E-E-D-I-N-G-S

2                                                           (8:37 a.m.)

3                     ACTING CHAIRMAN BORER:            Good morning.             I

4    would like to open the 92nd meeting of the Cardiovascular

5    and Renal Drugs Advisory Committee today, Thursday, May

6    24th.

7                     Before we open the meeting to public comment,

8    the Executive Secretary of the Committee will read the

9    conflict of interest statement.

10                    MS. STANDAERT:       The following announcement

11   addresses the issue of conflict of interest with regard

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

13   even the appearance of such at this meeting.

14                    Based on the submitted agenda for the meeting

15   and all financial interests reported by the Committee

16   participants, it has been determined that all interests

17   in firms regulated by the Center for Drug Evaluation and

18   Research present no potential for an appearance of a

19   conflict of interest at this meeting, with the following

20   exceptions.

21                    In accordance with 18 U.S.C. 208(b)(3), full

22   waivers have been granted to Doctors Thomas Fleming, Steve

23   Nissen, Ralph D'Agostino, Robert Fenichel, and Marvin

24   Konstam, which permits them to participate in all official

25   matters concerning the citizens' petition as it relates

                                 NEAL R. GROSS
                         COURT REPORTERS AND TRANSCRIBERS
                             1323 RHODE ISLAND AVE., N.W.
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                                                                                    4
1    to Cardura and the ALLHAT trial.

2                     A copy of the waiver statement may be

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

4    Freedom of Information Office, Room 12A-30 of the Parklawn

5    Building.

6                     In addition, Dr. Nissen's institution, the

7    Ohio State University's Cleveland Clinic, is involved

8    in unrelated studies sponsored by Pfizer.                   Dr. Nissen

9    has also presented lectures for Pfizer unrelated to the

10   product, competing products, or issues addressed in the

11   citizens' petition.

12                    Dr. Fleming's institution, the University

13   of Washington's Department of Biostatistics, has received

14   an endowed student fellowship grant from Pfizer.

15                    Dr. Konstam's daughter has been offered a

16   summer internship from Pfizer to work on women's health

17   initiatives.

18                    Although these interests do not constitute

19   financial interests in the particular matter within the

20   meaning of 18 U.S.C. 208, they could create the appearance

21   of     a    conflict.    However,      it   has    been   determined,

22   notwithstanding these interests, that it is in the

23   agency's best interest to have Doctors Fleming, Nissen

24   and Konstam participate in the Committee's discussions

25   concerning the citizens' petition as it relates to Cardura

                                 NEAL R. GROSS
                         COURT REPORTERS AND TRANSCRIBERS
                             1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433         WASHINGTON, D.C. 20005-3701        www.nealrgross.com
                                                                                 5
1    and the ALLHAT trial.

2                     In the event that the discussions involve

3    any other products or firms not already on the agenda

4    for which an FDA participant has a financial interest,

5    the participants are aware of the need to exclude

6    themselves from such involvement, and their exclusion

7    will be noted for the record.

8                     With respect to FDA's invited guests, Dr.

9    Barry Davis has reported interests which we believe should

10   be made public to allow the participants to objectively

11   evaluate his comments.

12                    Dr. Davis would like to disclose that he

13   serves as a consultant for Pfizer as a member of one of

14   their       data safety monitoring boards, and for Tapp

15   Pharmaceuticals, a partnership of Abbott, on one of their

16   advisory committees.

17                    With respect to all other participants, we

18   ask in the interest of fairness that they address any

19   current or previous financial involvement with any firm

20   whose products they may wish to comment upon.

21                    That concludes the conflict of interest

22   statement.

23                    I just also wish to make a correction to those

24   meeting dates which was distributed at the front table.

25    The meetings for the Cardiovascular and Renal Drugs that

                                 NEAL R. GROSS
                         COURT REPORTERS AND TRANSCRIBERS
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                                                                                        6
1    have been proposed for the coming year are August 9-10

2    and October 11-12, not the dates that were indicated on

3    that distribution.             That is my final statement.               Thank

4    you.

5                           ACTING CHAIRMAN BORER:           Thank you.        This

6    morning          the    Cardio-Renal      Advisory      Committee       is    to

7    consider          potential        labeling    changes      for   the     drug

8    doxazosin, based on the currently available data from

9    the ALLHAT study.

10                          It is a somewhat unusual circumstance for

11   us to be involved.                 As a result and because there are

12   so many people involved, I am going to have to be certain

13   that everyone understands that, if you are going to speak,

14   you are going to have to be recognized by the Chair.

15   We need to be sure that we can stay on focus here.

16                          For   the    Committee,     during     the    initial

17   presentations, I hope we will limit our comments to

18   questions of clarification, but the questions from the

19   FDA should give us ample opportunity to discuss the merits

20   of the data and the inferences we can draw from them.

21                          The initial portion -- The meeting is open

22   for public comment, and we have two members of the public

23   who have requested time to speak, first Dr. Sidney Wolfe

24   who is the director of the Public Citizen Health Research

25   Group, and then Dr. Franz Messerli.                   We will start with

                                        NEAL R. GROSS
                              COURT REPORTERS AND TRANSCRIBERS
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                                                                                          7
1    Dr. Wolfe.

2                         DR. WOLFE:      Thank you.      In the spirit and,

3    I guess, law of full disclosure with respect to financial

4    conflict of interest, I would like to state that we do

5    not take any money from the pharmaceutical industry and

6    have not, and don't expect to.

7                         You are being asked to recommend action to

8    the      FDA       based   on    a    published       analysis         of     the

9    Antihypertensive and Lipid Lowering treatment to prevent

10   Heart Attack Trial (ALLHAT).                 This trial compared the

11   alpha-blocker drug doxazosin (Cardura), produced by

12   Pfizer           to the generically available and much less

13   expensive treatment chlorthalidone, a member of the

14   thiazide family of diuretics or "water pills" for the

15   control of high blood pressure.

16                        I would just like to interject -- This is

17   not in the written statement -- that this trial was

18   designed to pick drugs that were typical of the classes

19   and findings, whether they were with respect to diuretics

20   or,      in      this   case,   alpha-blockers,            I   believe,       are

21   applicable to the whole class.                   I think that was the

22   intention of the trial, not to come up with conclusions

23   that were limited only to chlorthalidone but not to

24   hyperchlorothiazide or, conversely, only limited to

25   doxazosin.

                                     NEAL R. GROSS
                             COURT REPORTERS AND TRANSCRIBERS
                                 1323 RHODE ISLAND AVE., N.W.
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                                                                                      8
1                        This analysis found that patients taking

2    Cardura          were   almost    twice     as   likely    as   those       on

3    chlorthalidone to be hospitalized for congestive heart

4    failure.          The total incidence was actually twice as high,

5    had 25 percent more cardiovascular events, and had a

6    significantly elevated risk of stroke.

7                        Patients      who   had    originally   been       given

8    Cardura in the study greatly benefitted from being taken

9    off the drug in order to avoid the excess risks of heart

10   failure, stroke and other cardiovascular events when the

11   above results were made known in January 2000.

12                       Now almost 17 months later, thanks in part

13   to a massive misinformation and stonewalling campaign

14   by Pfizer, coupled with inadequate action by the FDA,

15   most of the hundreds of thousands of Americans still using

16   the drug have not had the advantage of stopping Cardura

17   and switching to other safer and usually less expensive

18   drugs such as diuretics and beta blockers.

19                       Equally appalling is the likelihood that

20   many patients not previously on Cardura before the results

21   of ALLHAT were known have started using the drug, despite

22   the dire warnings of that study.

23                       As physicians being asked by patients to

24   recommend drugs for the treatment of hypertension, which

25   affects me as well as the Advisory Committee and many

                                      NEAL R. GROSS
                             COURT REPORTERS AND TRANSCRIBERS
                                 1323 RHODE ISLAND AVE., N.W.
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                                                                                 9
1    others, it would be highly unlikely for you or for me,

2    knowing what we now know, to recommend an alpha blocker

3    such as Cardura as a first choice drug.                              The

4    fact that it is still in the now outdated JNC-6 listed

5    as a first choice drug really speaks to the fact that

6    that has not been revisited since this study came out.

7     It is inevitable when the next revision of JNC-6 occurs

8    that this will no longer be listed as a first choice drug.

9                     More likely, we would relegate it to a fourth

10   or lower choice drug, only after adequate trials of

11   diuretics, beta blockers, or ACE inhibitors, alone and

12   in combination, had been tried without success.                If this

13   is what we do for patients who consult us, what can be

14   done so that this evidence-based prescribing decision

15   will be made by other physicians and their patients and

16   that those already on alpha blockers will be switched

17   to other drugs?

18                    The task at hand is for you to delineate a

19   series of actions which the FDA can take to maximize

20   the odds that few, if any, newly diagnosed hypertensive

21   patients are started on alpha blockers such as Cardura

22   and that most, if not all, hypertensive patients now using

23   such drugs are safely switched to other agents.

24                    One year ago in the May 2000 issue of our

25   monthly newsletter Worst Pills News, which is a monthly

                                 NEAL R. GROSS
                         COURT REPORTERS AND TRANSCRIBERS
                             1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433         WASHINGTON, D.C. 20005-3701     www.nealrgross.com
                                                                                10
1    update on our book Worst Pills, Best Pills, we warned

2    our 120,000 subscribers a year ago against the use of

3    Cardura and other alpha blockers, based on the just

4    published findings of the ALLHAT study.

5                     The citizen petition that has been one of

6    the precipitating events for this hearing asks that:

7    (1) the FDA require Pfizer to notify all patients in the

8    U.S. who have taken or are taking Cardura to control their

9    blood pressure and that the FDA issue a press release

10   regarding the interim results of ALLHAT; (2) that FDA

11   require a boxed warning in the professional product

12   labeling or patient insert for Cardura and its generic

13   versions informing prescribers of the ALLHAT interim

14   results; and (3) that if deemed necessary by the FDA,

15   additional labeling changes for Cardura that may include

16   changes in approved uses, warnings, precautions and

17   contraindications.

18                    We would add to that a number of things, but

19   one of which is that, although this arose in litigation

20   concerning       doxazosin    and    Cardura,      these     should        be

21   applicable to all the drugs in the class.

22                    Public    Citizen       strongly      supports          the

23   fundamental      intention      of   this    petition      to     require

24   notification of physicians and patients of the ALLHAT

25   results, but although we support the principle behind

                                  NEAL R. GROSS
                         COURT REPORTERS AND TRANSCRIBERS
                             1323 RHODE ISLAND AVE., N.W.
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                                                                                       11
1    this petition, as it stands it will not achieve the desired

2    goal.

3                         Therefore, we are urging the Committee to

4    make additional recommendations to the FDA such as a

5    mandatory FDA approved patient guide (Med Guide), which

6    FDA has the authority for, to be dispensed with                       the drug.

7     Before          discussing    the    details        of    this     and      other

8    recommendations, we would like the Committee to first

9    consider Pfizer's role in stonewalling on the ALLHAT

10   results.

11                        You have this in your file, and I will just

12   mention for about a minute some of the more disturbing

13   findings.

14                        Pfizer contributed financially to the ALLHAT

15   study,           ostensibly   to     answer     an    important          medical

16   question:          Which antihypertensive drugs are the safest

17   and most effective in producing clinically meaningful

18   outcomes for patients?

19                        Pfizer did not like the answer, and the

20   petition's authors provide exquisite documentation of

21   corporate "damage control" to protect Cardura, one of

22   Pfizer's "Magnificent 7" drugs, a $800 million market.

23    The      company's       scripting      of   sales        representatives'

24   elusive responses to ALLHAT questions, broken down by

25   which subspecialty the doctor was in, coupled with the

                                     NEAL R. GROSS
                             COURT REPORTERS AND TRANSCRIBERS
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                                                                           12
1    revelation       that    sales     representatives        were      not

2    proactively discussing ALLHAT, is devoid of scientific

3    and medical ethics.

4                     Because it is clear that Pfizer cannot be

5    relied upon to provide scientifically accurate, useful

6    information to patients or physicians, this Committee

7    and the FDA must take a much more proactive role to ensure

8    that medical professionals and the public receive such

9    drug information.

10                    The first topic -- I'm just going through

11   the sequence of the possible ways -- and I say ways,

12   because I think all of them need to be used:              FDA press

13   releases.

14                    We support FDA's use of press releases or

15   public health advisories to inform the public immediately

16   about new drug safety warnings.             However, at the level

17   of the individual patient, this method of informing the

18   public relies primarily on chance and is available for

19   only a short period of time.              When you take a look at

20   how long articles, news articles, appear after such a

21   warning, not surprisingly, it occurs for a while.                 It's

22   a good first alert, but it isn't sustained.

23                    While   serving     as    an   initial   alert,           a

24   sustained effort to change the opinions of doctors and

25   patients must include permanent educational efforts

                                NEAL R. GROSS
                        COURT REPORTERS AND TRANSCRIBERS
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                                                                                             13
1    directed at both groups, as will be discussed.

2                          Safety labeling changes:                  We agree with the

3    petitioners that a black box warning should be required

4    in the professional product labeling for brand and generic

5    versions of Cardura and, we would add, all alpha blockers,

6    alerting health professionals of the ALLHAT results.

7    However, we would like this Committee to note that there

8    is a growing body of published evidence that safety

9    labeling         changes         to    a   drug's     professional             product

10   labeling alone do not protect a large proportion of

11   patients from preventable drug induced injury or death.

12                         The      concurrent       use        of     the       withdrawn

13   antihistamine                  terfenadine            or         Seldane            with

14   contraindicated antibiotics and antifungal drugs before

15   and after safety labeling changes and the issuing of "Dear

16   Doctor" letters has been assessed in several studies.

17                         A     retrospective        review         of   computerized

18   pharmacy claims from a large New England health insurer

19   found       that,         despite      significant         declines         following

20   reports          of   life      threatening       drug       interactions             and

21   additional warnings in the professional product labeling,

22   concurrent            use     of      terfenadine      and       contraindicated

23   antibiotics and antifungal drugs continued to occur.

24                         In a couple of studies, about a third of

25   patients who were given, for the sake of the study,

                                           NEAL R. GROSS
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                                                                                 14
1    prescriptions for both terfenadine and a contraindicated

2    drug had them filled, despite all of this doctor and

3    pharmacist directed publicity.

4                     Using pharmacy claim data from 1988 through

5    1994 from state Medicaid programs in Michigan and Ohio,

6    it was found that the concomitant use of ketoconazole

7    and erythromycin with terfenadine had fallen by 80

8    percent, but that means 20 percent still doing it.                          IN

9    a retrospective study of pharmacy claims, it was found

10   that       co-prescription     of    terfenadine        with         either

11   erythromycin or ketoconazole continued to occur after

12   regulatory action.

13                    The FDA reviewed reports of lactic acidosis

14   associated with the use of the diabetes drug metformin

15   (Glucophage) occurring from May 1995 through June 1996,

16   the drug's first year on the market in the U.S.                      Of the

17   47 patients with a confirmed diagnosis of the adverse

18   drug reaction, 43 or 91 percent had one or more risk

19   factors for lactic acidosis that were listed in the drug's

20   professional product labeling at the time of its approval.

21                    Recently,    the   effect     of     the     June      1998

22   regulatory actions in the form of a "Dear Doctor" letter

23   and additional safety labeling changes were assessed on

24   the       contraindicated     prescribing       of     cisapride            or

25   Propulsid, which this Committee is very familiar with.

                                 NEAL R. GROSS
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                                                                                   15
1       At one state Medicaid site surveyed for the study, in

2    the year prior to new warnings about the drug, the use

3    of cisapride was contraindicated in 60 percent of those

4    for whom the drug was prescribed.                    In the year after,

5    the proportion of contraindicated patients prescribed

6    this drug had decreased to only 58 percent.

7                     The      authors       of     the    study       published

8    concluded:       "The FDA's 1998 regulatory action regarding

9    cisapride use had no material effect on contraindicated

10   cisapride use.          More effective ways to communicate new

11   information about drug safety are needed."

12                    We strongly agree with this conclusion,

13   particularly       as     it     relates     to   providing       effective

14   communication to patients.             The FDA has had the authority

15   since June 1999 to mandate the distribution of Medication

16   Guides by pharmacists for five to ten drugs per year that

17   pose, quote, "a serious and significant public health

18   concern."

19                    Cardura         and   the    other       alpha    blockers

20   certainly        fit      this     category       when      compared          to

21   chlorthalidone for the treatment of hypertension.

22                    So we get to this issue of medication guides.

23    The only way to ensure that patients using Cardura are

24   notified of the ALLHAT results is for the FDA to require

25   a Medication Guide for the drug that reflects these

                                    NEAL R. GROSS
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                                                                               16
1    results in non-technical language and places the risks

2    in a context that can be used by patients.

3                     Many people believe that, when you go to a

4    pharmacy to get a prescription filled, the piece of paper

5    you get is regulated.            It is clearly unregulated.               It

6    does not emanate from any FDA approval process.                   It does

7    not emanate from the pharmaceutical company.

8                     It emanates from a small number of companies

9    that generate through computer software labeling for

10   patients, which we have done a couple of studies on two

11   classes of drugs there and find there's a lot of

12   incomplete, misleading, out-of-date information in them.

13    So that's not what we are talking about.

14                    We    are    talking      about    an   FDA   approved

15   Medication Guide, which it has the authority to do.

16                    It's interesting.          Back about 20 years ago

17   when there was a lot of prescribing of progestins for

18   preventing miscarriage after the fall of the estrogens

19   -- those were prescribed.            The required patient labeling

20   had an enormous effect not only on patient behavior but

21   on doctors, because the labeling which patients were going

22   to get, and the doctors knew this, stated essentially

23   this drug does not work to prevent miscarriage; this drug

24   may cause birth defects and so forth.

25                    The knowledge that the patient is going to

                                   NEAL R. GROSS
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                                                                                     17
1    get something, as in the case of these drugs -- this drug

2    is the last recommended drug for hypertension, and knowing

3    that it was the first recommended drug by a physician,

4    I think, would have an enormous impact, coupled with all

5    of the other kinds of things we discussed.

6                       Additional       labeling        and         Med        Guide

7    requirements:         Class labeling for the alpha blockers:

8    We also strongly suggest that the Advisory Committee

9    recommend to the FDA that the black box warning and Med

10   Guide developed for Cardura be the basis for a warning

11   for all alpha blockers -- also, the same is true for the

12   Med Guide -- marketed in the U.S.

13                      This would include, in addition to Cardura

14   and      its     generic   versions,      prazosin        or      Minipress,

15   terozosin (Hytrin), and tamsulosin (Flomax).

16                      Lastly, we also strongly suggest that the

17   Advisory Committee recommend to the FDA that all alpha

18   blockers approved by relegated, in labeling and patient

19   guides, to second, if not last or almost last, line therapy

20   for hypertension.

21                      I have about two minutes left.                I just want

22   to mention a couple of other things.                     One:     In looking

23   again at the extraordinarily well done study called

24   ALLHAT, which I had not looked at for a few months, I

25   noticed that by the end of the four years of the study,

                                   NEAL R. GROSS
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                                                                            18
1    47 percent of the patients originally assigned to the

2    doxazosin group, the alpha blocker group, had received

3    a step two or step three drug.

4                     Since the analysis showing the very striking

5    differences in both heart failure and stroke and a series

6    of other cardiovascular diseases applied to all the people

7    in the trial, one conclusion from that which I think will

8    probably be discussed and analyzed much further is that,

9    not only are these alpha blockers dangerous on their own,

10   as in comparison to chlorthalidone or possibly positively

11   dangers on their own, but even when they are used in

12   conjunction with other drugs which on their own, such

13   as beta blockers, have benefits, the net effects is still

14   a risk.

15                    There will, hopefully, be before too long

16   a stratified analysis that looks at the comparison between

17   those that just at the end were taking doxazosin compared

18   with chlorthalidone and those who at the end had been

19   stepped up to other drugs.             Whether one wants to look

20   at it that the alpha blockers neutralize the beneficial

21   effects of these other step-up drugs or the other way

22   around, the point is that taken in combination with other

23   drugs, which would be a step use as opposed to a primary

24   use for alpha blockers, also seems to be dangerous.

25                    I'd like to thank you for your time, and hope

                                 NEAL R. GROSS
                         COURT REPORTERS AND TRANSCRIBERS
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1    that the Advisory Committee will seriously consider the

2    suggestions that we have made and the suggestions that

3    are in the petition.

4                       I would be glad to try and answer any

5    questions.

6                       ACTING CHAIRMAN BORER:         Thank you very much,

7    Dr. Wolfe.        Again, only if there are clarifications here

8    of statements.           We don't really want to get into a

9    discussion of the merits of the issue.                    I guess we are

10   all set.         Thank you very much.

11                      The next speaker -- Oh, I'm sorry.                             I

12   announced that Dr. Messerli would be speaking, but

13   actually Edward Parr will be presenting Dr. Messerli's

14   comments.

15                      MR. PARR:     Good morning.           I am an attorney

16   from New Orleans, and I am here today, actually, to

17   represent the petitioner.              However, I have been asked

18   to read to you the comments which have been voluntarily

19   submitted to FDA in writing by Dr. Franz Messerli of New

20   Orleans.

21                      Dr. Messerli is the Medical Director of the

22   Division of Research at the Alden-Oxner Foundation

23   Hospital, a practicing cardiologist at the Oxner Clinic,

24   a professor of cardiology at the Tulane Medical School,

25   and was a member of this Advisory Committee from 1986

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1    until 1990.      His comments are as follows:

2                     To     the    Cardiovascular            Drugs    Advisory

3    Committee:       The Food and Drug Administration has been

4    petitioned to revise the labeling of doxazosin.                          As a

5    former member of this Committee, I ask that you consider

6    the following comments as you formulate a recommendation

7    to the agency.

8                     Congestive heart failure (CHF) is a common

9    outcome of hypertensive heart disease.                   In the Framingham

10   cohort more than 90 percent of patients with CHF have

11   a history of hypertension, and longstanding hypertensive

12   cardiovascular disease invariably leads to CHF.

13                    The prevention of CHF is, therefore, one of

14   the      major   therapeutic       goals      in   the      treatment        of

15   hypertension.         All major drug classes, diuretics, beta

16   blockers, ACE inhibitors and calcium antagonists, that

17   the Joint National Committee recommended for initial

18   therapy of hypertension have been shown to reduce the

19   risk of CHF when compared to placebo or active therapy.

20                    Until publication of the first results of

21   the ALLHAT study in March 2000, however, no such data

22   and no morbidity or mortality data were available for

23   the alpha blocker doxazosin, despite the fact that this

24   class of drugs has been promoted and used for the treatment

25   of hypertension for more than 20 years.

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1                      The data from the ALLHAT study published over

2    a year ago indicate the risk of CHF with doxazosin is

3    twice as high as in patients who are treated with a simple

4    diuretic.        Similarly, in the V-HEFT study, treatment with

5    prazosin, another alpha blocker, showed no benefit in

6    patients with CHF.

7                      In numerous drug company sponsored symposia

8    and journal supplements, alpha blockers have been touted

9    as being safer than other antihypertensive drug classes,

10   because alpha blockers not only lower the pressure but

11   had additional benefits in that they improved insulin

12   resistance and dyslipoproteinemia.

13                     Physicians, therefore, have been under the

14   impression that these drugs were particular efficacious

15   for the prevention of hypertensive heart disease, but

16   data from the ALLHAT study attests to the contrary.

17                     This Committee will be asked to make a

18   recommendation to the FDA.             I hope that you will agree

19   with me that changes to the labeling of doxazosin are

20   warranted.

21                     Inasmuch as physicians have been subjected

22   to years of what, in retrospect, must be considered

23   misinformation, it seems only appropriate that they now

24   be made fully aware of the new findings through a labeling

25   change for doxazosin and possibly other alpha blockers.

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1                         As I have stated in an invited editorial in

2    the Lancet, the revised labeling should state that

3    doxazosin, as opposed to other major drug classes, should

4    no longer be used as initial therapy for hypertension

5    and, in addition, doxazosin should be contraindicated

6    in patients with a history of CHF or who are at risk for

7    CHF.       Sincerely yours, Franz H. Messerli, M.D.

8                         ACTING CHAIRMAN BORER:         Thank you very much,

9    Mr. Parr.          Again, are there any required clarifications

10   from the Committee?             If not, thank you very much.

11                        Before we go on to the remainder of the

12   meeting, I received a communication from Dr. Philip

13   Hooper,          Assistant    Clinical      Professor      of   Medicine,

14   University of Colorado Health Sciences Center, who

15   reports that he has recently published an hypothesis on

16   how Cardura might bring about an adverse event on the

17   heart.           This is in a letter to the editor published in

18   the Journal of Human Hypertension 2001, Volume 15, page

19   205.       Copies of this are available at the back desk.

20                        Now we will move on to the presentation of

21   the petition and the information we will receive about

22   ALLHAT.          Before we do, this Committee has been asked by

23   the FDA to provide an advisory opinion about potential

24   labeling changes for doxazosin.                   The information that

25   has been presented to us is unusual for this Committee

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1    in that it really consists of a published paper without

2    the supporting data from a trial that is still ongoing.

3                     So the circumstances are somewhat unusual,

4    and I would like to take a minute to ask for a statement

5    about the specifics of the charge to us from the FDA before

6    we begin these proceedings.

7                     Is Ray Lipicky here?          Ray, can you make some

8    comments about specifically what kind of advice you want,

9    and how -- what form you want it in, and what information

10   you may have that would help us?

11                    DR. LIPICKY:          Well, I don't think this

12   meeting is different from other meetings in the sense

13   that what we want is an evaluation of the data that's

14   available, and whether or not you can draw                 conclusions

15   from the data that is available in order to take some

16   action.

17                    As    you    know,    we    are    sort   of   evidence

18   oriented, and we don't like to take actions when we don't

19   know what action we should take nor what the basis for

20   that action is.

21                    So we've been asked to make a decision from

22   published materials.            You have all of the information

23   that we have with one exception, which I'll show, and

24   we don't know anymore than you do.                 We have not reviewed

25   the subject, because it's not the usual stuff that we

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1    have to review, and we will be very interested in what

2    you say.

3                       The one thing that I can show for the sake

4    of orientation at the very beginning of the meeting is

5    data from the original doxazosin NDA which was approved

6    in 1990.         This is the mean data from two trials that were

7    the major trials in that NDA.

8                       I think you can easily see on the x-axis the

9    dose and on the y-axis the change from baseline placebo

10   corrected, and you see what the dose response looks like.

11    It looks like, when you get to 16 milligrams, it starts

12   having -- it's going to take off.                So that anything below

13   16 milligrams is basically not much drug.

14                      Now as hard as we tried retrospectively

15   looking through the reviews of 1990, it isn't clear that

16   there are any dose limiting side effects.                   So that it's

17   unclear to us at the moment as to why the dose wasn't

18   -- a higher dose wasn't studied or how it was settled

19   that 16 milligrams was the top dose.                 But, clearly, there

20   is a dose response for both systolic and diastolic blood

21   pressure, and it does have postural effects.

22                      As best as we can tell from the reviews,

23   although the data that is presented in tables doesn't

24   support          it,   the    principal       concern      was    postural

25   hypotension,           but   the   actual     incidence     of    postural

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1    hypotension didn't seem to be very dose dependent.

2                      Now with that as a kind of background, I think

3    the process is, as usual, we have treated the citizens'

4    petition as sort of a sponsor.            They are hear.    They will

5    talk.        They will interact, and they will argue, the way

6    in which it usually goes.

7                      So that although it is unusual to have a

8    citzens' petition come to the FDA -- I mean come to the

9    Advisory Committee -- it seemed like this was complicated

10   enough that it was worthy of public discussion with you.

11                     Does that help you, Jeff?

12                     ACTING CHAIRMAN BORER:           I think so.        Are

13   there, again, any clarification type questions from

14   members of the Committee?            Thank you, Ray.

15                     We will move on.      This meeting -- Sorry, Bob.

16                     DR. TEMPLE:        Just one point.          We have

17   addressed in the document the use of published data for

18   which we don't have any back-up, and there's no rule

19   against it, for one thing.

20                     A set of criteria are listed that include

21   such things as whether you know the protocol, whether

22   you know the details of how the study was done, the

23   persuasiveness of the people who did it, obviously a

24   highly subjective matter, multiplicity -- that is,

25   findings at more than one site -- and things like that.

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1                     So it's not impossible to believe data, even

2    though you don't have the back-up, and rely on it.

3                     ACTING CHAIRMAN BORER:           An important point,

4    and thank you for the clarification.

5                     Okay.      This meeting, as we have heard, is

6    called in response to a citizen's petition, and the

7    citizen petitioners will present a summary of that

8    petition, which we have just received a copy of.                       It's

9    a big petition.          So the summary will be very helpful.

10   That will be presented, I believe -- introduced by

11   Salvatore Graziano of the law firm of Milberg Weiss

12   Bershad Hynes & Lerach, if I pronounced it properly; and

13   comments will be made by Dr. Lawrence Krakoff of Englewood

14   Hospital, who I believe is the Associate Editor of the

15   American Journal of Hypertension.

16                    Mr. Graziano.

17                    MR. GRAZIANO:        Good morning.       I am not going

18   to spend much time up here.             I'm going to turn it to Dr.

19   Krakoff as soon as possible.

20                    I    want to thank the Committee and tell the

21   Committee that we very much appreciate the opportunity

22   to address the Committee this morning.

23                    We    also     did    distribute        our   citizens'

24   petition, and the compendium is very thick.                    So I just

25   want to take a minute a highlight some things in the

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1    compendium very quickly.

2                     There are 26 exhibits of documents, and Tab

3    Number 26, the last one, is an affidavit by Dr. Curt

4    Furberg where he is supporting the request that we are

5    making today.      He was the Chairman of the ALLHAT study.

6                     Tabs 15 and 16 are some internal Pfizer

7    documents that we received from litigation discovery that

8    show that awareness of ALLHAT is minimal.                Tab 13 is

9    another Pfizer internal document obtained from discovery

10   that shows that in Pfizer's opinion limited media coverage

11   of ALLHAT's adverse results were a good thing and,

12   therefore, they decided to keep it that way and not issue

13   any response to the ALLHAT findings, because there wasn't

14   very much media coverage out there.

15                    Tab 23 is another internal Pfizer document

16   where they internally comment amongst themselves that

17   they were able to get a change in a clinical alert issued

18   by the American College of Cardiology after the ALLHAT

19   adverse results were first released.

20                    Tab 12 is a good look at Pfizer's internal

21   sales force response to ALLHAT which was a dedicated

22   effort to make sure that the sales of this drug, Cardura,

23   continued after the ALLHAT findings.

24                    Now I would like to introduce Dr. Krakoff

25   who is really going to focus on the data, and I think

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1    that is what the Committee is most interested in hearing

2    about this morning.

3                      DR. KRAKOFF:        Thank you very much to Mr.

4    Chairman and members of the Committee for allowing me

5    to have the time to review this very serious issue.                             I

6    will use Powerpoint slides, and I hope the machinery works

7    so that I can refer to these.                 I guess, as you can't

8    usually see these, I'll wait a minute or two, if anyone

9    would like to be sure they can see the material.

10                     As you are doing that, my titles are given

11   here.        I am Executive Editor of The American Journal of

12   Hypertension, past President of the American Society of

13   Hypertension, and regarding conflicts of interest, at

14   present on review of my involvement, I have had an advisory

15   but intermittent advisory committees for the past two

16   years for Merck, Novartis, Bristol-Myers Squibb.

17                     In the past I have been involved with Pfizer

18   some years ago with the development of Procardio XL and

19   other members of the pharmaceutical industry in the

20   distant past.

21                     I   speak      to    you     today     from     several

22   perspectives:         As a clinician who treats hypertensive

23   patients on a regular basis, as a chief of a hospital,

24   community hospital, affiliated with a medical school

25   which has a medical residency and a medical staff of about

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1    170 for whom I am the responsible officer with regard

2    to quality of care, process improvement, and increasingly

3    the issues of safety that arise in the hospital setting.

4     So it is really with that background that I would like

5    to proceed.

6                        In addition, I did serve as a writer for one

7    of the sections of the Joint National Committee's sixth

8    report.

9                        This summarizes -- This is verbatim with my

10   emphasis from the current Cardura package insert, and

11   I am going to come back to this point about the use of

12   Cardura          for the indication of prostatic           --     benign

13   prostatic hyperplasia and the emphasis on monotherapy,

14   because this condition, as I am sure you well know, is

15   treated by primary care physicians as well as urologists

16   who may not be fully aware of the characteristics of the

17   patients that they treat.

18                       Then the second indication for Cardura,

19   which has, so far as I know, been in its insert and

20   information provided to the PDR, for example, since its

21   approval is that it may be used alone as monotherapy or

22   in combination with other drugs for the treatment of

23   hypertension.         This is unchanged, as far as I know, since

24   the drug was approved.

25                       Now as someone who does have some background

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1    in    pharmacology as well as clinical medicine, and

2    returning, actually, to ten years ago or 15, whenever

3    I    first       became   aware   of   doxazosin,         these       are     the

4    properties that it has and has had.

5                       It is an alpha adrenergic receptor blocker

6    at post-synaptic sites.           The initial hemodynamic effects

7    are to reduce systemic vascular resistance, and there

8    are      some     effects   on    serum    lipids        that     have      been

9    characterized.            They are small, but they seem to be

10   reproducible, particularly a slight reduction in LDL

11   cholesterol.

12                      It's a once-a-day drug, and in this sense

13   it is different from other members of the class, and it

14   has been shown in more recent studies since it was

15   originally approved for hypertension to reduce symptoms

16   of benign prostatic hypertrophy.

17                      Then there are some mechanistic studies that

18   suggested that it improves sensitivity to insulin, which

19   would be a valuable property, and possibly some effects

20   on platelets in at least one study I could find, which

21   might be considered beneficial as well.

22                      In other words, on the drawing board in

23   theory it looks like it ought to be a very effective drug

24   and possibly going back in time it looked better than

25   others with regard to treatment of hypertension, either

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1    by itself or in appropriate combination.

2                        I am going to provide background here which

3    I think we all are familiar with, but since I can't be

4    sure of that, I think it's best if I put the treatment

5    of hypertension in its current context.

6                        Why do we treat hypertension?                Not to lower

7    blood pressure, but to prevent cardiovascular disease.

8     This       includes     stroke     and    the   fatal      and       nonfatal

9    debilitating          stroke,    fatal     and   nonfatal          myocardial

10   infarction, prevention of progression to heart failure,

11   and increasingly, as we see from other studies, the

12   ability to prevent admissions to the hospital for cardiac

13   surgery or for coronary revascularization.

14                       Peripheral vascular disease possibly is a

15   target of antihypertensive treatment, but the data is

16   certainly less clear.

17                       In reviewing the history of antihypertensive

18   drug      treatment,      the    first     studies        were     done      with

19   diuretics, hydralazine, reserpine and methyldopa, and

20   showed in the VA studies that the treatment of very severe

21   hypertension within a year and a half resulted in a

22   reduction of cerebral hemorrhage, aortic aneurysm, and

23   the progression to malignant hypertension.

24                       The concept was proven, certainly, by 1972

25   or '73.          From the next 20 years a number of studies were

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1    conducted.           They have been evaluated in meta analyses

2    in middle-age patients with diastolic hypertension,

3    mostly 90 to 110 range, and showed that in these patients

4    antihypertensive               therapy      predominantly           based       with

5    diuretics, methyl dopa, reserpine, and then beta blockers

6    could            prevent     stroke      unequivocally,             monotonously

7    similarly from study to study, could attenuate coronary

8    heart disease in middle-age patients.                     Heart failure was

9    less a target.              It was less obvious in these studies.

10                        In this period the two crucial studies were

11   addressed to hypertension in the elderly with predominant

12   or     isolated        systolic       hypertension,           the    SHEP      trial

13   conducted in this country by the National Heart, Lung

14   and Blood Institute using chlorthalidone as its base

15   therapy, and then SYST-EUR conducted in Europe using

16   nitrendapine, a calcium channel blocker not available

17   here.

18                        Both of these showed high effectiveness in

19   reducing endpoints compared to placebo for stroke,

20   coronary heart disease, and in SHEP the prevention of

21   heart failure.

22                        So this is where we have been, and I think

23   this is universally accepted by the academic medical

24   community and those who are leaders in the field of

25   treatment of hypertension, that antihypertensive therapy

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1    is unequivocally effective.

2                      What has changed has been the recognition

3    that different drug classes are really not known, and

4    there are some clues that some might be better than others.

5     So there is a focus on strategies in recent years.

6                      There is a focus on the older patients who

7    were excluded from some of the other trials because their

8    blood pressure wasn't high enough, but their risk for

9    cardiovascular disease is increased due to diabetes or

10   their lipid status or already present target organ damage.

11                     Many of these patients don't have very high

12   blood pressures.           So we assume that antihypertensive

13   is therapy, and then it becomes a matter of strategy and

14   practice.        What is the best practice, and that is where

15   ALLHAT was designed in the early Nineties, I believe.

16   I don't know when the first steps were taken to design

17   it, but it was really designed to compare in high risk

18   patients, the kind that doctors see every day -- primary

19   care doctors treat on an hour-to-hour basis -- and look

20   at the different drug classes, because there has been

21   real question:        Are the diuretics really the best base

22   to start from?

23                     The new classes have never really been tested

24   in practice settings or in small studies that really

25   weren't designed to settle these issues.                Then the alpha

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1    blocker, doxazosin, which is similar in duration of action

2    to once-a-day drug and has these promising properties,

3    was included in the ALLHAT study to settle these issues.

4                         I bring the risk issue in, because in the

5    ALLHAT           study    the    average     entry     blood     pressure        of

6    145/83-84 in the two groups were remarkably low, lower

7    than were the entry blood pressures of any of the previous

8    antihypertensive therapy trials.                      This is a high risk

9    group with minimal elevation of blood pressure.

10                        A study from a clinician's perspective and

11   from the perspective of one who teaches evidence based

12   medicine on a weekly basis to residents and students and,

13   to some extent, attending staff, is impressive.                              This

14   is a big study, 15,000 in the chlorthalidone arm, 9,000

15   in the doxazosin arm, conducted in medical practices and

16   clinics          of the United States, really a remarkable

17   achievement.

18                        It is randomized perspective.               It is massed

19   or blinded.              It is multi-site, and to my knowledge the

20   statistical approach and interpretation is excellent

21   based upon what I can interpret from reading the study

22   and     also       the     individuals       involved     with    it.        High

23   percentage of follow-up, which is crucial for such

24   studies, and it is designed to answer important questions

25   that clinicians have been asking really since 1985.

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1                     The size and the power of this study should

2    allow it to answer questions that couldn't possibly have

3    been definitively answered in small, uncontrolled or

4    limited studies of 16 weeks or six months or with, say,

5    500-600 patients.

6                     So from my view, ALLHAT meets the criteria

7    from evidence based medicine as a superbly conducted

8    clinical trial, and this is based on what I have read.

9     It seems to me -- and this is an opinion -- it is very

10   unlikely that any similar study can ever be conducted

11   again in this country at least, and possibly nowhere else.

12                    These are the major results that may be

13   elaborated on later, but they are published in the JAMA

14   article that came out a year ago, and indicate that for

15   coronary heart disease similar outcomes.                For stroke,

16   a small .6 percent absolute difference in the rates that

17   were reported.

18                    If you calculate the number needed to treat,

19   this represents one stroke prevented for every 160

20   patients treated.          This is almost identical to the

21   calculation of number needed to treat that was made for

22   the ancient classic British MRC trial of treatment of

23   mild       hypertension,   not     terribly      high   statistical

24   significance.      It makes a low .05, but the direction is

25   in the right way, if you accept this, and the difference

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1    is clinical significance, particularly compared with an

2    old trial for stroke reduction.

3                     The    combined       cardiovascular        disease

4    endpoints are shown here, and this is a much more

5    impressive picture, because the absolute numbers are much

6    greater, and the difference between the two of about 3.5

7    percent suggest that the number needed to treat would

8    be about, I guess, about 25-30 patients to prevent an

9    event.

10                    The events that are most prominent are those

11   for congestive heart failure, which is now well known,

12   about a 40-50 percent reduction, highly significant; and

13   then coronary revascularization, which is one percent,

14   but one in 50 if you calculate the number needed to treat.

15                    Coronary revascularization in a community

16   hospital that has a growing cardiac program with cardiac

17   surgery and coronary intervention is a real issue.

18   Someone who is admitted for coronary revascularization

19   is a patient who is in big trouble and in jeopardy, and

20   something we want to avoid.          I think it's an appropriate

21   endpoint to be included in a clinical trial at this point

22   in time in this country.

23                    Was   ALLHAT    predictable?         This     is     an

24   interesting thing.        First of all, it wasn't obviously

25   predictable, because it would be unethical to do a study

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1    in which it was clearly thought that one drug would be

2    worse than the others.

3                        The    previous    studies       of   doxazosin      were

4    small.           They were narrowly focused, often on very low

5    risk patients, and I think they couldn't possibly reveal

6    real clinical differences, even summed up together to

7    predict that ALLHAT would have the results it had.                       And,

8    certainly, no, because the pharmacologic profile for

9    doxazosin certainly promised equal or greater benefit

10   compared to the diuretic, especially if one looks at the

11   small but statistically significant effects on serum

12   lipids.

13                       So to my mind, when I heard about ALLHAT,

14   I was surprised.           The results were unexpected, and I think

15   should be treated as any other unexpected and harmful

16   publication of harmful effect that wasn't, at least in

17   my mind, fully explained by the known actions of the drug.

18                       We have a treatment of hypertension that's

19   highly effective, a low dose diuretic therapy, possibly

20   other agents.          But this was a surprise and, I think, had

21   to be treated as such, in a powerful large study.

22                       What    happened     to    the    message?          After

23   presentation at the American College of Cardiology, there

24   was a publication that I became aware of in the JAMA of

25   2000.        No one sent it to me.         Actually, I picked it up

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1    from a copy of the JAMA that had been mailed to me as

2    usual, and I read it in the journal.

3                      I began to analyze it and look at it very

4    carefully because of some writing that I am doing in

5    preparing        some chapters for books on treatment of

6    hypertension and cardiovascular disease.

7                      There were notices on these websites.                            I

8    don't know if they were reached or looked at.                                 My

9    impression, and it's only that, is from colleagues, that

10   they didn't see these or were not aware of it.

11                     Then there's Dr. Messerli's comment in the

12   Lancet which you heard, and then there is an article by

13   Dr. Witt in the Cleveland Clinic Journal summarizing,

14   basically describing the results of ALLHAT.

15                     I actually personally made an inquiry to the

16   Chair -- one of the Chairs of the Joint National Committee

17   asking would there be a response on the part of the JNC,

18   and as I have been involved with the writing of the adverse

19   drug portion, I thought this was something we really

20   should do.       But I was told that there wasn't any immediate

21   plan to do that.

22                     Then,   as     you    are    aware,   there        was      no

23   information        forthcoming         from    the     Food      and      Drug

24   Administration or from the manufacturer by way of Letter

25   to Doctors or any change in labeling to the present time.

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1                     I think there is -- One of the things that,

2    I think, bothers clinicians when something appears that

3    is unexpected is can I understand it?                  What's the

4    mechanism?       It's puzzling that there isn't an obvious

5    mechanism for the differences, and I am just going to

6    briefly touch on these, not because they are convincing

7    but because they have come up in discussion.

8                     Do the differences in systolic pressure

9    between the groups explain the differences in outcome?

10    If so, the small difference of systolic blood pressure

11   of 3 millimeters of mercury or so between the groups was

12   not known to the treating doctors.            They couldn't detect

13   it, because you cannot measure from visit to visit a

14   difference of 3 millimeters of systolic blood pressure

15   in any patient.

16                    It is a variable pressure, and the most you

17   can probably pick up is 10-15 millimeters of difference

18   from visit to visit.        So the doctors can't detect this.

19                    Are there differences in compliance?               I'm

20   not sure why there should be, but if so, then failure

21   to comply is something that really concerns us, and any

22   drug that shows that it can't be complied with is a less

23   good drug to treat hypertension.               So this, in and of

24   itself, is a worry.

25                    If the explanation is unmasking of latent

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1    congestive heart failure who are people at entry because

2    somehow they were withdrawn from effective treatment,

3    how would the doctors know this?              How would a primary

4    care physician know this?           How would a urologist know

5    this?

6                     This is another safety issue, as far as I

7    am concerned.      You need to know a lot more about treating

8    the hypertensive patient than is normally done in the

9    usual work-up that is advised by our same guidelines.

10                    Tachyphylaxis or tolerance appeared with

11   prazosin in heart failure studies years ago, and if that

12   is the basis for this explanation, then again this

13   indicates that doxazosin is ineffective in a target

14   population where it ought to be beneficial.

15                    Recent changes in the strategy for treatment

16   of hypertension, I think, have to be emphasized here.

17   The JNC-6, now three or four years old, is not about to

18   be immediately changed based on what I have been told.

19    JNC-7 is not in press.       There isn't any JNC-7 at present.

20                    There is greater emphasis on drug treatment

21   of higher risk patients, stages 2-3 of B, and all of C

22   in the JNC classification.               These are in general.

23   There's emphasis on treating older patients with drugs,

24   those who have other risk factors, and target organ

25   damage, in other words, those like the ALLHAT recruitment

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1    cohort.

2                     Goals to treat hypertension have dropped.

3     There's emphasis on greater reduction of blood pressure

4    to less than 140 systolic, more use of drugs to lower

5    drug pressure, and in target groups such as diabetics.

6     The aim is to get near to normal, and this is not

7    universally accepted, but there's certainly -- This is

8    in print and recommended by many in the field.

9                     So the overall attempt is to increase the

10   fraction of hypertensive who are on treatment to start

11   at lower pressures than ever before and get to even lower

12   blood       pressures on treatment.           It's an aggressive

13   approach.

14                    The   consequences      of   this    will    be,     one

15   hopes, in a sense, more intensive drug treatment with

16   those who have minimal hypertension, slight elevations,

17   but who are at high risk for other reasons, and it is

18   not at all clear for these patients that small differences

19   in blood pressure between treatments are really going

20   to be the basis of outcome.

21                    Instead, if it looks like that the either

22   beneficial or adverse effects of drugs in treating these

23   kinds of hypertensive patients will emerge, the other

24   actions of the drugs will, in fact, determine the event

25   rate, the outcomes.        And as we have seen from the HOPE

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1    trial with ramipril and, I think, with doxazosin with

2    the ALLHAT study, this is exactly, I think, where the

3    other actions of the drug, known or unknown, that affect

4    cardiovascular disease emerge.

5                     So from my view as a clinician and one

6    responsible for the training and supervision of other

7    doctors, I think there must be a warning.              It is certainly

8    not too late, because Cardura is widely available, and

9    it's still recommended that it be used alone in the package

10   insert.

11                    So I don't think that it is at all too late

12   to issue a warning, and I am convinced, based on a polling

13   of my own staff within the past few days, that many

14   physicians are not aware of ALLHAT, are not aware of the

15   potential danger of doxazosin where it might be dangerous.

16                    So I would request that all providers be sent

17   a letter with a summary of the ALLHAT results indicating

18   that the use of doxazosin alone is only to be considered

19   as an add-on -- that is, a Step 2 or 3 drug -- in selected

20   individual cases, indicating that there is a risk of

21   congestive        heart     failure        and     possibly         other

22   cardiovascular disease endpoints in predisposed patients

23   as defined by ALLHAT entry characteristics, and then leave

24   it to the doctors as to if they need to know more about

25   the patients for considering this choice.

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1                        I think, certainly, the labeling ought to

2    be changed, because -- and it should include that in a

3    large and well conducted, randomized clinical trial, that

4    use of doxazosin was associated with a significantly worse

5    outcome compared to the diuretic treatment.

6                        I     would     personally        favor      prohibiting

7    monotherapy with doxazosin in any high risk patient,

8    irrespective of blood pressure, and this undoubtedly will

9    include          some    of   those     who    have    benign       prostatic

10   hypertrophy, and emphasizing the need for knowing more

11   about these patients before considering doxazosin as part

12   of the treatment.

13                       I conclude with:           This is a safety issue,

14   and I ask you to do the right thing.                        Thank you.

15                       ACTING CHAIRMAN BORER:            Thank you very much,

16   Dr. Krakoff.            Once again, do we have questions about Dr.

17   Krakoff's          statements         for     clarification         purposes?

18   Ileana?

19                       DR. PINA:       Thank you for your presentation.

20    I don't have any data in front of me about those early

21   trials like the VA cooperative trial back in the late

22   Sixties and some of the trials in the Seventies.

23                       What was the age group in that era of trials?

24    You said that a lot of the older patients were excluded.

25    Is there an age difference in all these trials that we

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1    are looking at?

2                     DR. KRAKOFF:     I don't remember the exact age

3    of the VA initial study, which really was a study of about

4    200 patients.       Most were middle-aged.            I don't recall

5    the exact age range.

6                     In the large HGFP trial conducted in this

7    country, the age range actually, I think, was from the

8    mid-thirties to 70.       Below age 50, actually, no benefit

9    of antihypertensive treatment could be shown.              The design

10   of that study was usual care versus special clinics, so

11   aggressive antihypertensive therapy versus relatively

12   little antihypertensive therapy.

13                    For those patients age 50 to 70, there was

14   an unequivocal, clear difference in the outcomes.                       So

15   the average age, I think, was in the late fifties or early

16   sixties, and this is also true of the British MRC trial

17   that I mentioned.

18                    Older   patients      are    excluded     for      many

19   reasons, not necessarily because they were older, in some

20   cases I think above age 75 or 80.            I don't remember the

21   details of each one, but largely because of concurrent

22   disease or risk factors.         So that it's not just the age

23   alone, but rather the mix of patients who were kept out

24   of the trials.

25                    DR. KONSTAM:    That was a great presentation.

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1     Could we ask you to reflect a little bit more deeply

2    on this 3 millimeter mercury thing, because the way you

3    indicated it, if I interpret your remarks, was that, okay,

4    but if that's the reason, then it doesn't matter because

5    the doctor can't distinguish the 3 millimeters of mercury

6    anyway.

7                      I guess I would challenge that in the sense

8    that the 3 millimeters isn't 3 millimeters of mercury

9    across 9,000 patients.            It's an average.        So there's some

10   patients         who    are     substantially        out    of     control

11   contributing to that mean 3 millimeters of mercury.

12                     Then thinking about that and reflecting on,

13   you know, Ray's comments about the fact that I guess the

14   dose was capped at 8 milligrams, 16 milligrams seems more

15   effective.        So could you go with that?               I mean, is it

16   really clear that if you didn't go ahead and get the blood

17   pressure down a little bit that some of these things

18   wouldn't have gone away?

19                     DR. KRAKOFF:        Well, I think that's a central

20   question in a sense, and it can be interpreted different

21   ways, and there are different points of view about these

22   small differences in systolic blood pressure.                     How many

23   had large reductions in pressure, and how many had modest

24   reductions in blood pressure?

25                     The physicians in the study and the nurse

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1    clinicians who conducted the study were given the same

2    instructions across the whole study.               They were blinded,

3    and they went by the blood pressures and their titrations.

4

5                      So does this mean that it's more difficult

6    in the clinic setting actually to know whether there is

7    control with one drug versus another, as one possibility,

8    or -- I mean, it's very difficult to explain, because

9    these are group differences across 9,000 plus 15,000,

10   and it tells us nothing about the composition of the

11   changes within the groups.

12                     That might be interesting, but for the

13   clinician it's not going to show up on their screen.

14                     The dosage issue -- This is an impression.

15    I don't have data on the use of Cardura by physicians.

16    My impression is that there are very few physicians who

17   used anything above 4 milligrams of Cardura before they

18   added or changed, and 8 milligrams which even then is

19   somewhat unusual for treating hypertension, and that many

20   physicians -- looking at charts, including my own -- would

21   just simply figure that if you didn't get much of a

22   response by the time you got to 4 to 8 milligrams once

23   a day, you were going to add or switch.

24                     DR. KONSTAM:       Okay, but just to follow on

25   that:        But then the message might be different, because

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1    if the underlying premise of ALLHAT is that at comparable

2    reduction in blood pressure, you know, what is the

3    differential effects on endpoints?             And if there was not

4    comparable effect on blood pressure, well, maybe the

5    message would then have to be, well, you need to do a

6    better job to control blood pressure, as opposed to saying

7    that at comparable reductions in blood pressure, there

8    are differences in these different drugs.

9                     DR. KRAKOFF:    I am not sure that the question

10   was asked exactly that way.          I think it was thought, and

11   the designers would have to speak to this, that this is

12   a trial of reduction of cardiovascular risk.            In a target

13   population defined as high risk, the question is does

14   one treatment do a better job than another as a starting

15   point of the four drugs that were at the start of the

16   race, as it were.

17                    I don't think the question could be asked

18   with precision, can you really do this at equal -- to

19   get everybody to the same blood pressure level?                    One,

20   the variance of individual blood pressures makes that

21   almost impossible to do.            You know, blood pressures

22   measure much less accurately than many other things such

23   as serum cholesterol, for example.

24                    So I think the issue was -- and ALLHAT is

25   a study in practices -- what is the best way within a

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1    high risk group who are defined as hypertensive in a

2    certain way, including being on treatment -- the best

3    way to reduce cardiovascular disease, and hope that the

4    groups -- You know, perhaps it was a thought, they will

5    come out very close to being similar.                       They can't be

6    identical, but then who does best?

7                        ACTING CHAIRMAN BORER:           Yes, Steve?

8                        DR. NISSEN:      I wonder if you could help me.

9     I can't find anywhere in here, what was the mean dose

10   of doxazosin used, and what was the mean dose of

11   chlorthalidone used?

12                       ACTING CHAIRMAN BORER:           Excuse me.        Before

13   you answer that, Dr. Krakoff, I think that the people

14   who actually did the study probably would be in a better

15   position than Dr. Krakoff to respond to those specific

16   questions. So maybe we could hold that stuff until we

17   get the NIH presentation.                  But are there particular

18   issues           that   anyone     --     particular        questions         of

19   clarification that we want to direct to Dr. Krakoff?

20   Bob?

21                       DR.   TEMPLE:         Larry,     I     think   I     might

22   understand your view of this.               But can you say something

23   about the distinction between initial therapy, which

24   after all was what was studied, and the use as an add-on.

25

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1                     Whether you think the results reflect, well,

2    the absence of a benefit or something else adverse really

3    matters a lot.      So my question is what do you think the

4    best explanation here might be?              Is it the absence of

5    a favorable effect in heart failure, which you could also

6    deduce from V-HEFT, I suppose, for the class, in which

7    case adding the therapy on might not be a worrisome thing,

8    or do you think it's more likely that something harmful

9    is going on here?

10                    I admit, you don't have full data.                 I'm

11   asking for impression.

12                    DR. KRAKOFF:    Well, I would like to, I think,

13   read that letter that was sent by someone who offers a

14   hypothesis about what might account for a possible harmful

15   effect of doxazosin.

16                    What I said was -- and this is really a

17   speculation.       The outcomes speaks for itself.               These

18   patients were started with one drug class, and then other

19   drugs were added along the way.             The duration of their

20   initial exposure to whatever they were assigned to is

21   something that people who have the actual data can speak

22   to.

23                    I would have to suggest that in a high risk,

24   hypertensive population there is an underlying, as I

25   suggested, latent heart failure component who people are

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1    unaware of it.            If they were aware of it, they would have

2    been kept out of the study, and that the treatment perhaps

3    exposed those individuals because of the ineffectiveness,

4    the tolerance issue or tachyphylaxis issue for doxazosin.

5                           That is the best hypothesis I can offer.

6    As I said, this is an unexpected finding, and to me it

7    has to be -- and it resulted in a lot of disease, and

8    I think that's the way it should be seen.

9                           ACTING CHAIRMAN BORER:         Okay.      Maybe we can

10   move on to the NIH presentation of ALLHAT, because I think

11   we are beginning to get into the questions now, and first

12   we ought to hear the data.

13                          The presentation will be by Dr. Jeffrey

14   Cutler,          the     Director     of    Clinical         Application       and

15   Prevention Program at the NHLBI.

16                          DR. CUTLER:       Thank you.          As the Chairman

17   just said, you've already heard quite a lot about the

18   ALLHAT           data,   and    certainly       the    Committee        has      an

19   opportunity to read a lot.                   So I'll try to concisely

20   summarize          the     data    that     was    associated        with      the

21   termination of the doxazosin arm early last year.

22                          There are only two of my slides that are not

23   strictly represented in what's in the paper.                            Just by

24   way of introduction, I am a physician at the National

25   Heart, Lung and Blood Institute.                  I have been there since

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1    1981, mostly involved in management and oversight of

2    randomized          clinical    trials,     cardiovascular      disease,

3    particularly hypertension.

4                        I'll just wait a second for the slides to

5    start.           I apologize for turning the Committee around

6    again.

7                        As already stated, these data were first

8    presented at the American College of Cardiology a year

9    ago March, and then published in April in the JAMA.                      The

10   remainder of the trial is continuing through next year.

11

12                       The close-out process for the remainder of

13   the trial begins in October, and in the process of closing

14   -- of continuing the trial and closing it down, there

15   is additional accumulation of late reported events that

16   occurred before the February 15, 2000, cutoff for this

17   portion of the trial.

18                       The members of the Steering Committee at the

19   time the results were reported are shown here.                           The

20   numbers in parentheses simply represent which of the nine

21   ALLHAT regions the particular member of the Steering

22   Committee is responsible for in terms of field monitoring

23   and such.

24                       Patients     were     recruited,      treated        and

25   followed at 625 clinical sites which were located in 47

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1    U.S. states, the Caribbean, Puerto Rico, and U.S. Virgin

2    Islands and eastern Canada.

3                     The settings are quite diverse, ranging from

4    a few academic centers all the way to some rural general

5    practices, including some 60-plus VA medical centers,

6    and all of this necessitated -- All of this diversity

7    of the sites necessitated following a large simple trial

8    model.

9                     For example, the follow-up form -- The

10   routine follow-up form has only four pages of data.               This

11   approach to the trial -- This practiced based approach

12   was required in order to enroll the sample size that was

13   aimed at as 40,000 patients, in the implementation was

14   actually 42,500, older hypertensive patients with at

15   least one additional cardiovascular risk factor.

16                    The trial was designed to compare diuretic

17   based regimen with each of three other regiments based

18   on representatives of three other drug classes, and I'll

19   show you that in a minute, for their effects primarily

20   on coronary heart disease.         It was a double blind, active

21   controlled trial.

22                    This shows the specific arms, the four

23   randomized groups, which included chlorthalidone as the

24   control group at a dose of 12.5-25 milligrams per day,

25   amlodipine, lisinopril and doxazosin, as you've heard,

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1    dose of 2-8 milligrams per day.                 One of the titrations

2    in the chlorthalidone group was actually a sham titration

3    from 12.5 to 12.5, and then the third dose being 25.

4                       The planned follow-up period was four to

5    eight years with an average of six.                      The design also

6    includes a sub-randomization to a lipid lowering trial

7    which was pravastatin versus usual care with an all-cause

8    mortality endpoint.             There were about 10,500 patients

9    in that portion of the trial, and I won't say anymore

10   about that today.

11                      Among    a   list    of   hypothesized       secondary

12   outcome questions, the four listed here are, of course,

13   total mortality plus the three main cardiovascular

14   secondary outcomes, the most inclusive of which was

15   combined         cardiovascular        disease    which     included        an

16   expanded          coronary        endpoint        that       encompassed

17   revascularization and angina, stroke, lower extremity

18   arterial          disease       involving        hospitalization            or

19   revascularization, angina treated either in hospital or

20   as an outpatient, and heart failure, fatal, hospitalized

21   or treated as an outpatient.

22                      In terms of blood pressure eligibility, just

23   to summarize this somewhat complicated slide, most

24   patients came in with previous treatment for two months

25   or greater and under eligibility criteria that had no

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1    lower level of blood pressure and had a maximum level

2    at the screening visit of 160/110 on one to two drugs.

3                     The aim here was to get patients in who would

4    be relatively easy to control to maximize the separation

5    of the three arms in terms of drug regiment required.

6    If    patients were newly treated or untreated, they

7    basically fell within JNC Stages 1 and Two.

8                     Among a variety of exclusion criteria, I just

9    wanted to mention specifically that symptomatic heart

10   failure or, if known -- not symptomatically sought but,

11   if     known,    low     ejection     fraction      were    reasons       for

12   exclusion.

13                    Summarizing         some    of    the    main   baseline

14   characteristics, a longer table is in the paper: First

15   of all, the sample size.                The chlorthalidone arm was

16   allocated 70 percent more patients in order to optimize

17   power in a four-arm trial.               In terms of baseline blood

18   pressure, it was given those eligibility criteria in the

19   fact that 90 percent of the patients came in on previous

20   treatment.       They were relatively low, 146/84.                 Average

21   age, in the mid-sixties.

22                    About one-third of the patients were black.

23    The intent of the trial was to try to over-recruit blacks

24   into this hypertension treatment trial.                      About half

25   women, and about a third, importantly, diabetics, an

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1    increasingly important high risk group.

2                     With regard to maintenance on assigned drug,

3    this slide summarizes the data.             Toward the later part

4    of follow-up for the diuretic group, about 86 percent

5    of those coming in for visits were maintained on the

6    assigned drug, and for doxazosin group it was about ten

7    percent lower.       This was in spite of greater use of

8    step-up treatment in the doxazosin group.

9                     The blood pressure data have been mentioned.

10    Diastolics, as shown in the paper, were identical in

11   the two groups, and the systolic blood pressure during

12   the first 12 to 18 months was about 3 millimeters higher

13   in the doxazosin group, and for the remainder of the trial

14   was about 2 millimeters higher.

15                    Other   intermediate       endpoints     that      were

16   measured were biochemical.          The expected more favorable

17   effect on serum cholesterol was seen in the doxazosin

18   group, about a five percent difference.                 Cholesterol

19   declined in both groups, partly because about one-eighth

20   of the cohort were actually randomized to Pravastatin.

21    So that affected the mean levels.

22                    Fasting serum glucose:        A slight rise in the

23   chlorthalidone group, which tended to come back toward

24   baseline, and a slight fall in the doxazosin group.                 This

25   difference is about three or four percent.

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1                     Now going to the endpoints and the decision

2    to terminate the arm, this decision was made in January

3    by the Institute following external reviews, and it was

4    based on two criteria.        The crux of the rationale:          First

5    of all, there was a futility criteria written into the

6    stopping guidelines, and if there was, certainly, a

7    comparison for the primary coronary outcome met that

8    criterion in that the conditional power for finding a

9    protocol specified 16 percent difference was about one

10   percent at the time it was stopped.

11                    The second part of the rationale was this

12   25 percent higher rate of a pre-specified secondary

13   endpoint, combined cardiovascular disease.              So now I'll

14   elaborate a bit on both of these aspects.

15                    First for the primary endpoint, the curves

16   pretty much stayed on top of each other throughout

17   follow-up.       Relative risk, relative hazard was estimated

18   as 1.03, and there was a little bit of a separation during

19   years two and three, but they came back together.                      If

20   you need a reason for those minor fluctuations, it could

21   represent the increasing crossover, particularly from

22   doxazosin to diuretic that occurred later on follow-up.

23                    The expanded coronary endpoint that include

24   hospitalized angina and coronary revascularization did

25   show a marginal difference, a ten percent higher rate

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1    in the doxazosin group with a P equal to .05.                     That's

2    in the paper.

3                       This is the combined cardiovascular disease

4    endpoint.        As I mentioned, it was prespecified.             It had

5    a p-value corresponding to about 10 or 11 zeroes.                        So

6    this is a compressed p-value.             And as was mentioned, the

7    absolute difference here was about one percent per year,

8    relative risk 1.25.

9                       One of the major components of combined

10   cardiovascular           disease   but    also    prespecified      as        a

11   secondary endpoint was stroke, about a 19 percent higher

12   rate in the doxazosin group, separated early and stayed

13   -- appeared to continue to separate through follow-up,

14   p-value of .04.

15                      Now from meta analyses of trials of blood

16   pressure lowering in a general hypertensive population,

17   not high risk as in this trial, a 3 millimeters difference

18   in systolic blood pressure could be expected to produce

19   about a 10-15 percent effect on stroke risk.                    So this

20   is certainly within the range of what might be expected

21   from the blood pressure difference that was seen based

22   on external evidence.

23                      The     combined       cardiovascular        disease

24   endpoint was, as you know, substantially driven by heart

25   failure.         These are the curves.         They separated early,

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1    but also did continue to slowly separate throughout

2    follow-up, twice the risk in the congestive heart failure

3    in the doxazosin group.

4                      This    difference     was    first   noted     during

5    monitoring after the Data Monitoring Board asked us to

6    disaggregate        the     combined      cardiovascular        disease

7    endpoint.        It was also seen for hospitalized and fatal

8    heart failure looked at separately, with a relative risk

9    of about 1.8.

10                     Now with due regard for heart failure being

11   a softer than certain other cardiovascular endpoints,

12   at the request of the Data Monitoring Board we did conduct

13   further analyses and attempt to validate the endpoint.

14                     Remembering that ALLHAT is a large simple

15   trial, did not have routine central adjudication of major

16   endpoints, there was a ten percent sample of coronary

17   events and strokes reviewed centrally.                  Heart failure

18   initially was not reviewed centrally, but a sample was

19   selected after this difference began to emerge and

20   reviewed blindly by the Trial Endpoints Committee based

21   on the hospital discharge data of those events.

22                     That review showed that, by and large, the

23   investigators were using the prespecified heart failure

24   criteria in their diagnoses.

25                     A second thing that was looked at had to do

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1    with -- Sorry, forgot to advance the slide.                 The first

2    point, I just made.         The second point is that, based on

3    a 50 percent sample of discharge summaries we reviewed

4    at the coordinating center for ejection fraction data,

5    and where those data were given in the discharge summary,

6    two-thirds of participants diagnosed with heart failure

7    in both groups had ejection fractions of 40 percent or

8    less.

9                     What was also looked at was drug treatment

10   following the heart failure diagnosis based on routine

11   follow-up forms and, by and large, the frequency of                   use

12   of open-label diuretics, ACE inhibitors and beta blockers

13   post-diagnosis       were    consistent       with     practice       and

14   recommendations in the community.                So the docs were

15   treating this as if it were real heart failure.

16                    Finally    and   probably      most    importantly,

17   following the diagnosis of heart failure in the hospital,

18   subsequent mortality, case fatality rates, as it were,

19   for these participants was high.            It was 20 percent over

20   a three-year period, and it was similar in both groups.

21                    This plot just subtracts out of the combined

22   cardiovascular disease the heart failure, just to show

23   you that indeed for the residual part of that endpoint

24   -- and this is not a prespecified analysis, clearly, but

25   there was a significant effect, a significant difference,

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1    once you exclude heart failure.

2                     Then for completeness, all-cause mortality:

3     There was no difference.          This is pretty much tracking

4    together throughout follow-up.              In terms of why the

5    cardiovascular difference, morbidity difference was not

6    translated into mortality difference.             I guess I can only

7    say that perhaps follow-up did not go long enough to see

8    that.

9                     Numerically, the trend in favor of the

10   diuretic for cardiovascular mortality was approximately

11   offset by a trend in favor of the alpha blocker in terms

12   of cancer mortality.         But that's what the data show.

13   We haven't published class-specific mortality yet, but

14   that's the description.

15                    So in conclusion, this tracks what we said

16   in the paper with regard to the overall results.                       In

17   patients such as in ALLHAT who are older patients with

18   additional risk factors, it appears that chlorthalidone

19   is superior for first line treatment of hypertension

20   because of greater drug compliance, better hypertension

21   control, and occurrence of some chiefly heart failure

22   and stroke cardiovascular events.

23                    There was no evidence of a differential

24   effect on major CHD, though angina related events,

25   including revascularization, tended to be more frequent

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1    in the doxazosin group.            Thank you.          I'll be glad to

2    answer questions.

3                     ACTING CHAIRMAN BORER:         Thank you very much,

4    Dr. Cutler.       That was really an extraordinarily clear

5    presentation of the data, and it is very helpful.

6                     I want to begin by asking a question that

7    may not be relevant to our deliberations today, but I

8    didn't quite understand it.              Perhaps you can tell me

9    something about it.

10                    In the paper there was a mention of the DSMB,

11   and then there was a discussion of independent reviews.

12    But a clear distinction between them wasn't made, and

13   other information we received -- I believe I'm correct

14   here -- that the DSMB did not vote to stop the trial,

15   and then a second independent committee was empaneled,

16   and did.

17                    Do I have that right?

18                    DR. CUTLER:       That is correct.           The DSMB,

19   more or less, split down the middle with regard to

20   continuation or stopping, which, in our view, just sort

21   of presented the Institute with an untenable situation

22   and, I think, has some precedence, and we constituted

23   a separate and, I think, very well qualified review

24   committee who took another look at the data and made the

25   recommendation.

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1                     ACTING CHAIRMAN BORER:            I'm not suggesting

2    that it's -- I'm just asking for clarification.                     Can you

3    tell us anything about the specifics of the differences

4    between the first committee and the second committee?

5    I don't know if the composition was any different in terms

6    of expertise or such, but in terms of the points that

7    were made or the points that were discussed, or is that

8    something that really is not something we can hear about?

9                     DR. CUTLER:        The data that they were shown

10   with regard to these two arms was identical, and the

11   attempt was made to focus the committee strictly on the

12   comparison       of    those    two    arms    rather      than    broader

13   considerations of the trial, which is, of course, the

14   charge to the DSMB itself.

15                    ACTING CHAIRMAN BORER:            Ileana?

16                    DR. PINA:      Maybe I missed this, and I haven't

17   seen it in the ALLHAT protocol that we have been supplied.

18    The definition of heart failure was similar to the

19   definition of heart failure in SHEP.

20                    DR. CUTLER:        Yes.

21                    DR. PINA:       What was the definition of heart

22   failure, and what was included to make a diagnosis?                              I

23   see here in one of your slides that the validation was

24   similar to what the guidelines were for the diagnosis.

25                    DR.    CUTLER:        I   have    a     slide with the

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1    criteria.        I can get it up for you.

2                      DR. PINA:     I would like to see that.

3                      DR. CUTLER:       Okay.      If I could have the

4    back-up carousel.

5                      ACTING CHAIRMAN BORER:          While we are waiting

6    for that, Tom, you had a question.               Why don't we do that,

7    and then we'll get back to Ileana.

8

9                      DR. CUTLER:       It will be Slide 35 in that

10   carousel.

11                     DR. FLEMING:      I don't know how far we'll get

12   with my questions before you turn back to this, but I

13   had two questions that are fundamental design questions,

14   the second relating to the dosing schedule that you chose

15   for the alpha blocker.

16                     The first question relates to the overall

17   choice of a superiority rather than non-inferiority

18   analysis.        This is an active controlled trial with the

19   diuretic as the active comparator, which, for example,

20   in SHEP, had been documented to have a favorable effect

21   on stroke, on major CHD events, and on heart failure.

22                     Recognizing      that    the     active     comparator

23   provided those benefits, nevertheless, the study was

24   designed not to show non-inferiority of these other

25   regimens, i.e., that they aren't meaningfully worse, but

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1    to actually require them to be superior, so that quality,

2    in essence, was viewed as an unacceptable result.               I would

3    like to get some sense about that.                 That's the first

4    question.

5                     The second question is:         With doxazosin what

6    was the rationale for the choice of a strategy of titrating

7    on a monthly rather than two-week interval and going to

8    an age rather than 16 milligram max?

9                     DR. CUTLER:      Okay.     On the overall design,

10   the focus on a coronary disease endpoint and on a

11   difference hypothesis really grew out of the earlier trial

12   literature       where meta analyses both of trials and

13   epidemiology suggested that diuretic based treatment or,

14   if you will, diuretic and sometimes beta blocker based

15   treatment was not achieving the expected coronary benefit

16   that would be expected by the degree of blood pressure

17   lowering, and there were certainly claims made, based

18   on intermediate effects of each of the newer classes of

19   drugs, that they may indeed provide a greater benefit

20   not only from the blood pressure lowering effect but also

21   for these ancillary effects.

22                    So it seemed reasonable to formulate the

23   hypotheses as potentially providing a better outcome for

24   coronary disease.         If you want more of a statistical

25   answer, I would be glad to call upon my colleagues,

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1    director of Center, Dr. Davis, who is here.

2                           DR. FLEMING:        Well, let me probe your

3    clinical answer first.               Basically, what you are saying

4    is there were plausible mechanisms of action that made

5    it reasonable to anticipate that effects could be better

6    than with diuretics.               Well, that does, in fact, argue

7    that superiority is a possibility.

8                           DR. CUTLER:     Yes.

9                           DR. FLEMING:     The null hypothesis, though,

10   ought to be based on what is minimally acceptable. Even

11   if one thinks that an experimental agent may be better,

12   if in fact it's the same -- and that, in fact, is an

13   adequate conclusion -- then a superiority design isn't

14   the appropriate design.               It should be a non-inferiority

15   design.

16                          So I am interpreting from this design that

17   there            are    other    features       of    the    experimental

18   interventions that required a superiority conclusion for

19   this to be an acceptable benefit-to-risk profile.

20                          DR. CUTLER:    Well, I'm not familiar with the

21   logic that somehow a null result is unacceptable in a

22   superiority trial.              It's acceptable.        It's what you see,

23   what the data show.             I'm not sure why that is considered

24   unacceptable.

25                          DR. FLEMING:       Well, the study should be

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1    designed         to,   in    essence,      address        an   alternative

2    hypothesis which, in fact, you would like to be able to

3    establish by ruling out a null hypothesis, that null

4    hypothesis generally being what you would consider to

5    be an inadequate level of benefit.

6                       So typically, if you would argue it's okay

7    to be the same, then you would set that up as ruling out

8    that you are meaningfully worse.                  If you set it up to

9    be a superiority trial where you are then trying to rule

10   out equality, then by logic that's saying equality isn't

11   an acceptable level of benefit.                 That's the logic with

12   hypothesis testing.

13                      So I am assuming, when the team set this up

14   as a superiority trial, there was a rationale given by

15   the team that equality of these efficacy effects would

16   not have been an acceptable conclusion.

17                      DR. CUTLER:        Well, I don't remember that

18   logical line of argument being pursued.

19                      DR. FLEMING:        If I could just pursue this

20   one more step, then why was it that the team gave as its

21   rationale for stopping the trial that the probability

22   of being able to prove benefit was now only one percent,

23   conditionally          given     current       results?           That's            a

24   conclusion that has a logical basis, if you are saying

25   I am only accepting this experimental therapy if it is

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1    better.

2                     DR. CUTLER; I      don't think the trial would

3    have been stopped solely on the basis of futility.                     It

4    was a combination of futility and the secondary endpoint.

5                     DR. FLEMING:      But I'm trying to get to that

6    very essence of the point.            It seems to me the team is

7    saying with the logic it is using that, if there's only

8    a one percent chance to prove superiority, therefore,

9    this futility has been established.

10                    It must be then that equality isn't adequate.

11    It has to be better, and you have ruled out a reasonable

12   chance that it could be better.           Hence, there is the basis

13   for stopping the intervention.

14                    DR. CUTLER:     Well, I guess I'm being dense.

15    I don't follow the twists and turns of your argument.

16                    ACTING CHAIRMAN BORER:            Can we have the

17   microphone on at the table, please?

18                    DR. DAVIS:       As I said, the coordinating

19   center came on board when most of the trial had been

20   designed, but I think that the key question that you're

21   asking, Tom, is they wanted to prove superiority in some

22   sense was in the background because of the believability

23   of the trial, at least three newer agents which had been

24   touted as being better than chlorthalidone, and it wasn't

25   a question of wanting to show non-inferiority but actually

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1    superiority for this to be believable.

2                     The reason -- As Jeff has said, the futility

3    was only one portion of this.         But it wasn't only looking

4    at the futility under just the null or -- and it wasn't

5    the present level.        It was the protocol level, and we

6    looked at even other levels.          It was just -- Probability

7    was extremely low.

8                     DR. FLEMING;        Let me try to answer my

9    question and see if, in fact, this is what the team is

10   saying it's trying to tell us with this decision to stop

11   this alpha blocker arm.

12                    Given other features of the profile beyond

13   the primary endpoint, the primary endpoint being fatal

14   CHD and non-fatal MI, the team is saying to us a

15   combination of two observations.              First of all, there

16   is an excess of other clinically important events, most

17   notably heart failure.            Heart failure was twice as

18   frequent.

19                    There are other features such as cost that

20   come into play.         When you think about these other

21   features, then it's not acceptable relative to the primary

22   endpoint to be the same.        You need to be better, and there

23   was only a one percent chance that you could be better.

24    Hence, you put all of those features together -- the

25   rationale for stopping.        Is that the essence of the logic?

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1                         DR. DAVIS:     Yes.

2                         ACTING CHAIRMAN BORER:         Before we go on to

3    the 8 milligram, 16 milligram and titration schedule

4    question, let's get back to Ileana's question and get

5    that answered.          Then we have Steve and Marvin and probably

6    several others, and Tom's.

7                         DR. CUTLER:     Well, let me first say that I'm

8    not an expert on the dose response of this drug.                     Is this

9    the next one you wanted me to go to?

10                        ACTING CHAIRMAN BORER:           No.     Let's talk

11   about the definition of heart failure.

12                        DR. CUTLER:     Basically, it required at least

13   one finding under Category A and one finding under

14   Category B.

15                        ACTING CHAIRMAN BORER:               Were these the

16   criteria that were used for the nonhospital based patients

17   as well as the hospital based patients?

18                        DR. CUTLER:      Yes, except that we have no

19   documentation in terms of how the diagnosis was reached

20   from the nonhospitalized cases.

21                        DR. PINA:     Let me continue along that same

22   line.            You said one from each category to make the

23   diagnosis.

24                        DR. CUTLER:     Yes.

25                        DR. PINA:     At entry, patients were excluded

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1    if an ejection fraction was known to be less than 40

2    percent, and yet two-thirds of the patients who ended

3    up with heart failure, in fact, had ejection fractions

4    of less than 40 percent.

5                         So I gather that there was no urge to find

6    out ejection fraction about a lot of these patients when

7    they were entered, and they were assumed to be okay.

8                         Another very interesting point, to me, in

9    the heart failure incidence here is the large number of

10   women that are included in this trial.                     Do you have a

11   breakdown of the percentage of women versus men who ended

12   up with heart failure in the doxazosin group?

13                        DR. CUTLER:       Yes.      We have the subgroup

14   findings.           They are in the paper, but I can show you a

15   slide.

16                        DR. PINA:      Is this appropriate, Jeff, to

17   continue at this point since, even from Framingham, we

18   know that, you know, in a large population of heart failure

19   individuals,           the    women    are     more    likely    to     have

20   hypertension as a background for their heart failure.

21   Do you have that slide?

22                        DR. CUTLER:        Yes.     I have the relative

23   risks.           I don't have the rates, but it's Slide 24 in this

24   current           carousel.         It's       actually    broken       down

25   concurrently by ethnicity and gender.

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1                     So basically, the fourth, fifth and sixth

2    set of bars are the men in respective ethnic groups, and

3    the next three are the women in respective ethnic groups,

4    pretty similar relative risks.

5                     DR. PINA:    Thank you.

6                     ACTING CHAIRMAN BORER:         Why don't we go on

7    to Steve's question, and then we'll go to Marvin and Tom

8    again.

9                     DR. NISSEN:      I'd like to get a very good

10   sense of what the exposure was to doxazosin, and what

11   the exposure was to chlorthalidone.                   I mean various

12   measures like the mean dose and so on.

13                    The reason I'm asking the question is I want

14   to try to understand whether there was some relationship

15   to the amount of drug the patient was exposed to and the

16   differences that were seen.            I know that may not have

17   been prespecified, but it's a big study.                So there's a

18   lot of opportunity to look at this.

19                    Was the difference the greatest in those

20   patients that got exposed to the most of these drugs or

21   the least of these drugs.

22                    DR. CUTLER:     That last question is one of

23   the topics of a manuscript we are coming close to closure

24   on, but not quite at the point of publicly reporting the

25   conclusions.

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1                      The first part of it, which is a description

2    of the dose exposure, I don't have the data in mind, but

3    my recollection is that the majority of patients in the

4    dox group ended upon the 8 milligram dose.                  Barry, do

5    you want to add to that?

6                      DR. DAVIS:     I'd say it's a majority, about

7    a third in the chlorthalidone group and, I think, 38

8    percent of the doxazosin group.

9                      DR. CUTLER:        Thirty-eight percent on 8

10   milligrams?

11                     DR. NISSEN:      So what was the mean dose?

12                     DR. DAVIS:      I'm sorry.        I read the wrong

13   page.        Forty-nine percent in the doxazosin group and 46

14   percent in the chlorthalidone group.

15                     DR. CUTLER:     On the higher dose, the highest

16   dose.

17                     DR. NISSEN:     So what was the mean exposure?

18    What was the mean dose?           Do we not know?      We must know

19   that.

20                     DR. DAVIS:     We haven't really done a formal

21   calculation of that.

22                     DR. NISSEN:      It's really not known?

23                     DR. LIPICKY:     It's not known to us, you, now.

24    It's not known.         So if you need that information, you

25   don't have it.

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1                     ACTING CHAIRMAN BORER:        Marvin, you had your

2    hand up there?

3                     DR. KONSTAM:      Yes.     I've got a couple of

4    questions.       One is:       Could you just help us again

5    reconcile the different points about mortality?               I guess,

6    so you find that in the patients who present with heart

7    failure, they go on to have a higher mortality, and yet

8    the overall mortality curves for the two groups is

9    absolutely superimposable.

10                    So how do you explain that?

11                    DR. CUTLER:       Well, I think we are both

12   overstating it to say they are absolutely superimposable,

13   but they are certainly not statistically different.

14                    DR.    KONSTAM:             Well,     they        look

15   superimposable.

16                    DR. CUTLER:    Do you want the slide up again?

17    It's in the paper.         I mean, I think it basically has

18   to do with the proportion of deaths that were attributable

19   to heart failure, which was, you know, modest.                I mean,

20   there were a lot of deaths, a lot of causes of death.

21   I can't tell you the exact proportion.                Barry, do you

22   have that?       But it was a relatively modest proportion

23   of deaths, and it's not enough to affect, with a play

24   of chance, the overall mortality.

25                    DR. KONSTAM:      I mean, just to reflect in

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1    terms of heart failure studies, I think it's a little

2    unusual, and also to have what appears to be a pretty

3    substantial        early      effect         on       heart      failure

4    hospitalizations.       I mean, I just wonder if you could

5    -- Maybe you don't have an answer, but what do you think

6    is going on there?         I mean, you have this very early

7    effect, and what is that?          I mean, is that some harmful

8    effect of doxazosin or is that, well, that chlorthalidone

9    actually treats heart failure, and you're not giving it.

10    I mean, can you comment on that?

11                    DR. CUTLER:     Well, I think it's got to be

12   predominantly that chlorthalidone is an effective drug

13   both for preventing and treating heart failure.                    It was

14   a very effective drug in SHEP at preventing heart failure,

15   50 percent reduction.

16                    You know, coincidentally, you see the same

17   relative risk of chlorthalidone versus placebo in SHEP

18   and chlorthalidone versus doxazosin in ALLHAT.

19                    DR. KONSTAM:       Well, it's going to be an

20   important issue for us to grapple with, is which one of

21   these things is going on.          Okay.

22                    I want to ask just about blood pressure.

23                    ACTING CHAIRMAN BORER:           Just before you do,

24   Joann, you had a follow-on on the heart failure?

25                    DR. LINDENFELD:      Yes.    I want to just follow

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1    up to what Marv said.        Can you tell us how many patients

2    were withdrawn from antihypertensive therapy, and how

3    many were started de novo in the study, what percentage

4    in each group?

5                     Then in follow-up to that and just this

6    question about withdrawing potentially effective failure

7    for heart failure, was there a difference in the incidence

8    of heart failure in those two groups -- that is, the groups

9    that had to be withdrawn?

10                    I'm concerned, because there's a very early

11   difference here.

12                    DR. CUTLER:       About 90 percent came in on

13   treatment.       Actually, the relative risk for heart failure

14   in those who came in untreated and those who came in on

15   treatment is essentially the same.                      We have those

16   numbers.

17                    ACTING CHAIRMAN BORER:          Do we know what the

18   distribution of treatments was from which people were

19   withdrawn who had heart failure?

20                    DR. CUTLER:      No, we don't.

21                    ACTING CHAIRMAN BORER:                Marvin, you had

22   another question?

23                    DR. KONSTAM:       Yes.     With regard to blood

24   pressure, you had target blood pressures for the treatment

25   algorithm.       Correct?     I mean, you were shooting for a

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1    certain blood pressure goal.

2                      DR. CUTLER:      Yes.

3                      DR. KONSTAM:       Can you comment on then why

4    do you think there was a 3 millimeter difference between

5    the two groups at the end?

6                      DR. CUTLER:      Well, of course, as a double

7    blind trial the clinicians were titrating without regard

8    to the base drug.        They were also somewhat constrained,

9    though in the end no constrained, as to what drugs they

10   could choose to add.          The protocol steered them toward

11   the drugs that were supplied by the study, and were not

12   any of the study drug classes.

13                     They did have both a systolic and diastolic

14   goal.        By and large, they were achieving the diastolic

15   goal equally in all classes.               I think it's true that

16   physicians are still not well oriented toward achieving

17   systolic blood pressure goals.                It's sort of been an

18   increasing emphasis and acceptance of that.

19                     So those are all factors, and I can't -- I

20   don't think I can go any further than that.

21                     DR. KONSTAM:       All right.         This is my last

22   question.        Have you looked at al at blood pressure effects

23   relative to events?         That is to say, you know, what are

24   the various blood pressure effects in patients who did

25   and did not have stroke, for example, and heart failure,

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1    for that matter, but as another way of getting at is the

2    difference in the events explainable on the basis of the

3    blood pressure?

4                         DR. CUTLER:       That's another analysis that's

5    part of this manuscript I mentioned.                    I think that those

6    kind of analyses have their limitations, as you well know,

7    but we are doing them.

8                         DR. KONSTAM:        So you don't have any answers

9    today.           Right?

10                        DR. CUTLER:        I don't.

11                        ACTING CHAIRMAN BORER:              Ralph, you had a

12   comment?

13                        DR. D'AGOSTINO:            I've got a couple of

14   questions, if it's all right.

15                        If I read the paper correctly, at the time

16   the analysis was done, you didn't have follow-up on all

17   individuals, but you had follow-up on about 90 percent

18   of the individuals.               I've been in the setting in data

19   safety           monitoring       committees       where       we    see       big

20   differences, and if you sort of wait a while, they go

21   away.

22                        Some of the differences in this graph that

23   we are showing and we're saying there's a big difference

24   at the beginning is obviously tied in with the scale.

25   So my question, my first question, is:                       Did you redo the

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1    analysis         with a better follow-up, a more complete

2    follow-up, and did that have any effect on the results?

3                       DR. CUTLER:       You mean subsequent to the

4    publication?

5                       DR. D'AGOSTINO:         Right.

6                       DR. CUTLER:      Yes.    We do look at that from

7    time to time, but we haven't -- Everything we've looked

8    at is completely consistent with the original analysis.

9                       DR. D'AGOSTINO:        Did you do an analysis on

10   those who were actually taking the drug?                 I agree to the

11   intent-to-treat analysis, but sometimes you might want

12   to chase down and see what were they actually doing.

13                      DR. CUTLER:     Yes.     That's also part of this

14   paper that I've been mentioning.

15                      DR. D'AGOSTINO:       And just one other question

16   now.       We have lots of different arms in the study.               There

17   are a number of different drugs being looked at, and I

18   realize that there's a sort of confidentiality.                    But I'm

19   trying to get a setting of sort of should I be surprised

20   -- Even though it's upsetting, should I be surprised by

21   one event being significant, driven very much by the CHF,

22   when I don't know anything about all the others, all the

23   other comparisons that were going on.

24                      Then also, if I do some subtractions and I'll

25   leave it to you to respond to it -- But if I do some

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1    subtractions, I get the overall CVD rate.                 That shows

2    a higher rate for the Cardura, and then I subtract out

3    the CHF and I subtract out the stroke, and then suddenly

4    I'm in the other direction.            Is there something else --

5    Is there some other event like PAD where maybe the

6    direction was the other way?

7                     I'm just trying to get a sense of how do I

8    look at this striking one result and understand how to

9    put it in context of all the possible results that could

10   have come out of -- all the possible differences that

11   could have come out of comparing the two drugs.

12                    DR. CUTLER:     No.     The PAD data are in the

13   paper, and also I have a slide, if you want to see it.

14    But, no, all of the components went in the same direction,

15   and I guess the subtraction you get into, the accounting

16   rules as to whether -- what's a first event and multiple

17   events in the same patient.             So it's a little hard to

18   sort it out in that way.

19                    The   answer    to    your    question     about       on

20   treatment analysis:        We also are doing that with this

21   paper that's forthcoming.

22                    ACTING CHAIRMAN BORER:         Alan.

23                    DR. HIRSCH:     A very nice presentation.                   I

24   remain concerned about the definition of heart failure,

25   just like everyone else, because that seems to drive the

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1    analysis.        As a clinician, though I am cognizant that

2    one has to have simple rules for these definitions in

3    a practice based trial, I want to make sure I know how

4    they were applied.

5                     If I were a patient in the trial and I were

6    going to have this heart failure definition applied to

7    me, did I have to have both an A category and a B category

8    as a new finding?      Alternatively, if I were in my doctor's

9    practice with ankle edema and I complained, or orthopnea,

10   did that become a heart failure definition?                That's my

11   first question.       I'll follow that up.

12                    DR. CUTLER:     I believe the instructions were

13   that they had to be new findings.

14                    DR. HIRSCH:      Both new?

15                    DR. CUTLER:      Yes.

16                    DR. HIRSCH:      So two new findings.          That's

17   helpful.

18                    Then you made the comment that, since we did

19   a post hoc adjudication of the heart failure outcome,

20   that this was largely consistent with the physician's

21   diagnosis, and I would like you to define "largely

22   consistent."

23                    DR. CUTLER:       In about two-thirds of the

24   cases, and most of the remainder were not because there

25   was evidence in the discharge summary that contradicted

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1    the diagnosis, but because there just was not sufficient

2    data.

3                     DR. HIRSCH;     And how was that handled?              In

4    other words, if one deleted that one-third.

5                     DR. CUTLER:    The central adjudication, both

6    for the heart failure and for the primary outcome and

7    for stroke, was not used to change the diagnosis.                  These

8    were quality control reviews.              The local physician's

9    diagnosis was maintained.

10                    ACTING CHAIRMAN BORER:         Ray.

11                    DR. LIPICKY:      This wasn't the question I

12   wanted to ask, but based on what you just said, does that

13   mean that two-thirds of the data that say it's congestive

14   heart failure are okay, and one-third is not, but you

15   accept it all?

16                    DR. CUTLER:     We accept it all.

17                    DR. LIPICKY:       Okay, fine.        I had three

18   questions to ask.       I'm sorry.       You disagree with that?

19                    DR. DAVIS:     Clarification.         That was for

20   the quality control.        Don't say that was for the whole

21   thing.

22                    DR. LIPICKY:      But what I hear is that you

23   knew that a third of the data couldn't be confirmed by

24   anything you read about the patient.

25                    DR. CUTLER:    You can't extrapolate from the

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1    sample very accurately to the whole dataset, and it may

2    very well be appropriate to do central review of a larger

3    sample.

4                     DR. LIPICKY:      So the driving force of the

5    whole business, you don't need to be certain of.                        All

6    you need is the number?          Is that right?

7                     DR.   CUTLER:      I    didn't       understand      that

8    question.

9                     DR. LIPICKY:     Well, you don't need to know

10   what you are talking about.             You just need to know how

11   many of what you don't know you're talking about you have.

12                    DR. CUTLER:        Well, that sounds like a

13   rhetorical question.

14                    DR. LIPICKY:      Well, yes, it was.              But my

15   three questions were:         In the publication it says that

16   patients who were randomized to chlorthalidone were on

17   chlorthalidone or a diuretic, as if they may not have

18   been on chlorthalidone.

19                    Then it says patients were randomized to

20   doxazosin or an alpha blocker, as though they may not

21   be an alpha blocker.        That's when the time in study --

22   the table of time in study in the publications, and the

23   slide you showed said doxazosin and chlorthalidone.                            I

24   would just like you to clarify that.                     What did the

25   publication mean when it said chlorthalidone or a diuretic

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1    and doxazosin or an alpha blocker?

2                      DR. CUTLER:     In each of those categories of

3    maintenance on assigned treatment, there was a small

4    percentage who were, in fact, on              an open-label drug of

5    the same class.         It's a small percent, but that's the

6    way we presented the data.

7                      DR. LIPICKY:      Okay.      So it is that it was

8    chlorthalidone or something that people thought was like

9    chlorthalidone?

10                     DR. CUTLER:      Yes.

11                     DR. LIPICKY:       Okay.      Then the second and

12   third questions might take a little longer to answer.

13   But I guess, since there is no information available,

14   I'd like to get a feeling for why the DSMB, which sort

15   of looked after the data for a long time, came to one

16   conclusion -- maybe it was a hung vote or maybe it was

17   50/50 -- but did not come to the conclusion that something

18   should be done, and that what the reasons were; because

19   we have no feeling for that.

20                     We don't know what directions things were

21   going in.        We don't know how any of the other groups were

22   faring and what they thought of the reasons.                 Then why

23   an independent group apparently quite clearly came to

24   a very different decision.

25                     Can you give some feeling for how that

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1    happened or what the thought processes were?            Then I have

2    one other question after that.

3                     DR. CUTLER:      Well, as you might imagine,

4    that's very hard to summarize.

5                     DR. LIPICKY:      That's okay.       If you can't,

6    you can't.

7                     DR. CUTLER:    No, no.     I'll say a few things.

8     You know, I think there was still on one or two members

9    some discomfort still with the heart failure diagnosis,

10   as has been evidenced by some of the questions we've heard

11   here.

12                    In fact, I think everybody who first sees

13   these data are skeptical.         They know that there are some

14   -- that alpha blockers cause in some patients peripheral

15   edema and so forth, and that this is just some sort of

16   an artifact.

17                    So we looked at everything within the study

18   dataset that we could to shore up our confidence in this

19   data, and some members of the Board ended up with more

20   confidence than others.         I think probably there was also

21   some feeling that with 60 percent of the information time

22   in, even with as low conditional power as we had, that

23   there's always some reluctance to stop a trial, and there

24   are different orientations in terms of what threshold

25   it requires to make that judgment, but depending on

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1    people's background and experience.

2                     DR. LIPICKY:      Well, I understand, but could

3    you put that in the context that the presentations --

4    the early presentations were, and that is this is a cut

5    and dried circumstance.         You ought to damn well know what

6    the conclusion is.        How could those boards vary so much?

7                     DR. CUTLER:       I wouldn't put it that way.

8    You know, I'm the one who is up here at the podium, and

9    I'm reflecting my orientation to the chain of events and

10   the data.        You know, I can't represent everybody's

11   orientation.

12                    DR. LIPICKY;       Then my third question, may

13   I?

14                    ACTING CHAIRMAN BORER:          Yes.

15                    DR. LIPICKY;     Okay, I'm sorry.      Give us some

16   insight into why you thought that you could pick a member

17   of a class and draw class conclusions, when in fact it's

18   pretty clear to me that members of a class behave

19   differently.      So I'd like to get your feeling for what

20   your rationale was for thinking that you were going to

21   be studying class effects.

22                    You might add to that why dose didn't matter.

23                    DR. CUTLER:      Well, at the end of the day,

24   of course, everybody has to make their inferences as to

25   whether these are single drug findings or class findings.

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1     But, certainly, every --

2                     DR. LIPICKY;     But you designed the study as

3    a class study.

4                     DR. CUTLER    I hadn't finished yet.        I mean,

5    you know, if you're going to do a trial addressing this

6    kind of question, you can only do it with a single drug;

7    and your decision is basically don't do it all or do it

8    with a drug that you feel is typical of a class.                 So we

9    chose the latter.

10                    DR. LIPICKY:      But fully well knowing that

11   like, say, beta blockers in heart failure -- they can

12   take beta blockers that have beta blockade and alpha

13   blockade and just pure beta blockers and all that sort

14   of stuff, and that they have a completely different

15   clinical outcome when you study them.            So that it doesn't

16   matter --

17                    DR. CUTLER:     I'm not sure that's the case,

18   but that's --

19                    DR. LIPICKY;     Well, take businolol and any

20   other beta blocker you want to name.

21                    DR. CUTLER:     Well, I'm -- I don't know if

22   we want to divert to that discussion.

23                    ACTING CHAIRMAN BORER:          We'll get back to

24   the issue of the extrapolability of the data from one

25   drug to a class.

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1                     DR. LIPICKY:      I just wanted to get a feeling

2    for the thought process in the design, is all I was looking

3    for.

4                     ACTING CHAIRMAN BORER:          I think we sort of

5    have that.       But you mentioned a dose issue, and Tom raised

6    the question initially, and maybe we could get back to

7    Tom's question now.        Maybe, Tom, you want to restate it.

8                     DR. FLEMING:      Well, I'd like to concur with

9    one of those who said this is an extremely important,

10   very informative trial in addressing relative safety and

11   efficacy issues in a real world setting.

12                    In that context, one would wish to choose

13   a dose and schedule for each of these regimens that best

14   matches what would be a real world delivery.            It has been

15   stated that we may have given doxazosin a less than optimal

16   opportunity by having a maximal dose of eight rather than

17   16.      I'm sure the team gave this great thought.

18                    Could you give us a sense for why it was

19   viewed that the most relevant, appropriate answer is the

20   one that is achieved from a maximal of 8 rather than 16?

21                    DR. CUTLER:        The aim, as was discussed

22   earlier, was to have as close as possible to equivalent

23   blood pressure control in these arms, so that one would

24   be in a position to test the effect on clinical endpoints

25   of ancillary properties of the            drug, and the doses were

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1    chosen           by our Steering Committee to aim for that outcome.

2                         Other    arms    in     the   study   also        didn't

3    necessarily go to maximum dose.

4                         ACTING CHAIRMAN BORER:         That's not actually

5    my reading of the paper or the protocol.                      Amlodipine,

6    you allowed up to 10 milligrams per day, which is the

7    maximally labeled dose.               Lisinopril was 40 milligrams

8    a day, which isn't the maximally labeled dose, but if

9    you read the label, the label makes the point that there

10   is no evidence that you get anymore benefit above 40.

11   I don't know the evidence one way or the other, but both

12   chlorthalidone and doxazosin were limited to half the

13   top labeled dose.

14                        So I think, you know, we need a better answer

15   than that to Tom's question.

16                        DR. CUTLER:      Well, I'm giving you the best

17   answer I can.           As I said, the aim was to achieve blood

18   pressure levels that were roughly equivalent across the

19   arms, and the doses were -- we were advised to use                            by

20   our leadership group was the doses we chose.

21                        ACTING CHAIRMAN BORER:          Steve?

22                        DR. NISSEN:      Yes.     I want to come back to

23   the issue of dose response curve and see if the sense

24   of the study group was the same as mine, namely that:

25   Is it not correct that the dose response curve to diuretics

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1    is very, very flat as compared to other drugs or would

2    you not agree with that?

3                     In other words, when you double the dose of

4    chlorthalidone,        very      little   incremental      effect,         as

5    opposed to some of the other agents used.                 Is that your

6    feeling also?

7                     DR. CUTLER:       Well, I think that's true.                   I

8    think that, if you look at clinical endpoints, there's

9    some evidence that higher dose diuretic -- that there

10   is better benefit for stroke, although probably not for

11   coronary disease.           So that's not the blood pressure

12   answer, but the clinical endpoint answer.                I guess that's

13   my response.

14                    ACTING CHAIRMAN BORER:           Bob?

15                    DR. TEMPLE:       You can think of a lot of good

16   reasons for limiting the dose of chlorthalidone to 25,

17   because larger doses don't work, and they probably are

18   lethal.

19                    I   have    a   question     about      the   follow-up

20   treatment.       Jeff, you've suggested at a number of places

21   that the protocol specified follow-up treatments were

22   apparently not considered sufficient, and so the people

23   ignored that and used whatever they wanted.

24                    Can you elaborate on that? The follow-up

25   treatments that I remember were reserpine, an alpha

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1    agonist, and one more, but I can't remember what it was.

2                      DR. CUTLER:      The most common step-up drug

3    was a beta blocker, atenolol, most commonly used.                            I

4    didn't mean to imply that investigators ignored the

5    protocol.        In fact, you can see from the paper that they

6    very commonly used the actual -- the drugs specified in

7    the protocol.

8                      All I was saying was that they didn't

9    universally use the drugs specified.

10                     DR. TEMPLE:     Okay.      But that leads me to my

11   question in some ways.          I imagine many people who start

12   with a -- This may relate more to the trial than to the

13   immediate question here.           But I imagine most people who

14   didn't get a satisfactory response to an ACE inhibitor

15   would add a diuretic.

16                     Well, they weren't really allowed to do that

17   here.        So that's a little peculiar, especially if               the

18   goal is to see how things work in practice.              Do you have

19   any sense of whether the limited options available as

20   follow-up therapy might have had anything to do with the

21   inability of the groups to get equal control of systolic

22   pressure, because it was a sort of odd constraint?                           I

23   mean, it wouldn't be what you would do in practice.

24                     DR. CUTLER:     It was a constraint imposed by

25   the decision to do a double-blind trial, and all trial

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1    designs have tradeoffs, and that was a tradeoff we chose.

2                     DR. TEMPLE:     Yes. I'm not criticizing, but

3    it's sort of a peculiarity.

4                     ACTING CHAIRMAN BORER:           Joann?

5                     DR.   LINDENFELD:         Just       quickly     for      my

6    education, was there a time specified for the drugs to

7    be taken and the blood pressure than to be checked with

8    each of the different groups?

9                     Then I guess I would also ask, is there a

10   difference -- Today we are just comparing the two drugs.

11    Is there a difference in the peak onset of action?                    What

12   I'm getting at here is have we measured the difference

13   in blood pressure between these two drugs adequately or

14   could there be a greater difference because of differences

15   in onset of action?

16                    DR. CUTLER:    Certainly, the diurnal pattern

17   was not a focus in this study.           Drugs were specified to

18   be taken in the morning, and they were all once-a-day

19   drugs, and blood pressure was -- The clinic visits were

20   scheduled at the physician and patient's convenience.

21   They may not have all been in the morning.

22                    DR. LINDENFELD:         Just in terms of the

23   systematic problem, most of my patients on morning

24   diuretics ask to come to the clinic in the afternoon.

25   You know, I think there just could be a difference in

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1    how we evaluate blood pressures.

2                        ACTING CHAIRMAN BORER:            Alan?

3                        DR. HIRSCH:       Well, sort of following up from

4    Dr. Temple's question, I would again want to think in

5    real life of how I might have responded as the patient

6    in the trial, and again I want to flatter the trial design

7    as being real world, and I'm not particularly worried

8    in its generalizability, because this is how life is

9    practiced.              But I'm trying to look for confounding

10   variables to explain the outcome, obviously.

11                       So if I were a patient enrolled in ALLHAT

12   with       a     left    ventricular       systolic         dysfunction,        as

13   undoubtedly some patients were, and if I were randomized

14   to doxazosin and, although the primary physician may not

15   have noted it, my systolic blood pressure were not quite

16   as well controlled, the secondary then use of beta

17   blockers does become important in unmasking one or two

18   of those clinical outcomes that would have created the

19   CHF diagnosis.

20                       Can you remind me of what the relative rate

21   was of secondary use of beta blockers in the two arms,

22   whether the committee had considered whether that by

23   itself might have provoked this CHF outcome difference?

24                       DR. CUTLER:       It's in the manuscript on page

25   1970, middle column, middle paragraph.                        Let's see.        At

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1    one      year,   beta   blocker      was     18    percent     in     the

2    chlorthalidone arm and 20 percent the doxazosin arm.

3    Corresponding percentages at three years were 25 percent,

4    chlorthalidone, and 29 percent.

5                     DR. HIRSCH:     Small differences of use, but

6    I don't know whether these could be extrapolated to an

7    outcome difference, and I guess I'm speculating on that

8    for the panel.

9                     ACTING CHAIRMAN BORER:           Dr. Fenichel.

10                    DR. FENICHEL:        Yes.        I just wanted to

11   clarify something that came out of Bob Temple's comment,

12   and that is there is a difference between speaking about

13   a difference in systolic blood pressure control and a

14   difference in systolic blood pressure outcome.

15                    The definition of control was that the

16   systolic blood pressure be below 140, and the definition

17   of control for diastolic was that it be below 90.                       If

18   those numbers -- If the number 140, in particular, had

19   not been prophetically chosen, it might well be that one

20   would have equal control and yet a different result, which

21   is to say perhaps everyone was below 140 indeed, because

22   the physicians were on the ball, but some were running

23   at 139 and some were running at 135.

24                    Some of the comments here are hard to

25   interpret, because I think the two terms are being used

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1    interchangeably, and they are not.

2                      ACTING CHAIRMAN BORER:           Tom, you wanted to

3    follow up on the response to your comment?

4                      DR. FLEMING:           Yes.     I'm just thinking

5    through the response that you had given for the selected

6    dosing and regiment, that actually involves both, the

7    titration as well as the maximal.                   In essence, if I

8    interpreted your answer, you said the selection of the

9    specific schedule of monthly titration intervals to a

10   maximum of 8 was based purely on the expectation that

11   this would give us comparable blood pressure control to

12   the other regiments.           Is that correct?

13                     DR. CUTLER:        Not purely.         Basically, the

14   charge to the protocol writing committee was that that

15   was the goal.         But I guess one of the factors was the

16   number of titration steps and keeping that the same in

17   all      arms    to   maintain     the    blind    and    to   keep      the

18   implementation as simple as possible.

19                     I must say, you know, the option of pushing

20   to 16 milligram doxazosin dose was not seriously advocated

21   by anybody on the protocol writing committee.                     So --

22                     DR. FLEMING:           Were there any issues of

23   safety that anticipated safety differences at 16 versus

24   8 that weighed in this in any way?

25                     DR. CUTLER:        Not to my recollection, but

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1    it's a long time ago.

2                      DR.    FLEMING:       And,    I   guess,   one     last

3    question:        Given that you have now seen the results for

4    relative systolic blood pressures, is it your judgment

5    that the choice of the specific schedule was appropriate

6    or would you now say that it was intended to deliver

7    comparable blood pressure control, but we may well, in

8    retrospect, now have judged that we should have allowed

9    to have a more rapid titration or a higher maximal dose?

10                     DR. CUTLER:        I think it would have been

11   appropriate to give it serious consideration.                   Whether

12   it would have been doable and practical in the context

13   of this protocol, I can't be sure.

14                     ACTING CHAIRMAN BORER:            Ray, you had your

15   hand up there.          Joann?

16                     DR. LINDENFELD:         Just a quick question.

17   Was the incidence of new diabetes any different between

18   the two groups?

19                     DR. CUTLER:       We haven't looked at that.

20                     DR. LINDENFELD:        It just seems to me here

21   we have this problem between no difference in mortality

22   and all these heart failure deaths, and doxazosin has

23   been said to improve insulin sensitivity.                So if we saw

24   a difference in the incidence of new diabetes, that might

25   completely change how we viewed -- and I think that's

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1    -- Given what you thought about this drug at the beginning,

2    I think that's a very important piece of information to

3    have.

4                     ACTING CHAIRMAN BORER:         Bob?

5                     DR. TEMPLE:     Do you know the answer to Bob

6    Fenichel's question?           Was there a lesser degree of

7    control to the desired endpoint as well as a difference

8    in average, or not?

9                     DR.   CUTLER:      I   think    there    was a few

10   percentage points difference.           You have that -- Overall,

11   the systolic blood pressure control across the arms was

12   in the range of 60 percent.

13                    DR. FLEMING:     I think at one year it was 61

14   against 54.      At four years, it was 64 against 58.

15                    DR. TEMPLE:     It's easier to translate the

16   millimeters of mercury to a difference in risk than that,

17   but it sounds like they are showing about the same thing.

18                    ACTING CHAIRMAN BORER:         I have one question

19   here, and it's really more for our two statisticians and

20   perhaps the NIH statisticians.

21                    A lot was made in our materials about a

22   doubling of risk and, in fact, Tom, you used that

23   terminology in asking one of your questions, that CHF

24   risk or frequence was doubled.

25                    Just for my own edification, I want to

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1    understand how confident we can be in the concept, in

2    the belief that the rate of congestive heart failure

3    development was doubled.

4                        My understanding is that -- and you must

5    correct me if I'm wrong -- that in a clinical trial, the

6    finding of sufficient consistency between outcomes allows

7    you to say that it's unlikely that that difference is

8    due      to      chance     alone.        The     determination       of     the

9    believability of the absolute point estimate, as I

10   understand it, is determined by other criteria, by

11   precision, by the size of the standard error, the size

12   of the standard deviation.

13                       So given that, and given the fact that there

14   are confidence limits that we saw -- they don't overlap,

15   but they are there -- and given the fact that there are

16   multiple         potential        confounding       factors,     additional

17   drugs, change in drugs, not taking drugs, this, that and

18   the other thing, difference in blood pressure control,

19   stopping the trial, this arm of the trial, in the middle

20   rather than going out to the end, how confident can we

21   be in the magnitude of the difference between the

22   doxazosin arm and the chlorthalidone arm in terms of

23   frequency of heart failure?

24                       You may want to respond to that first, Dr.

25   Cutler, and then maybe we have some committee members.

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1                      DR. CUTLER:     Well, the confidence limits are

2    right there at the end of that graph and in the paper.

3     They are low 1.79, high 2.32.           So pretty tight confidence

4    limits, really.

5                      ACTING    CHAIRMAN      BORER:        Tom,   can      you

6    respond?

7                      DR. FLEMING:      Well, I think maybe we'll get

8    into some of the issues that you have raised, Jeff, in

9    more depth this afternoon as you try to put all of these

10   results into the context of primary and secondary analyses

11   and interim analyses and the influence of that, the

12   influence of additional interventions being delivered.

13                     I guess I would say, in general, the study

14   is designed to address a strategy of delivery of an alpha

15   blocker against diuretics with additional supportive care

16   as needed.        One of the great strengths of the study is

17   it's a very large size and, as Dr. Cutler had pointed

18   out, high precision in the estimate.

19                     I don't know if Ralph has any additional

20   comments, but some of these issues we'll certainly get

21   back to more this afternoon.

22                     DR. D'AGOSTINO:       I think the issues will get

23   back, especially the way the sequence of questions are

24   laid out.        But I do think, you know, at this particular

25   point, not so much as a summary because you gave quite

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1    a nice summary in terms of what the issues are, but to

2    give another perspective from the statistics point of

3    view:        When you are looking at -- When I'm looking at

4    trials such as this, it's a complicated trial -- there

5    are      a       number   of    treatments;         number   of   possible

6    comparisons -- you look very to ask the question what

7    were the rules for stopping?                What were the predetermined

8    decision rules?

9                         If I read the materials correctly, and I

10   stand to be corrected -- If I read the materials correctly,

11   there was talk about this notion of superiority and

12   stopping for the futility.                  I do have a problem of why

13   would this be -- why is this a superiority as opposed

14   to noninferiority.              But they did sort of address that.

15                        What I don't find in any of the materials

16   is how they are going to grapple with interim looks at

17   efficacy variables and interim look at safety data.                        I'm

18   not sure what they thinking of in terms of the CHF.                        Are

19   they thinking of it as a safety problem or are they

20   thinking of it as efficacy?                It's both in this case here.

21                        You know, when I've served on these data

22   safety monitoring committees, as a number of us have done,

23   quite often with the safety you sort of just keep looking

24   at the adverse events and, if you see something that looks

25   really bizarre and problematic, you sort of chase it down.

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1                     I get the flavor -- and I would, again, like

2    to hear more about it.        I get the flavor that it was more

3    driven by that type of a sequence, that they looked at

4    the overall, but there was the safety that was beginning

5    to emerge.       It gets very hard to interpret these results.

6                     I mean, I think it's almost -- In terms of

7    the statistical p-values that you attach to it, it's

8    almost to a point where -- and I hope we do have more

9    discussion -- that maybe there's something meaningless

10   exercise in terms of saying does the p-value have

11   interpretation as opposed to is the safety issue so

12   serious that, no matter how we look at the data, it's

13   going to maintain itself.

14                    I think questions like the diagnoses are very

15   important, questions like what happens if you follow those

16   who really took the drug, what happens if you collected

17   more data.       Then what happens around the whole study?

18   I mean, how many other events, how many other endpoints

19   were problematic?         What did the committee have?             What

20   did this independent committee have that we don't have?

21                    I think, to try to interpret these numbers,

22   you really need that context.            It's not -- I don't think

23   you can focus on this confidence interval and say that's

24   a 95 percent confidence interval; therefore, it's there.

25    There's lots of uncertainty that you have to start

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1    attributing to it.

2                     If    it   really     is    safety      as   opposed         to

3    efficacy, then I think we're in a real bind in terms of

4    interpreting it.         if it's an efficacy, then you have to

5    ask the question, well, you saw nothing in the primary;

6    how do you start interpreting secondary variables?

7                     I'm not giving you a definite answer in terms

8    of how do you interpret it, outside of saying that it's

9    not easy to interpret, and I think we have a lot of

10   discussion on dealing with this.

11                    ACTING CHAIRMAN BORER:            Ray?

12                    DR. LIPICKY:         Can you suggest what should

13   be looked at to try to differentiate between whether there

14   was irreversible harm?             Let me put it in this sense.

15   Let's say that both the people in the chlorthalidone arm

16   and the people in the doxazosin arm were developing the

17   same degree of myocardial function abnormality, and that

18   chlorthalidone, which is a treatment for heart failure,

19   didn't allow the symptoms to develop, so it didn't get

20   diagnosed; that doxazosin, which isn't a treatment for

21   heart failure, let the symptoms be diagnosed.                        So that

22   we ought to regard this difference as reports of heart

23   failure, not as heart failure in the sense of having caused

24   an irreversible change in myocardial function.

25                    What data should we look at to tell whether

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1    that's true or whether, in fact, people in doxazosin arm

2    lost more cells or had a bigger decrease in contractility

3    or had some remodeling problem or something like that,

4    and that irreversible harm was actually caused?

5                           DR. CUTLER:     There won't be a lot more --

6    You know, there won't be a lot of mechanism data coming

7    from ALLHAT, because of the nature of the trial.                        We can

8    show you more detail on the ejection fraction, for

9    example, if you care.                But beyond that, there is not a

10   whole lot.

11                          DR. LIPICKY:     But only in the people who had

12   heart failure diagnosed.

13                          DR. CUTLER:     That's right.        These were not

14   routinely done as part of follow-up.

15                          DR. LIPICKY:      So in fact, the data won't

16   allow            the     differentiation         between       those         two

17   possibilities, and one can't take the inference that

18   irreversible harm was a part of the reporting of increase

19   in congestive heart failure.

20                          DR. CUTLER:    Well, the one thing that we can

21   do and may do is do continued mortality follow-up on these

22   cohorts, and that may be --

23                          DR. LIPICKY:     That may answer the question.

24                          ACTING CHAIRMAN BORER:          Okay.    I think we

25   can move along to the presentation by Pfizer, the response

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1    to ALLHAT.       I want to thank you very much, Dr. Cutler.

2     I'm sorry if it seemed like you were being skewered here.

3     That wasn't the intention.             This is a landmark trial,

4    and they are very difficult to do even if they are not

5    landmark.        So we're going to -- You know, I think that

6    when the trial is done, there will be a great deal of

7    important information available.

8                      Bob, did you have an additional question?

9     I wasn't going to actually take a break.                    It says on

10   the agenda that there's a break and, if anybody wants

11   to get up and go out, that's fine.                 But I think we'll

12   move along.

13                     Pfizer will probably take a minute or two

14   or three getting up here and getting the slides changed,

15   but we'll try and finish the Pfizer presentation before

16   lunch and then go on to the questions after the lunch

17   break.

18                     Pfizer's     response       to    ALLHAT    will       be

19   presented.        Now I'll actually -- I don't seem to have

20   the names written down on my agenda sheet, I'll allow

21   you to introduce all the people on your own.

22                     MS. LOGALBO:      Well, good morning.        I'd like

23   to thank the panel and the FDA for the opportunity today

24   to review for you the ongoing data that we have accumulated

25   on Cardura, doxazosin mesylate.

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1                     This was the slide you were looking for.

2    I'm Suzanne Logalbo, the team leader for the Regulatory

3    Affairs Group for the men's and women's health products,

4    and I am joined today by Dr. Patricia Walmsley, who is

5    our Senior Medical Director for the doxazosin worldwide

6    team, and Dr. Gretchen Dieck, our senior epidemiologist

7    in our Safety Evaluation and Epidemiology Group.

8                     Our agenda today:       We will go through a brief

9    introduction.      Dr. Walmsley will then review the clinical

10   data available on doxazosin.              Dr. Dieck will then go

11   through our epidemiology and safety evaluation.                      Dr.

12   Walmsley will return to provide our comments on the

13   preliminary ALLHAT trial observations, and then I will

14   return to take any comments that the panel may have.

15                    We have provided you with a more detailed

16   review of this information in your briefing document which

17   was provided prior to this hearing.

18                    Our objective today would be to review for

19   you the body of evidence that support the conclusions

20   that doxazosin does not precipitate congestive heart

21   failure, and to demonstrate that there is no signal of

22   a causal association between doxazosin and CHF, heart

23   failure-like events, myocardial infarction or stroke.

24                    We believe it is important to begin this

25   discussion today by reminding the committee of how we

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1    came to participate in this hearing.                   In early 2000, the

2    NHLBI informed us of their decision to discontinue the

3    doxazosin arm in the ALLHAT trial.

4                       We, frankly, we surprised by that action,

5    given the extent of the data that we had on doxazosin

6    through our ongoing safety and efficacy monitoring

7    process.         But nonetheless, we were supportive of their

8    decision to act as they believed appropriate in their

9    trial.

10                      What we did with that information is the same

11   process we go through whenever we are presented with new

12   information,        and     that    is    that    we    first     asked       for

13   clarification from NHLBI on several points that we were

14   looking for further information on, and we began to

15   re-review         our    accumulated        database       on     doxazosin,

16   beginning with the most rigorous data, that of clinical

17   trials, moving through epidemiology trials, and then

18   finally reviewing our spontaneous adverse event database.

19                      This first assessment was shared with a

20   number of leading cardiovascular experts, and a summary

21   was prepared and finalized in June of 2000.                                 This

22   assessment was shared with key regulatory bodies.

23                      Our    conclusion       at    that      time     was     that

24   doxazosin does not precipitate congestive heart failure,

25   and there was no causal association with the factors we

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1    are talking about today.

2                     We continued to review the data on an ongoing

3    basis through the next year, and when FDA asked us to

4    participate in this hearing, we began to prepare a

5    cumulative review of all the information that we had,

6    and prepared that summary that we've provided to you

7    through February of 2000.

8                     Our conclusions at that point did not change.

9     They remained the same.           I would now like to turn the

10   podium over to Dr. Walmsley, who will review our clinical

11   data.

12                    DR. WALMSLEY:         Good morning.         In this

13   segment of the presentation I am going to go through our

14   clinical trials, which is our most rigorous data.                   I am

15   going to be -- This is going the wrong way.              I am going

16   to be presenting a review of five of doxazosin's clinical

17   trials for selected cardiovascular events.               The review

18   will just be a summary of this comprehensive review.

19                    I will then discuss an ongoing NIH trial of

20   doxazosin in benign prostatic hyperplasia, and give a

21   summary of our literature review.

22                    As Suzanne said, in the interest of time,

23   I am only going to be giving highlights, and the details

24   are in your briefing document.

25                    ACTING CHAIRMAN BORER:         Excuse me.     Can you

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1    move the microphone toward you.

2                     DR. WALMSLEY:       Is that better?

3                     ACTING CHAIRMAN BORER:          Yes, much better.

4                     DR. WALMSLEY:         We reviewed all of our

5    Pfizer-sponsored doxazosin trials with the exclusion of

6    our Phase I studies.           That is the studies in healthy

7    volunteers.       We looked at trials for both indications,

8    both hypertension and BPH, and also for both formulations.

9     That is the doxazosin standard tablet which is available

10   in the U.S. and the prolonged release doxazosin GITS,

11   the controlled release, which is available in some other

12   countries.

13                    Now ALLHAT was designed to look specifically

14   for cardiovascular endpoints and, of course, our studies

15   were not.        So we looked at our studies from a safety

16   perspective, and we focused on specific cardiovascular

17   endpoints -- cardiovascular events, namely, CHF, MI and

18   stroke.

19                    I am going to be focusing on 316 clinical

20   studies, completed clinical studies, including over

21   49,000 subjects on doxazosin.           The vast majority of these

22   were monotherapy studies.

23                    The data from these studies are in two

24   databases.       The larger database of 271 completed studies

25   includes the studies from the BPH NDA as well as the

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1    studies submitted in the U.K. for approval of the GITS

2    formulation for both hypertension and BPH.             The smaller

3    database comprises the 45 studies from the hypertension

4    NDA.

5                     We reviewed both of these databases, and

6    basically the findings from the smaller database were

7    fully consistent with those in the larger database.                   So

8    we will just be presenting the results from the larger

9    database.

10                    These 271 studies, as I've said, included

11   both hypertension and BPH studies.               They included our

12   most rigorous group of studies, 84 comparative studies,

13   67 of which were cardiovascular and 17 were urologic.

14                    The population of our studies was somewhat

15   different from that in ALLHAT.             Patients in ALLHAT, as

16   we have heard, were specifically chosen to be at high

17   risk for cardiovascular disease, and our population is

18   at somewhat lower risk.         But our population is probably

19   closer to that in which doxazosin is generally used.

20                    The median age was 55 years, which is about

21   ten years younger than the ALLHAT population, and in our

22   studies we had a wash-out period before randomization,

23   which ALLHAT did not.         Also our studies used the full

24   dosage range of doxazosin.

25                    Another major difference is the duration of

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1    the studies.        Most of our studies were less than one year

2    in duration, and the vast majority, consisting of about

3    40,000 of the patients, had a maintenance period between

4    eight and 26 weeks.

5                       Now although this is very short, if you

6    recall the Kaplan-Meier plot for CHF that Dr. Cutler

7    showed, you will recall that the separation was very early

8    in the first few months of the trial, and had this been

9    an adverse effect of doxazosin, I think these studies

10   are long enough to anticipate that this would have shown

11   up in our studies, and it did not.

12                      Here you see the incidence of CHF in our

13   doxazosin patients in comparison with those on pooled

14   comparator.        The incidence is very low, and is similar

15   to that on pooled comparator, and there is no evidence

16   of a signal for early CHF events.

17                      Similarly, when we looked for MI and stroke,

18   the incidence of these on doxazosin was very low, and

19   was comparable to that on pooled comparator.

20              I would now like to look at our 84 comparative

21   studies.         Here you see the comparative class of agent,

22   the number of patients on each class, and the percentage

23   of subjects with CHF, MI and stroke.

24                      The percentage incidence of these events in

25   the doxazosin group is very low, much less than one

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1    percent, and is, in fact, comparable to that seen in

2    diuretic, which was the comparative agent in ALLHAT,

3    and in the same ballpark as placebo.

4                     When we separate out the 67 cardiovascular

5    comparative studies, we see a very similar pattern, with

6    very low incidence of these events, similar to that seen

7    with diuretic and in the same ballpark.               In fact, the

8    incidence is probably similar to what one might expect

9    in this patient population.

10                    These   are   the    17    studies   in   BPH      and

11   neurology, and again you see a very low incidence of CHF,

12   MI and stroke on doxazosin.           It's a little higher than

13   the incidence in the patients in the hypertension studies,

14   but this probably reflects the fact that in the BPH studies

15   the age was on the average about ten years older in the

16   BPH studies.

17                    One of the studies we reviewed specifically

18   looked at doxazosin in patients with congestive heart

19   failure, and this was included in the NDA filing for

20   hypertension.

21                    We took patients who were still symptomatic

22   from their heart failure, despite treatment with digoxin

23   and diuretics, and randomized them to receive either

24   doxazosin or placebo with a five-week titration period

25   and a 12-week maintenance period, and we saw no evidence

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1    of worsening of CHF with doxazosin as add-on therapy in

2    these patients.

3                          In fact, if you look at the number of cardiac

4    events,          it    is   much     higher     on    the   placebo       arm,

5    significantly higher, with three cases of worsening CHF,

6    two MIs and three sudden deaths in the placebo group,

7    with zero throughout on doxazosin.

8                          When we looked at the other parameters that

9    were evaluated in this study, we see that doxazosin was

10   associated with a significantly higher level of voluntary

11   submaximal exercise.               There was a trend to an improvement

12   in left ventricular ejection fraction and a significant

13   reduction in ventricular arrhythmias.

14                         Doxazosin was well tolerated.                The side

15   effect profile was consistent with labeling and, in fact,

16   was not significantly different from that in the placebo

17   group.           So all the objective parameters in this study

18   showed evidence of improvement.

19                         So based on our evaluation of the Pfizer

20   studies, we showed no evidence of a signal or causal

21   association            between      doxazosin        and    the    selected

22   cardiovascular events of early CHF, MI or stroke.

23                         I would now like to mention an ongoing NIH

24   trial of doxazosin in benign prostatic hyperplasia.                       This

25   is the Medical Therapy of Prostate Symptoms trial or

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1    MTOPS, and unlike ALLHAT, this is a placebo controlled

2    trial, compares doxazosin and finasteride in men with

3    BPH.

4                     The study started about the same time as

5    ALLHAT, and at the time that the preliminary ALLHAT

6    results were made public, the more than 3,000 patients

7    in MTOPS had all completed a minimum of two years

8    follow-up.

9                     In light of the ALLHAT findings, the MTOPS

10   Steering Committee appointed an independent committee

11   to review the MTOPS data for cardiovascular endpoints,

12   and they found a low absolute risk of CHF and no

13   significant difference in the incidence of CHF among the

14   treatment arms, and no difference between doxazosin and

15   placebo, and they recommended that there be no change

16   to the current MTOPS protocol.

17                    We anticipate getting final results from

18   this study in the coming year, about the same time as

19   the final ALLHAT results will be available.

20                    We also did a literature review.        We had two

21   selection criteria.        We looked for longer term clinical

22   trials with doxazosin, one year or longer in duration,

23   and we focused on these, because our own data was from

24   studies less than one year in duration.

25                    We also searched for publications discussing

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1    doxazosin and heart failure, and we limited this to

2    patients.        We excluded animal studies.

3                      We found 27 publications, including almost

4    6,000 patients.         When we reviewed these, we found no

5    evidence that doxazosin was causally associated with the

6    late occurrence of CHF, MI and stroke.

7                      So in conclusion, we found no evidence of

8    a signal to CHF, MI or stroke in the studies we reviewed.

9     There was no worsening of CHF with doxazosin when used

10   as add-on therapy to digoxin and diuretics in a placebo

11   controlled study in patients with CHF, and interim review

12   of MTOPS showed no significant difference in the incidence

13   of CHF in doxazosin versus placebo arms in men with BPH.

14                     So based on this, our conclusion is that

15   doxazosin does not precipitate CHF.

16                     I would now like to hand over to Dr. Gretchen

17   Dieck, our senior epidemiologist, who will discuss the

18   nonclinical        trial      post-approval         experience       with

19   doxazosin.

20                     ACTING CHAIRMAN BORER:         Before you do that,

21   are there any specific questions?               Yes?

22                     DR. D'AGOSTINO:         The ALLHAT trial has a

23   substantial number of females and a substantial number

24   of blacks involved.         These clinical trials that you are

25   summarizing -- how do the composition of male versus

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1    female, white versus black compare with ALLHAT?

2                     ACTING CHAIRMAN BORER:           Can we turn the

3    microphone on at the Pfizer table, please?

4                     DR.   WALMSLEY:        I    don't    have   specific

5    numbers, but we did include representative fractions of

6    both sexes and whites and blacks.             In fact, if you look

7    in our labeling, there is a statement that it's equally

8    effective in whites and blacks.

9                     ACTING CHAIRMAN BORER:         Ileana?

10                    DR. PINA:     In your MTOPS data where you have

11   a placebo controlled group, what were the ages of the

12   patients, and was there an exclusion for any evidence

13   of cardiovascular disease or how many of those patients

14   were hypertensive?

15                    DR. WALMSLEY:      I'd just like to point out,

16   this is an independent NIH trial.             It's not our trial.

17    But the mean age at entry was 63.              If you look at the

18   baseline data, 28 percent, I think, had hypertension in

19   addition to BPH.        Eight percent had diabetes, and 19

20   percent had something which was listed as a cardiac --

21   something relating to the heart, but it didn't specify

22   what cardiac diagnosis.

23                    DR. PINA:     So it sounds like it was a small

24   number of the patients who actually had at least a history

25   of hypertension.

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1                     DR. WALMSLEY:       Yes, 28 percent.

2                     DR. PINA:      Has that smaller subgroup been

3    looked at for the onset or heart failure occurrence in

4    that trial?

5                     DR. WALMSLEY:      I don't know, but I think we

6    may have Dr. Kusack here who is the NIH representative

7    for MTOPS.       He may be in the audience.            He had indicated

8    he would try and come.          He may be able to answer that.

9                     DR. PINA:     I have one other question.              Does

10   Pfizer have any data as to norhormonal levels, renin

11   levels, norepinephrine levels after the initiation of

12   doxazosin therapy?

13                    DR. WALMSLEY:      We do have a little data with

14   norepinephrine levels.            Dr. Leenen looked at this,

15   actually with prazosin, not with doxazosin, and found

16   some increase.       It was also looked at with doxazosin and

17   was not found, in fact, to show an increase.                 These were

18   small numbers of patients

19                    DR. PINA:     How about renin?         Do you have any

20   prazosin data?

21                    DR. WALMSLEY:       Renin, I don't know.

22                    ACTING CHAIRMAN BORER:          Alan?

23                    DR. HIRSCH:      Just to follow up again, what

24   ALLHAT provides is something that doctors kind of enjoy

25   looking at, which is unexpected results in a real-world

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1    setting, regardless of mechanism.                    But to follow up,

2    there's obviously great safety information in your

3    database that you didn't detail.                   But as you are well

4    aware, the sample is quite distinct.                  The quality of the

5    endpoints collection is different, and the follow-up is

6    short.

7                         Having said all that, what I would be looking

8    for to follow up on an ALLHAT finding that was unexpected

9    is to try to create a queried subset of the prior data

10   to try to match or case control, in a sense, the ALLHAT

11   population, realizing that it is, in a sense, a special

12   preselected population based on entry criteria.

13                        Instead of looking at the safety of the

14   global Pfizer database, have you made an attempt to try

15   to match or case control your database to match ALLHAT?

16                        DR. WALMSLEY:      I think this is a very good

17   point.           I think one of the difficulties is that we have

18   been looking at our safety databases, which don't include

19   all the information, and our databases from the individual

20   studies are individual databases.                I think this certainly

21   could be done, but it would take more time than we've

22   had up to now.

23                        I think this, you know, is something perhaps

24   that we should consider.

25                        DR. HIRSCH:     I recognize it's very difficult

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1    to do, although that would be the analysis I would want

2    to see to try to confirm or refute the findings.

3                     ACTING CHAIRMAN BORER:           Michael, did you

4    have -- Okay.      Bob?

5                     DR.   FENICHEL:        The    numbers     that      were

6    presented in your slides are certainly very reassuring,

7    taken on their face.        But you get down to the number of

8    cases, you know, I think -- I could be wrong, but I think

9    we're talking about a very small number of cases, perhaps

10   because you were just lucky enough to be in a healthy

11   population.

12                    If you could go back to your slide selected

13   cardiovascular events from 67 comparative studies, you've

14   got a total of 26 patients on doxazosin and, roughly,

15   I think you had three subjects with CHF in the doxazosin

16   group compared to one subject in the diuretic group out

17   of a total number of diuretics of 483 patients, and so

18   on.

19                    The number of subjects who actually had

20   events seems to be on the order of three or six or six

21   or two or one and so forth.        Are there -- Is it your belief

22   that your results are inconsistent with the results

23   suggested by Dr. Cutler?          In other words, where do the

24   confidence limits extend?

25                    DR. WALMSLEY:        Well, I think that's a

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1    difficult answer, because as I explained at the beginning

2    of my presentation, the patient populations are somewhat

3    different.            I mean, the ALLHAT patients were selected

4    as being at high risk for these kinds of events, and our

5    patients weren't selected in that way.

6                          We tried to select patients that were more

7    representative of the type of patients that are treated

8    with doxazosin.

9                          ACTING CHAIRMAN BORER:          Nonetheless, just

10   to follow up on Bob's point before we move on to another

11   issue, I couldn't do the addition quickly on                      the slides

12   as you showed them.            But in the booklet that we were sent,

13   between pages 16 and 18 there are a number of tables.

14                         I don't want to make more of these small

15   numbers          of   events    than    should     be      made    of    them.

16   Nonetheless, can you comment at least, for example, on

17   Table 2 on page 17 where a small but finite percentage

18   of patients on doxazosin had CHF and zero of the placebo

19   did.

20                         It may mean nothing, but when you see that

21   and you hear the hypothesis that would be generated from

22   the unexpected ALLHAT data, you have to ask why is this.

23                         DR. WALMSLEY:     You're comparing the 9 with

24   the zero?

25                         ACTING   CHAIRMAN     BORER:         Well,    the     .17

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1    percent with the zero, yes.

2                     DR. WALMSLEY:      Yes.     I would like to make

3    a comment here.       I am sorry.        I presented highlights,

4    and I perhaps should have included a table of just the

5    placebo controlled studies, and you'll find that in Table

6    6 on page 19.

7                     If you look at the 12 placebo controlled

8    studies, you see that this is zero throughout.                 I think

9    we can account for this by the fact that when you are

10   doing a placebo controlled study, you really make every

11   effort not to put the patient at risk.                So patients in

12   placebo controlled studies tend to be at lower risk.

13                    Whereas, when we are looking at Table 2,

14   we're including doxazosin patients from all of the

15   comparative studies, including active comparatives which

16   may have been at higher risk.

17                    ACTING CHAIRMAN BORER:         Okay.    Tom?

18                    DR. FLEMING:      I actually had a couple of

19   questions, and I wanted to follow in a similar spirit

20   to what Jeff was just asking, trying to interpret this

21   in the context of what we have from ALLHAT where, with

22   the alpha blocker and the diuretic we're looking at 25,000

23   people in a blinded, randomized trial that has yielded

24   1,000 fatal CHD, nonfatal MI events, 600 strokes, and

25   nearly 1,000 heart failure events.

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1                     As I probed through all of your data, the

2    two most informative elements that I found were in Section

3    2, the 84 completed comparative trials, which is the

4    information Jeff was just referring to, that basically

5    gives us in the doxazosin, placebo and diuretic arms ten

6    heart failure events, 26 Mi events, and 23 stroke events,

7    as well as the Section 5 medical literature review.

8                     The essence that I'm struck with here is that

9    these data weren't generated for purposes of really giving

10   us a reliable estimate of the relative effects on

11   important endpoints such as MI, heart failure and stroke.

12

13                    There will undoubtedly be in the medical

14   literature review publication bias.                    There's clearly

15   going to be under-reporting.            There's relatively short

16   duration of follow-up.         There's a relatively small sample

17   size.

18                    If we took the data that Jeff was just

19   referring to at face value, it would suggest that

20   diuretics may have an adverse effect on strokes and no

21   effect on MIs.      Obviously, that's inappropriate, because

22   these are extraordinarily small numbers.

23                    In your view, do these data truly provide

24   us even a glimmer of relevant insight relative to the

25   magnitude of the relevance of ALLHAT?

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1                         DR. WALMSLEY:         I think you're absolutely

2    right.           ALLHAT was the first cardiovascular outcome study

3    that studied doxazosin.               What we've done is looked at

4    our database for our most rigorous studies to see what

5    we can find from a safety point of view.

6                         Perhaps after you've heard our comments on

7    ALLHAT, some of our comments on that, perhaps we could

8    take this a little further then.

9                         DR. FLEMING:       Okay.     I'd be happy to come

10   back to that then.            I did want to, though, ask one more

11   question, because you emphasized this two or three times.

12                        Your conclusion was that available data

13   demonstrate           that   there    is    no   signal    of   a    causal

14   association for either heart failure, MI or stroke.                         In

15   essence, are you saying then that doxazosin, in your view,

16   has no effect on those endpoints?

17                        DR. WALMSLEY:         I think the early heart

18   failure is the strongest, because based on ALLHAT, we

19   would have expected to have seen an adverse effect, if

20   this was what ALLHAT was showing, in studies of this short

21   duration.           I think that is the strongest data.

22                        I agree with you that the MI and stroke, the

23   studies are much too short.                 But we included them for

24   completion, and we wanted, you know, to review all of

25   our safety data that was relevant.

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1                      DR. FLEMING:           Is it your intention to

2    establish        the   conclusion       that    there      is     no     causal

3    relationship with heart failure, MI or stroke, i.e., that

4    there neither is an adverse effect nor is there a favorable

5    effect?

6                      DR. WALMSLEY:          Well, I think what we are

7    saying is we didn't see any evidence of an adverse effect

8    in our database, and there are limitations, as you've

9    pointed out.

10                     DR. FLEMING:          What is the intention of

11   treatment with doxazosin?              Is it not, in fact, through

12   effects, in particular reduction of blood pressure, not

13   specifically to reduce blood pressure but mediated

14   through that to achieve beneficial effects on endpoints

15   such as MI, cardiovascular related deaths, strokes and

16   heart failure?

17                     DR. WALMSLEY:        Well, that's not just why you

18   use doxazosin.          I think that's why you use any drug to

19   lower blood pressure.                You are not lowering blood

20   pressure just to lower blood pressure.                    You are lowering

21   it to reduce the complications of the elevated blood

22   pressure.

23                     DR. FLEMING:         And your conclusion is your

24   data, in essence, suggests no evidence of a causal

25   relationship.          So if, in fact, there is interest in being

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1    able to establish a favorable relationship, you would

2    need to go to other sources of data such as ALLHAT?

3                         DR. WALMSLEY:       Yes.

4                         ACTING CHAIRMAN BORER:          Steve?

5                         DR. NISSEN:     I wonder if Pfizer has any data

6    on peak-to-trough effects for doxazosin at the various

7    doses?           Again, I'm trying to understand relative to the

8    doses used in ALLHAT what -- Blood pressure was measured

9    at a specific time when patients visited the clinic, and

10   I would like to know whether you -- what do you know about

11   peak-to-trough effects at various doses for this drug?

12                        DR. WALMSLEY:      Well, I do remember, when we

13   presented this data as part of the NDA, the comment was

14   made      by      the   FDA   that   this     was   some   of      the     best

15   peak-to-trough data that they had seen at that point,

16   based on the 24-hour detail.              I don't remember the actual

17   figures, I'm afraid.             It's ten years ago.

18                        ACTING CHAIRMAN BORER:            I'm sorry.          Ray?

19   No.

20                        DR. LIPICKY:        I have a question that is

21   somewhat like Tom's.             Tom, you shouldn't be picking on

22   them.        You ought to be picking on us.           Right?      We usually

23   look at a database of the size that they have -- a tenth

24   of the database, the size that Pfizer just showed, and

25   say we are going to conclude something about safety.

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1    So it isn't just their fault.

2                       The question that I wanted to ask was:                That

3    placebo controlled trial and the heart failure -- it might

4    be okay for giving some confidence that you don't find

5    some signal, but you must not believe it, because you

6    never pursued it.         You don't have an indication for heart

7    failure.         What happened?

8                       DR. WALMSLEY:       Well, this was done a long

9    time ago, and the ACE inhibitors have since been approved

10   for heart failure and shown to be very effective.                    I mean,

11   at the time, really, people were looking for something

12   to help digitalis and diuretics work in patients who were

13   still symptomatic, and they were looking at the addition

14   of vasodilators, and this is why we tested this.                           But

15   --

16                      DR. LIPICKY:      Okay.

17                      DR. WALMSLEY:        -- it really showed that

18   there was no harmful effects, but I don't think it really

19   showed enough benefit to make us pursue this as a CHF

20   indication.

21                      ACTING CHAIRMAN BORER:           Why don't we move

22   ahead then -- Thank you very much -- to Dr. Dieck, and

23   we will hear the next part of the Pfizer presentation.

24                      DR. DIECK:       Thank you.           I would like to

25   continue our discussion in decreasing order of scientific

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1    rigor.           I would like to describe the results of an

2    epidemiologic study that had been carried out in the early

3    Nineties, and I would also like to review our spontaneous

4    reporting experience.

5                        Prescription event monitoring, or PEM, is

6    an epidemiologic technique that was developed by the Drug

7    Safety Research Unit in the U.K.             PEM is generally carried

8    out -- or it's a means of being able to identify a cohort

9    of patients using prescriptions and follow them for

10   several months for their adverse experiences.

11                       Typically, in the U.K. PEM is carried out

12    shortly after a product's launch, and approximately

13   8-12,000          prescriptions      are     identified       from       the

14   prescription          pricing    authority.          The   prescribing

15   physician then sends out what are known as green cards

16   on a monthly basis to the patients, and they in return

17   fill out the form with adverse experiences they may have

18   had, self-reported, and send them back to the Drug Safety

19   Research Unit.

20                       For doxazosin approximately 8500 patients

21   were identified from March of 1989 through January of

22   1991, and the report from the Drug Safety Research Unit

23   identified that event rates for cardiac failure, cerebral

24   vascular accident and ischemic heart disease, again

25   self-reported diagnoses, were consistent with those

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1    observed for other PEM studies of antihypertensive

2    agents.

3                     We can see this on the next slide.              These

4    are the first month's results, but the report also

5    concludes that the average of months two through six had

6    similar types of results.

7                     Here we have the event rates for doxazosin

8    compared to other antihypertensive agents, and there is

9    no signal here that these events are being reported with

10   greater frequency for doxazosin than these other drugs.

11                    I would now like to review our spontaneous

12   reporting information for completeness, and our safety

13   alert database is comprised of spontaneous cases reported

14   to Pfizer by medical professionals and consumers, by the

15   medical literature and also by other adverse events

16   registries.

17                    It is important to keep several things in

18   mind when interpreting spontaneous reported information.

19    First, it is important to note that it is anecdotal in

20   nature and, whereas the clinical trials in epidemiology

21   are carried out in a scientific or quantitative framework,

22   that's not the case with spontaneous reports.

23                    The   reporting     rates     themselves      are         a

24   function of a variety of external factors such as the

25   indication of the drug or the drug itself with immediate

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1    exposure and regulatory actions and so forth.

2                      Most importantly, the spontaneous reporting

3    information provides us with a reporting rate, but this

4    is no means an incidence rates.

5                      We review our spontaneous reporting data on

6    an ongoing basis, and what Ill show you are the cumulative

7    results of our February -- cumulative through February

8    2001.        I want you to keep in mind that these results are

9    in the universe of 4.1 billion patient days of therapy

10   for over 13 years of worldwide experience with doxazosin.

11                     Our   safety      review    of    events       of     heart

12   failure-like        events,    stroke-like         events,     myocardial

13   infarction or related events were similar as those and

14   consistent with those generally seen for these types of

15   agents.

16                     Here we've compared -- This is a reporting

17   rate percentage over all cases reported, and we are

18   comparing        doxazosin     to    amlodipine,        glipizide          and

19   nifedipine.        Glipizide is a sulfonurea, but it was used

20   in a similar patient age and sex population as the other

21   drugs.

22                     Here again we have reporting rates for heart

23   failure-like        events,    myocardial      infarction,          related

24   events, and stroke-like events.               We are simply stating

25   here that there was no signal in our continuous review

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1    of the spontaneous reporting system that these events

2    were being reported at a higher rate with doxazosin than

3    similar types of drugs.

4                     I would now like to hand the podium back to

5    Pat Walmsley so she can discuss Pfizer's comments on

6    ALLHAT.

7                     DR. WALMSLEY:        Thank you.         I would now like

8    to present Pfizer's comments on ALLHAT, although many

9    of these have already been touched on.

10                    I first of all wanted to remind you that the

11   primary endpoint of ALLHAT, fatal coronary heart disease

12   and non-fatal MI, showed no difference between doxazosin

13   and chlorthalidone, and this was despite a two to three

14   millimeter difference in systolic blood pressure.

15                    We    feel    that    additional        information         is

16   essentially to fully interpret the study findings.                           We

17   would like to know the details of therapy, dose and blood

18   pressure for all the blood pressure with CHF and stroke

19   events.

20                    Although intention-to-treat analysis is the

21   normal way to analyze these large trials, we feel that

22   in this instance an on-treatment analysis would help to

23   clarify the relationship of therapy to events, in view

24   of the fact that at one year almost one patient in five

25   in the doxazosin group was not taking his assigned

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1    medication, and this increased to one patient in four

2    by four years.

3                     We feel that, to make an assessment of the

4    relationship between events and therapy with a view to

5    looking at this from the safety aspect, we really need

6    to look at the patients who were actually taking the drug.

7

8                     We would like to know the mean dose of

9    doxazosin in the patient population in order to relate

10   this to blood pressure control, and we also would like

11   to suggest an analysis of those patients who reach blood

12   pressure goal versus those who did not to help determine

13   the relationship of event to class of therapy.                    There

14   was, in fact, a difference in systolic blood pressure

15   reduction in the two arms.

16                    I would now like to look at the secondary

17   endpoint of congestive heart failure that was the one

18   causing the most concern.            As the paper discussed and

19   as you have head, other secondary endpoints, stroke and

20   angina, in fact, were attributed by the authors to

21   possibly being -- probably being related to the difference

22   in systolic blood pressure.

23                    Now here, as you've seen, there is a dramatic

24   and very early separation of the curves in the first year,

25   with maximal separation occurring by the first year.

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1    This raises the question of the role of discontinuation

2    of prior therapy.

3                          We know that 90 percent of the patients were

4    taking prior therapy.               We don't know what this was, but

5    just based on general prescribing patterns in the U.S.,

6    we can assume that many of these would have been on the

7    diuretic or an ACE inhibitor.

8                          We know that these patients were at high risk

9    for developing CHF.                 They were older.            Forty-five

10   percent          of   them    had   atherosclerotic         cardiovascular

11   disease at baseline.                   About a third were diabetic.

12   Sixteen percent had LVH, and it's likely that some of

13   these at entry may have had latent CHF that was being

14   treated by their diuretic.

15                         When this diuretic was stopped and doxazosin

16   substituted, doxazosin, of course, being a drug that is

17   not used to treat heart failure and, moreover, in some

18   patients can cause some fluid retention, it's likely that

19   this latent CHF would have become manifest and been

20   diagnosed as an event.               This, of course, wouldn't have

21   happened in the group where you are discontinuing diuretic

22   and replacing it with another diuretic.

23                         Latent CHF is difficult to diagnose in this

24   primary           care       setting     without       a    sophisticated

25   cardiovascular workup.                  And as we've already said,

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1    chlorthalidone is an effective treatment to CHF, and

2    doxazosin is not.

3                           CHF is a complex syndrome with a high

4    mortality rate, and we have already seen the all-cause

5    mortality         slide        which     shows    no    difference      between

6    doxazosin and chlorthalidone.                    This lack of a difference

7    in all-cause mortality is difficult to understand in view

8    of the difference observed in CHF incidence.

9                           As ALLHAT had no placebo group, as the

10   authors pointed out in the paper, we cannot say whether

11   the incidence of CHF is increased on doxazosin or

12   decreased on chlorthalidone, although studies such as

13   the SHEP trial indicate that it may possibly have been

14   more related to the latter, and this was, in fact,

15   discussed in the ALLHAT paper.

16                          If we look at SHEP, the Systolic Hypertension

17   in the Elderly Program, this is an NHLBI study that was

18   first reported about ten years ago.                        It included over

19   4,700 patients over 60 years of age with isolated systolic

20   hypertension, and it compared                          chlorthalidone with

21   placebo.

22                          The follow-up was a little longer than

23   ALLHAT, 4.5 years versus 3.3, but like ALLHAT heart

24   failure          was    a     secondary      endpoint.         Moreover,       the

25   diagnosis of CHF, the criteria for diagnosis of CHF in

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1    ALLHAT were based on those in SHEP.

2                     Now when we compare the incidence of CHF in

3    SHEP versus ALLHAT, you see the percentage incidence of

4    CHF on placebo compared with diuretic in SHEP.               There's

5    a difference of a factor of approximately two.              When you

6    look at the ALLHAT data, we see the same ratio between

7    the incidence of CHF on doxazosin versus diuretic as we

8    do in SHEP in placebo versus diuretic.

9                     This seems to suggest that possibly the

10   relative difference that is seen in CHF in ALLHAT may

11   be more representative of the beneficial effect of the

12   diuretic on CHF than an adverse effect of doxazosin.

13   In other words, the doxazosin is behaving like the placebo

14   group with regard to CHF with no benefit and no adverse

15   impact.

16                    We have already touched a little on this,

17   but in studies such as ALLHAT, in many studies, there

18   are practical considerations which prevent the optimal

19   usage of the drug.      There are limitations that are based

20   on things like the need to blind the drug and also the

21   need to standardize visit intervals, etcetera, which mean

22   that you can't always use the drug in the way that it

23   would be used as labeled.

24                    Perhaps a drug like doxazosin is at a bigger

25   disadvantage here, because doxazosin has five different

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1    dosage levels.         So it's difficult to blind against an

2    agent that has two or three dosage levels.                              So

3    one has to accept limitations, and this meant that there

4    was a slower titration to a less than maximum dose with

5    doxazosin, the maximum in the trial being eight versus

6    16 in the labeling, and this may have impacted on blood

7    pressure control and event rate in the early months,

8    particularly in vulnerable patients.

9                       If you look at the mean systolic blood

10   pressure         results,   although      the    mean    systolic       for

11   doxazosin is below the goal of 140 for most of the trial,

12   you see that it takes longer to reach that goal.                In fact,

13   it is about 12 months before we are actually at that goal.

14    Whereas, with chlorthalidone we get to the goal at

15   somewhere round about four months.

16                      This means, as these are only means, that

17   the outliers -- that there would probably have been many

18   more patients with systolic well above goal.

19                      Finally, we would like to remind everyone

20   that the ALLHAT are preliminary data, and there are many

21   questions that remain before the full implications of

22   the study can be understood.             We would like to reiterate

23   that we would like an on-treatment analysis to fully

24   interpret the results.

25                      Our overall conclusions are that doxazosin

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1    doesn't cause CHF, as seen in our review of our clinical

2    studies, literature review, the post-marketing studies,

3    and spontaneous reporting.

4                     We would like to emphasize that ALLHAT

5    documented a relative difference in incidence of CHF.

6    It didn't demonstrate causality, and there are several

7    factors which may have contributed to this relative

8    difference, the most important probably being that

9    chlorthalidone is an effective drug in the treatment of

10   CHF, and this is supported by SHEP, as I showed you.

11                    Many of the CHF events were early, and

12   discontinuation of prior therapy with diuretics and ACE

13   inhibitors may have played a role, as may the fact that

14   doxazosin, as we have discussed, was not able to be used

15   to optimal efficacy.

16                    I would now like to hand back to Suzanne

17   LoGalbo for some closing comments.

18                    DR. D'AGOSTINO:       We've heard a number of

19   times that the separation between the two drugs is early,

20   and that somehow or other is interpreted that, if you

21   explain the early separation, you're fine.              But if you

22   look at the graph of the congestive heart failure -- and

23   I'd like Tom's comment on this also -- it's consistently

24   a relative risk of about 2, no matter what year you're

25   going through.

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1                      We have a longer follow-up.           We have more

2    individuals in the follow-up at one year, but it isn't

3    that it only happened at one year and then it pulls

4    together.        It's consistently a relative risk of 2 across

5    the board.       So it's more than just a quick effect of the

6    congestive heart failure showing itself.

7               ACTING CHAIRMAN BORER:         Can we have the mike on

8    at the table, please?

9                      DR. WALMSLEY:      I think that's true.           There

10   is, obviously, more than one factor here, and I think

11   the role of discontinuation, together with the fact that

12   doxazosin wasn't used at its optimal dose, may well have

13   played a role in the early cases of CHF and, as you said,

14   there is a slight continuing divergence total time, but

15   we are comparing --

16                     DR. D'AGOSTINO:         Yes.      It's not slight.

17   It's consistent.

18                     DR. WALMSLEY:        We are comparing an agent

19   that treats CHF with one that doesn't treat CHF, and it

20   may be that some of the patients on chlorthalidone, in

21   actual fact, would be developing CHF if they weren't on

22   treatment, that it's already controlled and, therefore,

23   not diagnosed.

24                     DR. D'AGOSTINO:         I have another question

25   which may be unfair, but let me ask it.

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1                     You raise the question that maybe it's a

2    beneficial effect of diuretics as opposed to a negative

3    effect of Cardura.        Does that mean that ALLHAT should

4    have continued with the arm?            If that is true, should

5    ALLHAT have continued with the arm?

6                     I mean, say the separation is real and we

7    believe it, and we say, well, we shouldn't worry about

8    it, because it's just that the diuretics were a lot better

9    for CHF, so let's continue on.

10                    DR. WALMSLEY:     Well, we haven't seen all of

11   the data, and we certainly haven't seen the data that

12   the people who made this decision have seen.                  I think

13   we felt we should support their decision, because it's

14   their study, and they have seen the data, and we would

15   support them.

16                    I think it's a hard question to answer when

17   one hasn't seen what they saw.

18                    ACTING CHAIRMAN BORER:        Tom and then Ileana

19   and Ray.

20                    DR. FLEMING;      I'd like to get to Ralph's

21   question as well, following up on that.               But two other

22   real quick preliminary issues.

23                    You had raised what you were suggesting was

24   maybe an inconsistency between the difference in CHF

25   without the difference in mortality.             But the difference

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1    in CHF was a 4.4 versus 8.1 percent occurrence or about

2    a 3.7 percent excess; whereas, mortality estimates were

3    about 9.08 and 9.62.

4                      So in essence, is it that inconsistent to

5    say that, if there are 3.6 percent more cases of heart

6    failure, that may translate into .6 percent more deaths?

7                      DR. WALMSLEY:      I don't know.      I'd like to

8    ask someone with more statistical experience than I have.

9                      DR. FLEMING:     Okay.     Well, I'll just go on

10   to say it's not so obvious to me that that is inconsistent.

11                     The second point:      You noted that there was,

12   in fact, this titration schedule that led to a potential

13   delay in getting to more optimal doses.                That would --

14   or ore optimal dose levels, and that may, in fact, in

15   particular, influence stroke rate, I would think.                     Yet

16   there were no difference in stroke rates over the first

17   nine months.

18                     So is it, in fact, plausible that it was the

19   titration        schedule   that     really     accounted      for      an

20   apparently unfavorable effect of doxazosin?

21                     DR. WALMSLEY:     I guess I was just trying to

22   explain all the possible reasons that we could think of

23   that might account for it, and there's no doubt that the

24   blood pressure was less more controlled in the first year,

25   and there's no doubt that patients weren't on an optimum

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1    dose.

2                     If you look at the paper, I think 37 percent

3    of the patients were on less than 8 milligrams at one

4    year, of doxazosin.

5                     DR. FLEMING:       Let me move to the third

6    question, which is somewhat related to Ralph's.

7                     Your general sense in interpreting the data

8    is that doxazosin didn't harm the occurrence of a risk

9    of heart failure, but rather the diuretics provided

10   benefit, and you drew that conclusion by looking not only

11   at the results of ALLHAT but also SHEP.

12                    I actually tend to agree with you.             That's

13   my interpretation as well.         These data would suggest that

14   diuretics are particularly effective in reducing risk

15   of heart failure and, when you put the data together from

16   the two studies, it would suggest that doxazosin is

17   neither harmful nor at all beneficial.

18                    Granting then your conclusions, you then go

19   on to look at the primary endpoint of fatal CHD and

20   non-fatal MI, noting no difference.             In a certain sense,

21   I interpreted you were looking at that in a favorable

22   way.

23                    Why is it favorable?       If we're comparing to

24   an alternative control that we've granted is much more

25   effective on an endpoint as important as heart failure,

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1    why is it okay to just be the same then on cardiovascular

2    deaths and non-fatal MIs?

3                     DR. WALMSLEY:     Well, I was trying to point

4    out that there was no difference, that we were no better,

5    but we were no worse.

6                     DR. FLEMING:      And is that a good thing or

7    a bad thing?

8                     DR. WALMSLEY:     Well, I certainly don't think

9    it's a bad thing, but I'm not a statistician.

10                    DR. FLEMING:     Well, this isn't statistical.

11    This is clinical.       If we grant your statement that the

12   diuretic control regiment is unequivocally better in

13   treating heart failure, then why is it adequate when you

14   are comparing to that comparator to be the same on

15   cardiovascular related deaths and MI?                 Shouldn't there

16   in some sense be an area where you would hope the

17   experimental therapy is better then?

18                    DR. WALMSLEY:       Yes, I think you're right.

19    I mean, we had hoped that we would show superiority when

20   we entered the trial.

21                    ACTING CHAIRMAN BORER:         We have Ileana and

22   then Ray.

23                    DR. PINA:    Yes.     I wanted one question to

24   follow up my previous question, and then a clarification.

25

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1                        You made a statement that doxazosin makes

2    retention of fluid, and I had asked you before if you

3    knew what happened to things like renin level and other

4    neurohormonal            levels    with    the    drug.           What        do    you

5    postulate is the mechanism of fluid retention in this

6    type of agent?

7                        DR. WALMSLEY:         Many vasodilators do cause

8    some elements of fluid retention, and I don't know that

9    the mechanism has really been fully worked out.

10                       DR. PINA:        Some vasodilators cause edema,

11   not necessarily true fluid retention, which may be two

12   different things.

13                       My     second     point       is       a    clarification.

14   Chlorthalidone is not a commonly used diuretic at all

15   in heart failure patients, and it's a difference between

16   congestion and heart failure, and they are two different

17   things.          All heart failure patients are not congested.

18

19                       I tend to agree with you that something got

20   unmasked, because it happened very early.                              So I agree

21   with Dr. Fleming's point, but that fluid retention

22   somewhere in there needs to be explained.

23                       ACTING CHAIRMAN BORER:             Ray?

24                       DR.    LIPICKY:         Well,      I       just     wanted        to

25   reiterate, because I think it got forgotten and I'm not

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1    sure it's right, that the distinction between -- that

2    somehow or another one needs to make the distinction here

3    for congestive heart failure whether irreversible harm

4    occurred; because if this is just reports of heart

5    failure, then in fact that's a different thing from heart

6    failure occurring as a progression of disease.

7                        I repeat the statement that the two groups

8    may have had heart failure progressing equivalently, but

9    that one group would have had more reports of heart

10   failure,         because in fact they weren't receiving a

11   diuretic.           So    that    that    distinction,      I     think,        is

12   important to make, and particularly when we get to it

13   this afternoon, since this is a drug indicated for benign

14   prostatic hypertrophy.

15                       If you think that there is, in fact, some

16   effect of doxazosin on the heart that causes heart

17   failure, then people with BPH shouldn't be receiving it

18   either.          So this is a subtle distinction that, I think,

19   needs to somehow or another be debated.

20                       ACTING CHAIRMAN BORER:            Marvin?

21                       DR. KONSTAM:        Can I just add one other point

22   to that, Ray.             I mean, we talked about the potential

23   effect of the diuretic, but there's also a potential

24   effect of the blood pressure difference that may not be

25   directly linked to irreparable harm, and that is to say

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1    that, if your blood pressure is higher, your afterload

2    is higher, and you are more likely to present with heart

3    failure, independent of whether that has any significance

4    with regard to natural history and irreparable harm.

5                     So there are a couple of things going on early

6    on.      One could be the diuretic effect -- you know, as

7    has been pointed out, not only the 3 millimeter difference

8    but the year that it took to get to below 140 in the mean.

9     So that could be also influencing people coming into

10   the hospital with heart failure.

11                    DR. TEMPLE:     Let's suppose it's really true

12   that -- not that it's easy to know this -- that doxazosin

13   doesn't actually make you get heart failure, but it's

14   merely not a drug that treats it.              It's suppose that's

15   true for the moment.

16                    What do you feel the proper role in therapy

17   is for a role like that when a lot of people, it turns

18   out, not known to have heart failure before they entered

19   the study turn out to be at high risk of heart failure,

20   and     the consequence of using doxazosin instead of

21   something else -- we all wish we knew what the other drugs

22   in ALLHAT had been doing in this case, but we don't.

23   What's the implication of that for first line versus

24   second line therapy, whatever the explanation.

25                    Maybe it's even that it takes longer to get

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1    to goal.         Whatever the explanation, doesn't that suggest

2    that it's not a very smart first line drug, as other people

3    have suggested?         How do you all feel about that?

4                       ACTING CHAIRMAN BORER:          Can we turn on the

5    mike at the table, please?

6                       DR. WALMSLEY:          ALLHAT was a high risk

7    population, and I think when you are looking at patients

8    who are at lower risk, particularly at lower risk of

9    developing heart failure, doxazosin can be a very useful

10   drug, particularly --

11                      DR. TEMPLE:       Take for a moment the SHEP

12   population.         I don't know whether that's very high risk

13   or not, but the benefit of a diuretic compared to a drug

14   -- that is, placebo -- with no effect on heart failure

15   was apparently obvious there also.

16                      So let's say doxazosin just has no beneficial

17   effect on heart failure, but is here              neutral.     So that's

18   another place in which there seems to be some benefit,

19   not      necessariliy      that    that     affects      survival,       but

20   hospitalization isn't good, and heart failure symptoms

21   aren't good.         Why would one do that?

22                      I'm trying to take your best case assumption

23   and follow up what the implications of it are.

24                      DR. WALMSLEY:        I think most people these

25   days seem to feel that the most important thing is to

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1    get the blood pressure under control, and if you are giving

2    a drug like doxazosin, whether you are giving it first

3    line or as add-on, you need to get the blood pressure

4    under control.         If the blood pressure isn't controlled,

5    you need to give something else with it.

6                      I   think      in    patients          who    have       mild

7    hypertension and low risk, and particularly patients,

8    for instance, who have mild hypertension and BPH, it's

9    very useful as initial therapy.                But I think it's very

10   important to make sure that the patients don't have any

11   increased risk for CHF and that they do get to goal.

12                     DR. KONSTAM:        Can I ask you a question, Dr.

13   Walmsley?        Can you tell us something about how doxazosin

14   is used in the community?             You know, how often are doses

15   above 8 milligrams used?              How different is ALLHAT from

16   -- I understand the packet insert, but in terms of actual

17   use?

18                     DR. WALMSLEY:         Well, I think this is an

19   interesting question, because if you look at our studies

20   that we've done, the mean daily dose for efficacy is close

21   to 8, just under 8.           But if you look at the real-world

22   population, most physicians don't titrate it that far.

23

24                     I think this is one of the problems with our

25   standard doxazosin formulation, because if you start with

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1    an effective dose, you might get an excessive hypotensive

2    response.        We start with a dose 1 milligram and titrate

3    up, and very few patients will respond to 1 milligram,

4    and 2 milligram is not a great deal better.

5                      So physicians don't tend to like to keep

6    titrating, and they get fed up and switch.

7                      DR. KONSTAM:      Well, so just to go with that

8    for a second -- I mean, you've raised some important points

9    about needing to know more about the doses used in ALLHAT

10   -- actually used in ALLHAT.            But let's say for the sake

11   of argument we find that it isn't that different from

12   what's going on in the community.

13                     Then we say, well, part of the difference

14   in the events may be a function of less effective blood

15   pressure control in the doxazosin arm.                  What conclusion

16   would you draw from that?            Would you say that something

17   has to change in terms of educating practitioners on how

18   to use doxazosin or what conclusion would you draw from

19   that?

20                     DR. WALMSLEY:         Well, I think there is

21   another difference in ALLHAT.                Again, because of the

22   design of the study, that means doxazosin isn't used

23   typically in the way it's used in the community, and that

24   is the choice of additional therapy to get to goal.

25                     I think very few physicians would add to an

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1    alpha-blocker reserpine, hydralazine, fonadine.                        I think

2    the usage --

3                         DR. KONSTAM:       But it sounds like that's not

4    actually what was added most of the time in ALLHAT.

5    Right?           It was beta-blocker most of the time.

6                         DR. WALMSLEY:        Well, beta-blocker was the

7    most frequent, but if you add up the incidence of the

8    others -- I don't know the data, but from the paper it

9    looks as if there were a significant number of patients

10   who received the others.

11                        I   think    in    the    clinic       situation      most

12   physicians, if they are using something in combination

13   with doxazosin, would probably choose either a diuretic

14   or an ACE inhibitor or calcium blocker rather than one

15   of the other agents.

16                        ACTING CHAIRMAN BORER:           Ray?

17                        DR. LIPICKY:        You left the topic of which

18   is better too soon for me.                    If I were a practicing

19   physician, and I'm not and haven't been in sometime, I

20   would prefer to use doxazosin if I knew that it didn't

21   cause heart failure; because I want to know when my

22   patients are developing myocardial problems, and I want

23   to be aware of that, because that definitively changes

24   their prognosis, and I want to tell them to get their

25   lives in order.

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1                          I do not want to mask the symptoms of heart

2    failure and, therefore, delude both the patient and

3    myself.          So I would suggest that there isn't any clear

4    answer           to   which   is     better.       It       depends    on     the

5    circumstances, and that I don't know which is going on

6    here.

7                          ACTING CHAIRMAN BORER:            Okay.    I think we

8    are getting into the discussion of the questions here,

9    and rather than do that, maybe we can let Pfizer complete

10   its presentation, and then everybody who wants to can

11   go to lunch.

12                         I want to point out while you are coming up

13   here that we don't take breaks, because the United States

14   government expects us to give a full day's work for a

15   full day's pay here or, in the case of this committee,

16   a full day's work for no pay, and we're going to do that.

17                          MS. LOGALBO:      Okay.     I just want to quickly

18   just answer one of the questions.                   About 70 percent of

19   the use in the U.S. is add-on therapy on doxazosin.

20                         I would like to indulge the committee for

21   a second and introduce Dr. Sverre Kjeldsen, who is the

22   Chief Cardiologist at the Ullevaal University Hospital

23   in Oslo.          He has some comments on the trial design which

24   might be helpful in coming to some conclusions before

25   we move on.

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1                     He does have some overheads.             Is there a way

2    to have the screen brought down and the overhead turned

3    on?

4                     DR. KJELDSEN:            Committee members, ladies

5    and gentlemen, is it possible for me to show some few

6    slides?

7                     ACTING CHAIRMAN BORER:                Can we have some

8    audiovisual help to get the overhead back?

9                     DR.        KJELDSEN:          I   am    a       practicing

10   cardiologist based on the University Hospital in Oslo,

11   and I am invited here because I am heavily involved in

12   clinical trials, outcome trials in hypertension, and I

13   am currently involved in leadership of studies comprising

14   about 45,000 hypertensives, including the VALUE trial

15   supported by Novartis, the LIFE study supported by Life,

16   and the ASCOT trial which is supported by Pfizer.

17                    In the ASCOT trial in U.K. and Scandinavia,

18   we have randomized 19,000 hypertensives at very high risk

19   comparing outcome on atenolol and amlodipine, and in that

20   trial we use doxazosin as add-on treatment, and we have

21   decided not to make any changes in that.

22                    I just want to make some few comments on the

23   ALLHAT population.           First of all, this is taken from the

24   publication.           We    see   that    it's    a    very     high      risk

25   population, high age 67.           Ninety percent were previously

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1    treated with probably two drugs.               Could be diuretics,

2    beta-blockers, ACE inhibitors.                About half of these

3    subjects had coronary heart disease.              Twenty percent had

4    LVH, and a third of them qualified into the trial with

5    diabetes.

6                     So it's very likely that a lot of these

7    subjects really had latent heart failure.                    This is not

8    really a primary prevention study.               To me, it seems to

9    be much like a secondary prevention study.

10                    Elderly subjects:        Very high risk of heart

11   failure, and then previous medication is discontinued.

12    I mean, medication including probably diuretics and ACE

13   inhibitors       treating    heart    failure,         and   then       these

14   subjects are rolled over onto either something that is

15   treatment for heart failure, chlorthalidone, or something

16   which is insufficient dose of an antihypertensive agent

17   like doxazosin.

18                    Whether this is true heart failure or just

19   fluid retention cannot be decided, because we haven't

20   seen the data.      But the curve really suggests when they

21   separate very early on that much of this could just be

22   explained by fluid retention in subjects predisposed to

23   having heart failure.        And there is a slightly separation

24   on, which could possibly be explained by new cases of

25   heart failure, probably then caused by difference in blood

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1    pressure.

2                       This is taken from a previous review of 12

3    clinical trials based on diuretics, comparing placebo.

4    Heart failure was reduced by about 50 percent.                              It

5    suggests that if doxazosin -- in the worst scenario,

6    doxazosin is neutral.            It's like placebo.

7                       If in case one claimed that doxazosin is

8    causing heart failure, it should be causing a deadly

9    disease.         But mortality, as we have seen now repeatedly,

10   is      completely       unchanged        between        doxazosin        and

11   chlorthalidone.

12                      Just wanted also to emphasize on the primary

13   outcome:         Coronary heart disease is probably the main

14   reason for heart failure, and there is no difference

15   between doxazosin and chlorthalidone in the ALLHAT trial.

16    This is the primary endpoint the trial was designed to

17   investigate.

18                      This is quite interesting, even in light of

19   the difference in blood pressure. Despite the fact that

20   blood pressure has not been properly treated in the

21   doxazosin arm, the outcome, the primary outcome is

22   identical.          No difference in coronary heart disease

23   between the two groups.

24                      So putting it altogether, comparing the

25   ALLHAT data with data from other large clinical trials,

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1    comparing different antihypertensives during the recent

2    years, there is really no difference if you just focus

3    on the primary endpoint.

4                     I think we should focus on the primary

5    endpoint in these trials.           That's what they have been

6    designed to investigate, and current knowledge in the

7    treatment of hypertension says that it's the blood

8    pressure lowering effect per se which we should go for,

9    and that all these drugs actually are equal in preventing

10   the primary endpoint.         Thank you.

11                    ACTING CHAIRMAN BORER:           Okay.      Are there

12   any other comments from Pfizer?

13                    MS. LOGALBO:      Just the one that we wanted

14   to leave you with before you go to lunch.                 In essence,

15   it's what we have been saying for most of the morning,

16   that based on the totality of the data that we have

17   reviewed over the time that these findings have been

18   found, that we know that doxazosin does not precipitate

19   CHF, and that our recommendation at this time is that

20   there is no action that is required and that, if diligent

21   monitoring should be continued and if in the future there

22   are further findings that more elucidate these results,

23   we would be happy to work with regulators on an ongoing

24   basis.

25                    Thank you very much for your time, and I'm

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1    sure we would want to make some closing remarks before

2    we go to lunch.       Thank you.

3                     ACTING CHAIRMAN BORER:         Thank you very much.

4     I really want to thank all the formal presenters. This

5    is a very serious question or series of questions that

6    are     being    raised   here,    and    we   will    go     over      them

7    preliminarily       after    lunch    before     getting        into      the

8    particular issued raised by the FDA.               But we have heard

9    a tremendous amount of information presented in concise

10   and clear fashion, and I want to thank everybody who has

11   done that.

12                    We are going to break now for lunch.                   It's

13   important, if you intend to do that, to know that the

14   NIH no longer has a cafeteria in its basement.                       If you

15   haven't been here in a while, that's going to come as

16   a surprise.

17                    It is on the second floor.            So you can go

18   out to the second floor, have lunch, and we'll come back

19   here and begin no latter than 1:15.

20                    (Whereupon, the foregoing matter went off

21   the record at 12:12 p.m.)

22

23

24

25

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

2                                                                      (1:16 p.m.)

3                        ACTING CHAIRMAN BORER:                  Do we have the

4    Committee members in the room?                  While we are all getting

5    together, it may be useful to make a couple of short

6    points.

7                        First of all, it would be unfortunate if,

8    in     the       discussion     this     morning,     a     few    facts      were

9    forgotten.          Number one, that it's virtually impossible

10   to answer all the questions you want to ask in a single

11   clinical trial.            So it's not surprising that many of the

12   issues about which Dr. Cutler was asked couldn't be fully

13   answered in a rigorous way.                You just can't do that with

14   one single trial, and this was an outstanding trial, but

15   it's just one trial.

16                       Important information on specific points can

17   be obtained, and the citizens' petition suggests that

18   sufficient information has been obtained thus far from

19   this trial to support changes in the instructions for

20   use of the drug, and the FDA has asked us whether we,

21   the Committee, agree with that.

22                       We    are    going    to    go   over     the      specific

23   questions that the FDA asked the Committee this afternoon.

24    They fall into three categories, I think, or two with

25   a subset, and I believe it's useful to keep these in mind

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1    as we go through these.

2                     First, not in this order necessarily:                 Is

3    labeling needed?        We heard a fair amount of discussion

4    about this just before lunch.          Is a labeling change needed

5    if one antihypertensive drug doesn't provide all the

6    benefits of blood pressure reduction that are expected

7    and seen with all other drugs?              That's one issue.

8                     That is separate from the issue of whether

9    the data we have been presented indicates that the drug

10   in question here doesn't provide these benefits, given

11   the issues of dose, time and all the issues that were

12   raised.

13                    Then as a subset of that second issue, we

14   have to decide whether or not this drug, doxazosin, causes

15   irreversible myocardial dysfunction or damage or whether

16   it allows irreversible myocardial dysfunction to happen

17   that wouldn't have happened if a different drug were used

18   or dysfunction that wouldn't have occurred if another

19   drug had been used.

20                    Those are the things that we are really being

21   asked to respond to.         Those are the issues we are being

22   asked to respond to, but we are being asked in a program

23   fashion with several questions.

24                    Our   reviewer     for    the   Committee    is     Tom

25   Fleming, and before we go through the questions, which

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1    we will do in structured format and may have questions

2    for the formal presenters while we are doing that, it

3    would be useful to hear Tom's overview, since he is the

4    reviewer for the Committee and has some specific comments

5    to make.

6                      DR.     FLEMING:         Thanks,         Jeff.      There's

7    obviously a myriad of complex issues here and several

8    pages of questions, and what I will try to do is try to

9    give a quick overview and summary, focusing more on

10   specific         data      and     preliminary         or      first       line

11   interpretation of that data, and assume that we will get

12   into much more details as the discussion goes on.

13                     Essentially,         I've      organized     my     summary

14   thoughts in the context of, first, looking at the data

15   presented to us by Pfizer, then touching on the ALLHAT

16   data, and then SHEP, and then some summary thoughts.

17                     Pfizer's presentation was based on their

18   review of available clinical and post-marketing data on

19   doxazosin, and they focused on heart failure, MI and

20   stroke, and in essence have provided in Sections 2 through

21   5 of their report information on overall trials, their

22   early alert safety database, their prescription event

23   monitoring, and their medical literature review.

24                     In essence, in my review the data that really

25   was potentially most informative came from their Section

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1    2 comparative trials in which there were 271 and 47,000

2    participants.           In particular, I focused on the 84

3    completed        comparative trials, 67 of which were in

4    hypertension involving about 5,000 patients receiving

5    doxazosin and 1600 on placebo, and about 500 on diuretics.

6                      As    I   had    mentioned      this    morning,      what

7    certainly stands out is that that information in terms

8    of heart failure, MIs and strokes are really very limited

9    compared to what we learn from ALLHAT with 10, 26 and

10   23 respectively events in total on those three arms,

11   compared to roughly 1,000, 1,000 and 600 heart failure,

12   MI and stroke events that we see from ALLHAT.

13              In addition, the source of information here,

14   obviously, is going to have -- because of its nature as

15   a safety database, in particular, is going to be looking

16   at much shorter duration, smaller sample sizes and

17   under-reporting.            In fact, that database would suggest

18   that, if you took literally what the results show, that

19   diuretics themselves don't provide favorable benefits

20   on heart failure, MI and stroke;                  and obviously, that

21   would be very misleading to conclude that in those small

22   numbers.

23                     In    their     medical      literature     review        in

24   Section 5, the biggest source of data in those 5900

25   subjects came from 4200 subjects in a surveillance trial

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1    in Norway, and again in a surveillance study such as this

2    one has to be incredibly cautious about publication bias,

3    under-reporting, relatively short duration, follow-up,

4    and small sample sizes.

5                     It was noteworthy, though, that in that

6    experience HDL cholesterol levels did seem to fall, which

7    they had noted as one surprising observation.

8                     Overall, the sponsor concluded in their

9    review of all of this information that there was no signal

10   regarding a causal relationship between doxazosin and

11   heart failure, MI and stroke.

12                    My own sense is that such surveillance data

13   certainly do play a role, and this type of information

14   would be very informative in detecting safety events that

15   occur with a very high relative risk.

16                    Essentially, though, if we are trying to use

17   these data to generate some relevant and informative

18   insight in the context of the ALLHAT data, I see that

19   this       information   is    not     particularly     additively

20   informative in the sense that it is not going to be

21   effective in detecting increases in adverse events where

22   the relative risks are less than or equal to two, which

23   is what we are looking at here in ALLHAT, as well as being

24   able to really address longer term effects, where many

25   of these sources of information were for very short

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1    periods of time for treatment, on the order of one month.

2                     ALLHAT then presents for us an incredibly

3    important resource for understanding relative efficacy

4    on primary and secondary endpoints and in safety measures.

5                     Based on what the protocol had indicated,

6    as well as where the focus has been by the study team,

7    the primary endpoint is fatal CHD and non-fatal MI, which

8    clearly are critically important outcomes.                 When one

9    looks at other clinically compelling or very important

10   outcomes, certainly stroke and heart failure are key.

11                    So from a statistical perspective, even

12   though outcomes that address effects on stroke and heart

13   failure are secondary endpoints, they clearly stand out

14   as especially important, clinically important endpoints.

15                    What we've seen, as has been discussed at

16   length, is an increase in the rates of all of these

17   endpoints on the doxazosin intervention, although for

18   the primary endpoint the increased relative risk is very

19   close to one, 1.03.

20                    Pfizer has raised several important concerns

21   about the interpretation of ALLHAT.              I'll just quickly

22   pass through them, because these will certainly be

23   important in our discussion today.

24                    One is whether or not the titration schedule

25   and maximum dose contributed to a less than optimal blood

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1    pressure management, and one of the issues that we need

2    to address is:        Nevertheless, is this schedule and dose

3    used in ALLHAT in essence consistent with what is a

4    real-world schedule?

5                       Marv was in essence probing a very important

6    issue, and that is does this match what people do in the

7    real world?         How often do people get to 16?

8                       Certainly, one of the major issues that one

9    would raise with a less than optimal blood pressure

10   control, in particular, would be less than optimal control

11   for stroke.        It's noteworthy that the diastolic outcomes,

12   though, were the same between the diuretics and the alpha

13   blocker.         The systolic differed by 3 millimeters at one

14   year and 2 thereafter.

15                      It was of interest, though, in my review of

16   the data that stroke differences that emerged, emerged

17   after nine months.         There were no differences in the first

18   nine months, and the stroke differences at two years were

19   only a third of the overall stroke differences seen at

20   four years.

21                      So where the differences in blood pressure

22   between the alpha blocker and the diuretic were most

23   apparent in the first year, over the first two years the

24   excess stroke rate was half of what the excess stroke

25   rate was between years two and four.

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1                         The sponsor has also pointed out that there

2    is a need for additional data that's not yet been presented

3    by the publication.              Certainly, that is an important

4    issue.           We have only received what we have been provided

5    in the main publication of this study, and there are many

6    additional important analyses that aren't yet possible,

7    based on the data that have been presented.

8                         One of those sets of analyses that have been

9    asked for are on-treatment analyses and analyses of

10   patients who actually reached their blood pressure goals.

11    Being an intent-to-treat enthusiast as I am, I would

12   argue, though, that even though those could be of some

13   merit as supportive analyses, the most interpretable

14   analysis is the analysis that was presented to us in the

15   manuscript, the ITT analysis.

16                        One is always left, for example, when you

17   are looking at subgroups of people that, for example,

18   met their blood pressure goals, of sorting out what, in

19   fact, represent a treatment effect versus what are the

20   intrinsic characteristics that define patients who could

21   reach those goals versus those who couldn't, and that

22   confounding forever leaves those kinds of analyses,

23   beyond treatment analyses and the analyses of people who

24   reach targeted goals, as very difficult to interpret.

25                        The sponsor, Pfizer, also noted that there

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1    was an early emerging difference in heart failure, and

2    the overall doubling in heart failure seems to be

3    inconsistent with the lack of mortality differences.

4    In fact, Ray has raised the question:                  Is, in fact, the

5    heart failure effect really an unmasking effect that we

6    are seeing?

7                     It's    difficult        from         my   perspective

8    statistically to sort that out.                The excess in heart

9    failure is 4.5 percent versus 8.1 or about 3.6 percent

10   overall, and there is a .6 percent difference in mortality

11   at four years.

12                    It may be, if one followed for a longer period

13   of time, that additional differences may emerge.                   That's,

14   in fact, one of the important additional insights that

15   may, in fact, come from more complete data.

16                    The sponsor made one other key point, and

17   that was that the diuretics regimen does decrease heart

18   failure by a factor of about two, if you go back to the

19   SHEP data.       In turn, if you use ALLHAT, diuretics reduce

20   heart failure by a factor of two relative to the alpha

21   blocker, leading them to conclude that, in fact, the alpha

22   blocker is probably the -- is inert, neither favorable

23   nor unfavorable.

24                    I find that a fairly strong argument.                      In

25   fact, it draws my attention to the SHEP data.                     In fact,

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1    going to the SHEP data, one of the issues that I think

2    is extremely important for us to address is what nature

3    of effect does one need to see on the primary endpoint,

4    in particular, but also on secondary endpoints, to

5    conclude that doxazosin, in fact, is beneficial?

6                       The    Data        Monitoring      Committee        and      the

7    Steering Committee recommended termination of the study,

8    in essence based on what I would call a superiority

9    analysis, i.e., the data reflected little difference on

10   the primary endpoint between doxazosin and diuretics.

11                      Conditionally given the analyses that had

12   been observed in that 60 percent of projected events,

13   the      calculation          was    there    was    only    a    very       small

14   probability of superiority being seen on the primary

15   endpoint in the final analysis.                     Roughly less than one

16   percent, I think, was that analysis.

17                      To justify termination then based on a low

18   likelihood of a positive result, it is implicit then that

19   no     difference        is    unacceptable.          In    essence,         as        I

20   interpret what the Data Safety Monitoring Board and

21   Steering         Committee      has      judged,     is    with     compelling

22   evidence of lesser benefit on heart failure and other

23   considerations such as cost, that if doxazosin, in fact,

24   yields only the same result as diuretics on the primary

25   endpoint of fatal CHD and non-fatal MI, then that's an

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1    unacceptable effect.

2                     That's an issue that I think deserves some

3    considerable discussion by us this afternoon.                   I would

4    like to maybe add a little bit of insight before we get

5    into that discussion.

6                     An alternative approach, an alternative

7    interpretation of these data would be to say SHEP

8    established diuretics to be effective.                If, in fact, we

9    can show alternative regiments are equally effective,

10   then that in essence leads to the conclusion that we have

11   an intervention that, in fact, is better than placebo.

12    That's the classical noninferiority argument.

13                    So the question might be raised:                    Even

14   though I believe the protocol team clearly provided strong

15   evidence that, if ALLHAT were to continue to its full

16   completion,      the probability of being able to show

17   superiority of the alpha blocker to the diuretics was

18   very low, which I believe is established, can one at least

19   conclude that the alpha blocker has a beneficial effect

20   on fatal CHD and non-fatal MI?

21                    To address this, essentially I used two

22   sources of information, SHEP to give me the active

23   comparator effect, and ALLHAT to give me the relative

24   effect of the alpha blocker against the diuretic.

25                    In essence, I did this quick analysis on

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1    heart failure, stroke and the primary endpoint.                  We have

2    already discussed the heart failure.                  So moving on to

3    stroke, the SHEP analysis indicates a 36 percent reduction

4    in stroke for diuretics; whereas, the ALLHAT trial

5    indicates that the alpha blocker has a 19 percent higher

6    rate of stroke.

7                     If you use the Hasselblad and Kong imputed

8    placebo approach as a way of trying to merge this

9    information, one then draws the conclusion that there

10   is a 24 percent reduction in the rate of stroke from the

11   alpha blocker versus an imputed placebo.                     But that

12   confidence interval includes one.              So this data would

13   not be viewed as significant evidence of a favorable

14   effect on stroke.

15                    If you do the same kind of analysis on the

16   primary endpoint of fatal CHD and non-fatal MI where SHEP

17   indicates that diuretics have a 27 percent reduction and

18   ALLHAT indicates that the alpha blocker is three percent

19   worse than diuretics, one gets an estimate of about a

20   24 percent reduction, but a confidence interval that

21   essentially is at one.

22                    So bottom line, what is this saying?                What

23   it's saying to me is we have certainly clear evidence

24   that the alpha blocker provides a beneficial effect on

25   hypertension, on blood pressure.                There is also the

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1    anticipated      effects,     lipid    effects.            However,        as

2    suggestive as these markers may be of clinical effects,

3    there are a myriad of examples in the literature that

4    have shown that, until one actually validates that the

5    intervention that achieves these marker effects actually

6    achieves the clinical effects mediated through those

7    marker effects, there is uncertainty.

8                     The best data that I can see from what is

9    available, if we are really trying to say from all of

10   this information what does doxazosin do relative to

11   important clinical endpoints, it's the combination of

12   information from ALLHAT and studies such as SHEP.

13                    The data do, to my way of thinking, clearly

14   show that diuretics are effective in reducing the risk

15   of heart failure by a factor of two, and suggest that

16   the alpha blocker has no effect on heart failure.

17                    Relative    to   stroke     and      to   the    primary

18   endpoint of fatal CHD and non-fatal MI, SHEP provides

19   significant evidence of favorable effects on both of those

20   endpoints.       ALLHAT suggests that the alpha blocker is

21   less effective in stroke, possibly because of the blood

22   pressure issue, and essentially the same, if not just

23   slightly less effective, on the primary endpoint.

24                    Clearly, then these data do not establish

25   superiority of doxazosin to the diuretics.                       Do they,

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1    though,          at    least      establish       efficacy    through             a

2    noninferiority            argument      using      an   imputed     placebo

3    analysis?

4                          Even with that much weaker standard, the data

5    do not establish significance for an effect of the alpha

6    blocker          on   stroke,     and   are    essentially     marginally

7    adequate for establishing significance on fatal CHD and

8    non-fatal MI.           I'll argue that's using a method that many

9    of us would argue is relatively less rigorous than the

10   typical standard we would ask for today in designing an

11   active controlled trial.

12                         So using even a very permissive approach,

13   these data don't establish that there is, in fact, an

14   effect.          They are suggestive of an effect on stroke.

15   They are suggestive of an effect on fatal CHD and non-fatal

16   MI.       But they don't prove an effect according to the

17   standards that we would rigorously ask for today if we

18   were designing a noninferiority trial design.

19                         So in essence, to summarize, far and away,

20   even with issues of concern with ALLHAT, ALLHAT provides

21   far and away the most informative source of information

22   about the effect of doxazosin on the critically important

23   clinical endpoints of fatal CHD, non-fatal MI, and stroke

24   and heart failure; and evidence suggests no effect on

25   heart failure.            Evidence suggests favorable effects on

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1    stroke and fatal CHD, non-fatal MI.              But not at a level

2    of     rigors    that   we    would   typically        require     from         a

3    noninferiority trial design.

4                     ACTING CHAIRMAN BORER:          Tom, can I ask for

5    a clarification here?          You looked carefully at the SHEP

6    data, the available data, and that's a large trial.

7                     My perception is that when we've used the

8     putative placebo concept to determine efficacy with an

9    active comparator, we've typically looked across multiple

10   trials to make sure that the difference between placebo

11   and active drug is relatively consistent, so that we can

12   be reasonably certain that the placebo effect we are

13   imputing or the difference from placebo we are imputing

14   is probably right.           But here we are using one trial.

15                    Is it big enough so you can be reasonably

16   confident of that approach?

17                    DR. FLEMING:         Well, in the interest of

18   brevity, I didn't get into any of those very key questions

19   that you've just raised.           The typical analysis that we

20   would require for a noninferiority comparison, as you

21   say, Jeff, requires substantial precision in estimating

22   the effect of the active comparator and the ability to

23   say with confidence that the effect of the active

24   comparator, in this case the diuretic whose effect is

25   understood through SHEP, that that effect as estimated

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1    in SHEP is relevant to,             specifically in this case,

2    effects in ALLHAT.

3                     It's the reason I said the analysis that I

4    had given that doesn't meet the standards for strength

5    of evidence is, in fact, a permissive or lenient analysis,

6    because it hasn't begun to address the relevant points

7    that you have made.

8                     I have only used SHEP.        It's a single study,

9    and     it's certainly questionable as to whether the

10   estimates of the diuretics effect in SHEP apply to exactly

11   to what the diuretics would have yielded in ALLHAT.

12                    ACTING CHAIRMAN BORER:          Bob?

13                    DR. TEMPLE:      You would be hard put to make

14    the case for a noninferiority design probably in any

15   antihypertensive study, but certainly here; because the

16   populations are always different from one to the other.

17                    This isn't the SHEP population.             It isn't

18   even that much like the SHEP population.                How can you

19   in this study decide what the effect size is actually

20   going to be?       You have to make some major assumptions

21   like it's going to be the same as in SHEP, which may be,

22   maybe not.       These people are all getting their lipid --

23   Well, some of these people are getting their lipids

24   aggressively treated.

25                    It's very different.         I don't read them as

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1    having tried to do a noninferiority design or tried to

2    address the question do any antihypertensive drugs work,

3    which is what we usually do in noninferiority studies.

4

5                        They make the assumption, probably -- I mean,

6    we could ask -- that if you lower blood pressure, it

7    probably does things in a good direction.                    The question

8    is whether lowering it with one thing is better than

9    lowering it with another.

10                       That, of course, you can ask and get an

11   answer:          I couldn't show it or I could.            But the usual

12   noninferiority paradigm where you are using it to try

13   to see if the drug has any effect at all -- there was

14   no preparation for that in this case.                     That's not what

15   the trial was for.

16                       DR. FLEMING:       Absolutely.        I agree fully,

17   Bob.       The analysis as I have presented essentially is

18   anticipating discussion which says -- and in fact, the

19   sponsor presented this -- the primary endpoint result

20   looks the same.         The primary endpoint result on non-fatal

21   MIs and cardiovascular deaths were the same between

22   diuretics and alpha blockers.                   Hence, isn't that a

23   positive result?

24                       If one wished to take that approach, then

25   rigorously, in essence, what one has to ask is whether

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1    the evidence of the same effect is sufficiently compelling

2    that allows us to reliably conclude that you're better

3    than a placebo.

4                       I'm not arguing that is adequate.                          I'm

5    arguing, even if you take that permissive approach here,

6    you still don't even satisfy a permissive application

7    of a noninferiority argument.

8                       If we then, however, move to a higher

9    standard, which is to say we actually have to show

10   superiority which, I would argue, could be reasonably

11   defended for many reasons -- one of those is the set of

12   reasons you've just mentioned -- how do you come up with

13   a     permissible         margin      in    this     case       to     justify

14   noninferiority?

15                      Another is to say, if you are comparing to

16   an active comparator that is accepted to be better on

17   another and very important element, i.e., heart failure,

18   then don't you need to show superiority?                         That is in

19   essence what I think the study team has decided is the

20   minimum standard.              It is, in fact, the reason they

21   justified termination.

22                      You can only justify termination, in my view,

23   of the ALLHAT trial regimen of alpha blockers if you

24   conclude         that   the    minimum     you     have    to   achieve         is

25   superiority, because the conditional analysis that they

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1    gave was stating, given what you currently have, even

2    if you have the beneficial effect we hope to have, you

3    only have a one percent chance of achieving superiority;

4    hence, we're stopping.

5                         Well, the logic of that says it's not

6    acceptable to achieve anything less thana superiority

7    argument.           I accept that argument.           I'm saying, if one,

8    though, is even far more permissive and takes the approach

9    here of saying, well, maybe this is a positive study since

10   results overlap, anticipating that discussion, I wanted

11   to at least put things in the context of noninferiority,

12   which would be the basis for justifying that conclusion.

13                        DR. TEMPLE:       But, Tom, is that what they

14   really did?          When someone asked Jeff specifically, what

15   he said was there was no chance of showing an overall

16   advantage.            But   in    addition,      we    found   this       clear

17   disadvantage on something that was important.

18                        So I don't know how that fits into the usual

19   noninferiority trial.              It's not exactly the same.

20                        DR. FLEMING:      You and I are saying the same

21   thing.           That's what I just said.         That's what they are

22   doing.           That's what, in fact, I consider to be relevant

23   as well.           However, if one is much more permissive than

24   that, saying you don't have to show superiority, SHEP

25   has proven diuretics are very effective on the primary

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1    endpoint, yielding a 27 percent reduction in the rate

2    of the primary endpoint.                 Isn't it enough to show it's

3    the same?

4                        We were shown those data.                The sponsor made

5    that point.             So if you are going to make that argument,

6    my point is even that argument doesn't statistically

7    rigorously hold, because then you have to argue in terms

8    of noninferiority, and for all the reasons you've said

9    together with the statistical analysis I've given, it

10   doesn't          meet    the   criteria      we   would       have   even      for

11   noninferiority.

12                       ACTING CHAIRMAN BORER:            Tom and then Steven

13   and Ralph.

14                       DR. GRABOYS:          Well, I'll take a 30 second

15   editorial comment, because I don't really understand all

16   the incredibly complicated statistical analysis.                               All

17   I know is that as a clinician and going back into the

18   community, because that's really the bottom line, is what

19   we are trying to do is do the right thing for our patients

20   in the community, is that I see a red flag here, that

21   there is something awry and that we haven't reached

22   closure on that, and I don't expect us to reach closure.

23                       We are talking about a drug that is being

24   used increasingly in an elderly population who are

25   developing BPH.             We are using a drug in individuals who

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1    need to be treated for their hypertension, but what I

2    am hearing and seeing is that in the community it's not

3    uncommon for us to see 75, 80, 85-year-olds who are coming

4    in who will need a drug for their BPH and need a drug

5    for their hypertension, and these folks, I think, can

6    best be served by acknowledging that there is a red flag,

7    that there's something wrong perhaps with the drug in

8    this population.

9                     If that's the case, we have to take a step

10   back and seriously consider how we are labeling this drug.

11                    ACTING CHAIRMAN BORER:         Steve?

12                    DR. NISSEN:     Tom, I'm concerned about some

13   of the confounders here in comparing SHEP with ALLHAT.

14    One of them I'm very concerned about is the lipid issue.

15                    We have seen in some other trials -- the one

16   I remember the best was the QUIET study -- where patients

17   with very high LDL levels, the amount of benefit they

18   got from the ACE inhibitor was very different from those

19   that had low LDL levels.

20                    So since we have no information here about

21   lipid lowering therapy, I am very worried that this is

22   a really important confounder that we just can't analyze

23   with what's in front of us.

24                    The second confounder that I'm terribly

25   worried about is dose and dose titration, that again,

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1    you know, if it's true that the dose that was ultimately

2    used in this ALLHAT study was an inadequate dose, then

3    it doesn't make as much sense to look at this in comparison

4    to a trial where presumably adequate doses of the drugs

5    were being used.

6                     Would you comment on those two confounders

7    and your thoughts about them?

8                     DR. FLEMING:     The first point is well taken.

9     It is related to Bob's concern that an               noninferiority

10   analysis that takes the estimate of the effect of

11   diuretics from SHEP and imputes that in ALLHAT is risky,

12   and we are all on the same page.

13                    I'm arguing, even if you make the assumption

14   that it's sufficiently reliable to do a noninferiority

15   analysis, you still don't meet the standard for strength

16   of evidence that you would require.

17                    So your points, Bob's points -- and I agree

18   with them -- strongly urge us to be very cautious about

19   any noninferiority assessment.           The consequence of that,

20   though, is that simply showing the same result, a point

21   estimate of the same result on the primary endpoint, isn't

22   rigorously adequate evidence of a establishing benefit.

23                    One is left, in essence, in those types of

24   settings with needing to establish superiority and, in

25   fact, that's the way the protocol was interpreted, the

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1    results          were    interpreted,         when     this    study        was

2    terminated.

3                       ACTING CHAIRMAN BORER:            Ralph and then Ray.

4                       DR. D'AGOSTINO:         Tom, let me ask a different

5    view of this, or ask about a different view of this study.

6                       When we sit on these data safety monitoring

7    committees, we oftentimes do the computation of will we

8    show a positive effect, possibly show a positive effect

9    on effectiveness, and we oftentimes lay that out.                           But

10   I must admit that we, at least the committees I'm on,

11   do that, and we realize that maybe the data is not all

12   there and so forth, and we sort of look at it.                      But what

13   oftentimes drives these committees is safety concerns.

14                      I'm not sure that the stopping of the study

15   or the stopping of that arm was driven by safety.                         They

16   don't care about this noninferiority or superiority, if

17   they've flagged a safety issue.

18                      Then in many of these data safety monitoring

19   committees you jump all over the place in terms of looking

20   at       that      outcome.            With      the       cardiovascular,

21   unfortunately, cardiovascular studies where the normally

22   safety outcomes now become efficacy outcomes and is a

23   real confusion.

24                      So if you were to step aside and say let me

25   forget for a moment the noninferiority and superiority,

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1    but do I have a really big flag for safety and should

2    I respond to that, how do you --

3                        DR. FLEMING:      Ralph, I agree that issues of

4    safety are certainly going to be weighed heavily, and

5    in this setting -- this might be semantics here -- do

6    we view the more favorable effects on heart failure by

7    the diuretics arm to be an efficacy issue or a safety

8    issue as it reflects the alpha blocker?

9                        That, to my way of thinking, is somewhat

10   semantics, because in fact a favorable benefit on heart

11   failure is efficacy, and that may be the cause of the

12   difference.          It may, in fact, reflect a favorable effect

13   by diuretics or an unfavorable effect may, in fact,

14   reflect harm that's induced by the alpha blocker.

15                       Actually, if I am on the data monitoring

16   board, in a certain sense the semantics, to me, don't

17   matter.          The reality is heart failure is a very important

18   clinical endpoint itself, an important secondary measure,

19   and I have two interventions in hand here.                One of those

20   interventions, diuretics, is clearly better than the

21   other, alpha blockers.

22                       As a result, it is an additional basis that

23   justifies my conclusion then that, unless alpha blockers

24   are better on the primary endpoint, then I don't have

25   a favorable benefit to risk profile, not even mentioning

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1    other things such as cost.

2                     DR. D'AGOSTINO:      What I'm obviously raising

3    is that the study, the ALLHAT study, in and of itself,

4    one could ask these questions:             I have this dataset in

5    front of us; how do I respond to it?

6                     I think, as you are describing now is the

7    way to start piecing it together.              But I think it's a

8    different -- It's a different set of concerns and

9    different set of considerations than this noninferiority

10   type of aspect:      Am I so upset by what I see?

11                    ACTING CHAIRMAN BORER:         I think before Ray

12   makes his comment, I want to remind everybody of the gist

13   of an earlier portion of this discussion.             That is the

14   potential importance -- we may not be able to resolve

15   it, but the potential importance of separating harmful

16   effects for the myocardium that may affect natural course,

17   etcetera, etcetera, and the development of pulmonary

18   vascular congestion without intrinsic damage to the

19   myocardium; because if you knew that such a difference

20   existed, you might choose a different strategy to deal

21   with patients who manifested the symptoms.

22                    Again, I'm not taking a position on this,

23   because we don't have the data.         But we do have to consider

24   that in our thinking.        Ray, you made that point, and you

25   had a comment here.

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1                       DR. LIPICKY:         Well, I was going to suggest

2    that you might start answering the questions, because

3    all these are really responding to an overview which was

4    erudite but could be picked on for the next hour and a

5    half.

6                       ACTING CHAIRMAN BORER:                 Okay, very good

7    thought.         In fact, it was the very suggestion I was about

8    to make.         So with that superb suggestion --

9                       DR. KONSTAM:         Hey, Jeff, could I just ask

10   Tom one question, because maybe I'm looking at this a

11   little differently.           One thing that I want you to address,

12   I'm not sure whether you've addressed or not.

13                      You know, we wouldn't be sitting here today

14   if there were not some differences in terms of nominal

15   p-values,         in    terms      of     some     endpoints         between

16   chlorthalidone and doxazosin.                   So the question I have

17   is:      What do you do with those p-values for secondary

18   endpoints, and particularly components of secondary

19   endpoints, when you have no significant difference in

20   your primary endpoint?

21                      DR. LIPICKY:         That's a specific question

22   that you will have to address.                  It's on the list.

23                      DR. KONSTAM:         Okay.

24                      ACTING CHAIRMAN BORER:           Okay.     We'll begin

25   then with the questions.              What I want to do here is to

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1    allow everyone to make a short response to each of these

2    questions, because this is a very difficult set of issues

3    to resolve, and I think, for the FDA to get optimal advice,

4    it should hear the varied opinions of all the people that

5    it has empaneled.

6                            Some of these questions depend more on

7    clinical judgment than on statistical judgment, some more

8    on statistical analysis than clinical judgment, and we

9    will try to vary the order of response, depending upon

10   my judgment of which of these this is.

11                           The   first   one,    the     first   question         is:

12   Consider           the        following      issues     related        to      the

13   interpretation                of   the    ALLHAT      findings       regarding

14   doxazosin.              1.1, I think, really does require a little

15   bit of clinical judgment here.                     That is:

16                           1.1    The ALLHAT protocol restricted the

17   maximum dose of doxazosin to 8 mg, but the label encourages

18   use up to 16 mg.              ALLHAT had dose titration at one-month

19   intervals, but the label encourages titration at one to

20   two-week intervals.                Do the results of ALLHAT apply to

21   doxazosin when it is used as labeled?

22                           Why don't we begin at one end, on Marvin's

23   end, and move this way.                   Marvin, you made some cogent

24   comments about this.                  Why don't you start out?                 I'm

25   sorry.           Bob?

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1                         DR. FENICHEL:          I      guess there are two

2    different ways that the question could be interpreted,

3    though.          One is do the results apply to doxazosin as it

4    is used, period, meaning how do the ALLHAT results apply

5    -- how do we think they apply to the population now

6    receiving doxazosin presumably on the basis of its label.

7

8                         Then a different question is how do the

9    ALLHAT           apply   to    a    hypothetical       population       whose

10   physicians were actually conforming to the behavior

11   suggested in the label?                That's a different population.

12   That's a different and hypothetical population, but

13   that's important.

14                        Well, it's important.           Let me just clarify

15   it in a very quick way.                 What we heard, I think, from

16   several sources is that people, in fact, don't use 16

17   milligrams.          The labeling says they ought to on occasion,

18   but in fact they don't.

19                        So the first question is how does the ALLHAT

20   physician behavior compare to the real behavior out in

21   the world.          The second question is how does it compare

22   to the proposed behavior which is now in the label?

23                        DR. LIPICKY:        So maybe some clarification

24   has to be made in the questions.                        I understand the

25   distinction being made.                We don't know how doxazosin is

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1    used in practice or for whom it's used in practice.                  That

2    data hasn't been presented.            So I don't see how we can

3    answer that question.

4                     DR. FENICHEL:      Well, people alluded to it.

5                     DR. LIPICKY:      I don't see the data.          Do you

6    have it written down somewhere?             Okay, so we don't have

7    it.

8                     ACTING CHAIRMAN BORER:          What I will try to

9    do, since Marvin actually raised that issue himself in

10   his earlier comments, we'll try to deal with --

11                    DR. LIPICKY:      Well, I suggest you don't deal

12   with that.       You don't know what you're dealing with.

13                    ACTING CHAIRMAN BORER:          Okay.

14                    DR. LIPICKY:       We had written a label for

15   doxazosin that says use doxazosin thusly.                That is the

16   label that we have to make a modification to, and to just

17   make the illustration complete, if I had to incorporate

18   ALLHAT results in the labeling, what I would say is don't

19   use doxazosin like it was used in ALLHAT.                  I wouldn't

20   be able to say don't use doxazosin because look at what

21   ALLHAT found.

22                    Okay.    So it is to the existing labeling,

23   and we can deal with that.             We know what the existing

24   labeling is, and the other business we can swim around

25   in for a long time.

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1                         ACTING CHAIRMAN BORER:          Okay.   Marvin, why

2    don't you begin?

3                         DR. KONSTAM:      I was just going to say no as

4    my answer to the question.              Now I don't know what to say.

5     I mean, the question as asked, I think the answer clearly

6    is no.           I mean, ALLHAT did not deploy the drug as used

7    in the label, and from what we hear -- So we don't know

8    how it's used in practice.

9                         The information that I'm hearing about how

10   it's used in practice -- I think the answer would also

11   be no, because I heard in the majority of cases it's not

12   used as first line therapy.                 So I think the answer is

13   going to wind up being no for both.

14                        ACTING CHAIRMAN BORER:           Bob, did you want

15   to make a comment?

16                        DR. TEMPLE:      Well, I just think -- I think

17   Bob Fenichel's question is of interest and ought to be

18   addressed.          I mean, if in fact -- and I know Pfizer can

19   tell us or others can tell us -- almost nobody is using

20   16 milligrams and everybody sort of does a leisurely

21   titration, it may be highly relevant to the way it's used,

22   especially if we don't know why they are not using the

23   right dose.

24                        Maybe there's a reason.         We don't know that.

25    So I would like to hear people comment on both of those

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1    things.

2                         ACTING CHAIRMAN BORER:                Okay.      We can

3    certainly do that.            The fact is that we are going to get

4    to an answer to that question further down the list, even

5    though it's not specifically stated.                       So we are going

6    to have to deal with it one way or the other.

7                         Be that as it may, let's go on to Michael.

8                         DR. ARTMAN:         No, I don't think you can

9    extrapolate to a higher dose and a more rapid titration.

10    So I don't think it is applicable.

11                        ACTING CHAIRMAN BORER:          Ileana?

12                        DR. PINA:     No.

13                        DR. HIRSCH:      No, but it's not the relevant

14   question.

15                        ACTING CHAIRMAN BORER:          Do you want to make

16   a comment about the relevant question?

17                        DR. HIRSCH:      Sure.     The relevant question

18   is:        ALLHAT was designed by its investigators, and the

19   petitioners' design asked us how it's applied in the real

20   world.           So I think we really have to come back and ask

21   that question.           Compared to the real world, does this

22   provide us guidance?             But we'll get to that in a minute.

23                        ACTING CHAIRMAN BORER:          Okay.     Tom?

24                        DR. GRABOYS:        Yes.   The real world is all

25   anecdotal at this point, but I think it's substantiated

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1    by the folks from Pfizer who indicated that it -- you

2    don't go up, and rarely do we see these folks going up

3    to 16.           It's much lower than that.        So I guess I'm along

4    the "no" line.

5                         ACTING CHAIRMAN BORER:                Joan, you don't

6    vote.        Tom?

7                         DR. FLEMING:       I don't know the answer to

8    this, partly -- well, for two reasons.                       First of all,

9    I don't know whether, if you had a two-weekly rather than

10   a monthly titration with a maximum of 16 rather than 8,

11   whether that matters in terms of efficacy.                    I don't know.

12                        I also don't know how important it is because

13   if, in fact, the way the clinical practice proceeds is

14   largely consistent with ALLHAT, then this is not a

15   relevant issue.           If it is very different, if people would,

16   in fact, use more rapid titration and go to 16 frequently,

17   then the question is more relevant.                  But still, I don't

18   know whether that would have impacted safety and efficacy.

19                        DR. LIPICKY:      But can I interject with Tom.

20    You do know that the greater the dose, the greater the

21   blood pressure reduction up through 16.                       And you know

22   that in the study the blood pressure reduction was less

23   than with the other drugs, and you know that the treatment

24   of hypertension is supposed to influence the variables

25   that were measured.

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1                      So what is it that's missing from your logic?

2

3                      DR. FLEMING:      True, true and true.

4                      DR. LIPICKY:      Yes?     They are unrelated?

5                      DR. FLEMING:       What's missing is that I'm

6    going to have to now make the assumption that, if you

7    had the titration schedule on two-weekly rather than

8    monthly, allowing --

9                      DR.   LIPICKY:         No,     no.       Forget        the

10   titration.       Just dose.

11                     DR. FLEMING:      -- allowing to go to 16 rather

12   than 8 -- if you had that, your question requires me to

13   somehow model whether or not that would have eliminated

14   the difference in systolic blood pressures.                  There were

15   no differences in diastolic.                     So assumption one,

16   model one is, if I did take the different maximal dose,

17   the question is:         Would that have altered the overall

18   blood pressure control to a level that would have given

19   me comparable control with the diuretic?

20                     I don't know the answer to that.              It might

21   have.        That's point one.      That's assumption one.

22                     Assumption number two is:             Even if it had,

23   would that have made a difference in the endpoint?                    Well,

24   you're asking the wrong person, if you want somebody to

25   believe in surrogates.

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1                     DR. LIPICKY:      That's correct, but let me put

2    it this way.       Let's say I -- Let's just make the thing

3    more exaggerated.        Let's say that doxazosin was placebo.

4     So it was the equivalent of a very small dose, but let's

5    say it was .001 milligrams of doxazosin, but people were

6    randomized to doxazosin.

7                     Would you now be willing to conclude -- and

8    the results were the same.                   Let's just make that

9    assumption, and you did an intent-to-treat analysis.

10   Would you now conclude that doxazosin caused the heart

11   failure, because that's what you are doing here in your

12   unwillingness to accept the notion that you ought to study

13   things that at least they are the doses that the

14   instructions for use include.

15                    DR. FLEMING:        I'm not arguing that they

16   shouldn't have used 16.            I don't know what the right

17   answer is.       I'm just responding to your assumptions              that

18   you have made, pointing out that those are assumptions

19   that may be true, but they may not be true.

20                    DR. LIPICKY;      Well, I guess I'm not making

21   the assumptions that the question asks:                Are the results

22   applicable to the current labeling?

23                    DR.   FLEMING:        The    results    are     clearly

24   applicable to what was defined as the regimen in the

25   protocol.

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1                      DR. LIPICKY:        Yes.

2                      DR.     FLEMING:           Now    whether      they       are

3    applicable to the label requires insight that I don't

4    have, and that is, if you had in fact instead had the

5    protocol have 16, (a) would that have yielded a different

6    blood pressure control, and then another major assumption

7    (b) would that have translated into a better control of

8    stroke and a better effect on heart failure?

9                      I don't know the answers to those.              My second

10   original comment was I don't even know how important the

11   question         is,     because       if,     in     fact,the         actual

12   implementation of the protocol specified regiment doesn't

13   meaningfully differ in the vast majority of cases from

14   the actual implementation of the label, then it isn't

15   a critical issue, and I don't know whether that's true.

16                     ACTING CHAIRMAN BORER:            Joann?

17                     DR. LINDENFELD:         I have to agree.           I don't

18   think that the current results of ALLHAT apply when

19   doxazosin is used as labeled, but again I can't really

20   answer this because we don't know exactly how it's used.

21    That's a different question.

22                     ACTING CHAIRMAN BORER:            Steve?

23                     DR. NISSEN:         Yes.     I agree with everyone

24   else, but I would add one more point.                     We don't really

25   even know how doxazosin was used in ALLHAT.                       I mean, i

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1    don't know what the mean dose was.

2                     So there is absolutely no way to answer this

3    without having the data.         So, you know, we know what the

4    maximum possible dose was, and that's all we know.                             I

5    think you can't extrapolate that to the label without

6    knowing more.      So we really have a vacuum there.

7                     ACTING CHAIRMAN BORER:         Bob?

8                     DR. FENICHEL:      No.

9                     ACTING CHAIRMAN BORER:         Ralph?

10                    DR. D'AGOSTINO:      No.

11                    ACTING CHAIRMAN BORER:           Okay.      And final

12   vote, I agree.      I think that we can't say that it applies

13   to the label or to doxazosin when it's used as labeled,

14   because we don't have the data, and we don't know what

15   was done, just as Steve said.

16                    That   sounds     like     a    fairly       unanimous

17   response, Ray, for your advice.

18                    DR. LIPICKY:     Thank you.

19                    ACTING CHAIRMAN BORER:               You're welcome.

20                    At three years, only 76 percent of subjects

21   randomized to doxazosin were still taking it.                How should

22   subjects not taking doxazosin be included in any analysis?

23                    This seems to have more statistical than

24   clinical implications.          Why don't we begin with Ralph

25   and then Tom, and we'll see if anybody disagrees with

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1    what they say.

2                     DR. D'AGOSTINO:        I think the appropriate

3    analysis is an intention-to-treat analysis. I do think,

4    though, that as you do these analyses, you want to have

5    a sense of what happens in subsets.              What happens if I

6    perturbate the data?        Do I still see a robust result?

7                     In that context, the ALLHAT investigators

8    looked at, I think, gender differences or gender groups

9    and looked at age groups and saw a robustness.               I think

10   that in order to really feel comfortable interpreting

11   the results, I would like to see this type of an analysis

12   where those who took the drug, in fact, are analyzed.

13   I don't expect a different result.

14                    I mean, when we do these things, they tend

15   to give the same -- but for completeness.             There's also

16   the question, which is not here, that if I again read

17   the article correctly, they only had data on 92 percent

18   or so of the individuals.           I'd like to see what would

19   happen if you took as many individuals as possible in

20   your analysis.

21                    It's more for the robustness of it, not that

22   I think that you would end up getting a different result,

23   and it's sort of the general question of completeness

24   of the analyses which is touched on in a number of these

25   questions, and the availability of the data that this

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1    alludes to.        In that case, I think that this plus other

2    analyses really do need to be performed before we can

3    feel really comfortable with the ALLHAT results.

4                       ACTING CHAIRMAN BORER:             Tom, what should we

5    do with the other subjects?

6                       DR. FLEMING:       I think I largely agree with

7    what Ralph has already said.               The protocol is designed

8    to answer a question, which I think is a very relevant

9    question.        That is, what strategy is to be preferred when

10   you look at overall benefit to risk, a strategy that is

11   based on the diuretic or a strategy that's based on the

12   alpha blocker?

13                      Certainly, in any trial you are going to have

14   people who are not adherent, people who can't tolerate

15   the therapy, people who may take other supportive care.

16    The overall intention-to-treat analysis is the analysis

17   that       gives    us    the     unbiased      and,      I   think,      most

18   interpretable results.

19                      The 24-5 percent of people who had three

20   years        weren't     on     doxazosin,      are     people     who      are

21   intrinsically different than those who were, and I have

22   to in essence, if I'm going to exclude them, exclude the

23   same people from the control regimen.                     I don't know who

24   those people are.

25                      I would agree, though, that whereas the

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1    primary analysis should be exactly what ALLHAT presented,

2    which is the ITT, it's certainly important to give a

3    descriptive         analysis of what was overall                 level of

4    adherence.         What were the frequencies and the timing of

5    patients receiving ancillary care that, in particular,

6    could be anticipated to influence the endpoints?

7                        So I would argue descriptive analyses that

8    provide          more globally what adherence was                and what

9    supportive care was are relevant and should be also

10   considered.

11                       ACTING CHAIRMAN BORER:        Let me specifically

12   ask Bob Fenichel, do you have any additional comments

13   to make about this issue?

14                       DR. FENICHEL:      No.

15                       ACTING CHAIRMAN BORER:               Okay.    Anything

16   else that the Committee members want to add beyond what

17   we've heard from the two statisticians?

18                       DR. HIRSCH:     Maybe one brief comment, just

19   that this is not your classical randomized clinical trial

20   between two treatment groups.              You have to remember what

21   ALLHAT really is, which is again the real-world trial

22   of what happens when doctors prescribe medications.

23                       I look at this 76 percent continued use rate

24   over many years and say that would be great to achieve

25   in real life.         That's exactly the analysis ITT that we

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1    want to have to understand what we are being told in

2    ALLHAT.

3                     ACTING CHAIRMAN BORER:         Okay.     Yes, Bob?

4                     DR. TEMPLE:     You can't tell precisely, but

5    since much of the difference between the two treatments

6    was that it was observed early, it seems likely that the

7    on-therapy rate was much higher when             much of the action

8    was going on.       So that might affect some of the other

9    outcomes, but maybe not that, maybe not the heart failure

10   outcome so much.

11                    ACTING CHAIRMAN BORER:         You say much of the

12   difference was early. You're thinking heart failure

13   difference was early.

14                    DR. TEMPLE:     That's all I'm referring to.

15                    ACTING CHAIRMAN BORER:               Stroke, I might

16   argue, somewhat surprisingly to me, was more evident

17   emerging later.

18                    DR. TEMPLE:      Right.      I tend to discount

19   that, because it's easily explained by the blood pressure,

20   but leave that aside.

21                    ACTING   CHAIRMAN       BORER:          Well,       blood

22   pressure differences were greater early.                   The length

23   between pathophysiologic changes and ultimate natural

24   course of a disease, I think, we don't know so well. So

25   maybe that's a side issue we'll get at later.

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1                        Okay.   Have you heard enough, Ray, to give

2    you advice about what the Committee thinks about how to

3    deal with the other patients?

4                        DR. LIPICKY:      Yes.

5                        ACTING CHAIRMAN BORER:                1.4.       Diastolic

6    blood pressure control was similar in the doxazosin and

7    chlorthalidone treatment groups, but systolic control

8    was less similar.           Might any differences in outcome be

9    attributable to the degree of systolic blood pressure

10   control?

11                       I think we've heard a fair bit about that,

12   but just to make sure that there is some sense of

13   everybody's idea, Marvin, why don't you start again?

14                       DR. KONSTAM:      Yes.     I certainly think that

15   certainly at least some of the results may be attributable

16   to blood pressure differences.                I think, frankly, in my

17   mind, I think a large percentage of the results could

18   be attributed to or at least significantly contributed

19   to by the blood pressure difference.

20                       You know, as Bob just said, magnitude-wise

21   it seems very rational to say that with regard to the

22   stroke.          You know, I just want to comment about the heart

23   failure magnitude.             You know, I don't know what the

24   magnitude effect means anymore when you are getting to

25   a component of a secondary endpoint, and how reliable

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1    is the magnitude of the effect.

2                     I just want to say that point.           But I think

3    even there, assuming that that magnitude is correct, I

4    think that the blood pressure differences could be

5    contributing to that in a couple of different ways.

6                     One is effect on natural history of events

7    with regard to the myocardium, but the other is ongoing

8    afterload effects which, if different, I think, could

9    have been contributing significantly to that early

10   difference in heart failure.               So I think the blood

11   pressure has probably a fair amount to do with it.

12                    ACTING CHAIRMAN BORER:         Michael?

13                    DR. ARTMAN:    Well, I was impressed with the

14   difference in the time to achieve target blood pressure

15   in the doxazosin group versus chlorthalidone.                I think

16   that was an important consideration and may, in fact,

17   contribute to the differences.

18                    I think also that the issues related to

19   stroke, I think, are more likely related to differences

20   in blood pressure control.           The heart failure issue, I

21   think, is still pretty murky.

22                    ACTING CHAIRMAN BORER:         Ileana?

23                    DR. KONSTAM:     Can I just add one thing?                I

24   think, again, the thing about 3 millimeters -- you know,

25   I think there could be an awful lot going on with that

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1    3 millimeters, and it would be lovely to see, again, the

2    range of blood pressure responses, to what extent there

3    might be some -- just the proportion of patients who were

4    way out of control in one group versus the other group,

5    and then finally, you know, actually see an analysis,

6    again, linking or relating the events to blood pressure

7    control in those patients who have events.

8                     So those are all important issues.

9                     DR. PINA:     I think that 3 millimeters alone

10   doesn't give me any sense of confidence about the

11   occurrence of heart failure.            However, if patients were

12   coming off of drug that had them -- that are controlled

13   and they are going on whatever the study drug is -- in

14   this case, doxazosin -- and the blood pressures are

15   higher, that could contribute to the early separation

16   of the curves.

17                    Again,    I'm    very     struck      by     the      early

18   occurrence of those curves splitting apart, and I don't

19   think the effect early on, necessarily, has anything to

20   do with the blood pressure.               But I think the blood

21   pressure is contributing to what we are seeing.

22                    The fact that the blood pressure remains high

23   for a year later, higher than in the chlorthalidone group,

24   I think that may be contributing to the stroke level,

25   but not necessarily to the heart failure, which is seen

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1    very early.

2                     ACTING CHAIRMAN BORER:         Alan.

3                     DR. HIRSCH:       Well, on a blood pressure

4    interventional trial comparability of blood pressures

5    is important, and 2-3 millimeters is important for stroke.

6     Like Ileana, I'm not sure it explains the heart failure

7    outcome, but the analyses, as Marv said, are certainly

8    very important.      I'd love to see them as well.

9                     ACTING CHAIRMAN BORER:         Tom?

10                    DR. GRABOYS:     Yes.

11                    ACTING CHAIRMAN BORER:         Tom?

12                    DR. FLEMING:     This is again a tough issue.

13    Diastolic pressure was the same.                Systolic was less

14   similar, 3 millimeters, then 2 millimeters after a year.

15    My sense is that it is very unlikely that this explains

16   the full having of the heart failure that diuretics

17   provide.

18                    Marv,   you    referred      to      the     difficulty

19   interpreting that estimate because it came from an interim

20   analysis, and you are certainly right about the fact that

21   there is a bias that arises in estimates of effects when

22   you have interim monitoring, and that interim monitoring

23   --

24                    DR. KONSTAM:      Well, not only interim but

25   also a component of a subset -- a component of a secondary

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1    endpoint.

2                         DR. FLEMING:      Yes.     When you have -- That's

3    more regression to the mean kind of phenomenon where you

4    are looking at multiple endpoints, but it's really the

5    same phenomenon.            It's just multiple testing.           You are

6    noting it as multiple testing, as one element of many

7    in and outcome.           I'm noting it as over periods of time.

8                         There is, in fact, some bias that arises,

9    although not anything close to what would account for

10   this having.          There are other phenomenons, though, that

11   could.           Is it maybe just a masking, so the having isn't

12   really real, and those are completely different issues.

13    But from a statistical perspective the multiple testing

14   has more of an impact on significance levels and your

15   interpretation of those rather than bias in the point

16   estimate, even though - you're right -- there is some

17   bias, but not at a level that I would think could explain

18   this.

19                        So my sense is its very unlikely that the

20   difference of 3 millimeters that becomes 2 millimeters

21   in systolic when diastolic is the same could, in its own

22   right, account for the difference in heart failure or

23   a large part of it.

24                        It could account for the differences in

25   stroke, although again it's speculation as to whether

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1    it would.        I'm interpreting too much into the data, but

2    where the biggest difference is in blood pressure is not

3    over the time frame where I see the largest excess in

4    stroke, and I don't know if it's a delayed effect or what.

5     I don't know.

6                      It's difficult to also understand whether

7    this is important, and let me clarify.                    If we used the

8    wrong regimen, and if we had used the right dose schedule,

9    we would have achieved the right blood pressure control,

10   then this is a relevant question.

11                     On the other hand, if there is something

12   intrinsic about delivering an alpha blocker as opposed

13   to a diuretic that makes it harder to achieve full blood

14   pressure control, then it's a moot point, because this

15   is an intrinsic characteristic of the regimen.

16                     If    I   achieve      lesser     efficacy     mediated

17   through lesser biologic effect on blood pressure and

18   that's intrinsic to the regimen, then it doesn't matter.

19    So I'm left also with trying to -- coming back to the

20   first question again.               Can I say with any kind of

21   reliability that I would have achieved the right blood

22   pressure control, had I had the right schedule and dose?

23                     DR. KONSTAM:           I'm sorry.         Tom, you've

24   confused me about something you said.                     I mean, I hear

25   you say -- Getting back to the multiplicity issue, whether

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1    it be multiple looks or whether it be multiple endpoints,

2    I heard you say, well, that influences the statistical

3    validity of the finding but not necessarily the magnitude

4    of the finding?

5                     DR. FLEMING:       Well, there are two ways of

6    doing -- I mean, there are two important aspects to

7    statistical analysis.         One is estimation.       The other is

8    inferential or testing.            Multiple testing influences

9    both, i.e., when you do multiple testing over time or

10   you have multiple different outcomes and you happen to

11   choose the one that really looked the most impressive,

12   there's a regression to the mean phenomenon.               It looked

13   that impressive, partly because there was a real effect,

14   but you happen to have seen an overestimate of that real

15   effect, and that's why it stood out.

16                    So in that sense, you're right about the fact

17   that there's some overestimate.               I'm saying that that

18   statistical phenomenon, though, doesn't explain the

19   magnitude of what we are seeing when you put into context

20   the number of analyses that were done and the fact that

21   stroke wasn't one of 100 different endpoints or heart

22   failure wasn't one of 100 --

23                    DR. KONSTAM:        I'm just saying that the

24   magnitude of the heart failure effect seems pretty large.

25    I'm just saying that --

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1                            DR. FLEMING:      It's the same size as in SHEP.

2                            DR. KONSTAM:       No, no. Okay, but I'm just

3    saying the degree to which we are confident about that

4    magnitude diminishes substantially as we get to the fact

5    that it comes from an interim look, and the fact that

6    it's a component of a secondary endpoint, as opposed to

7    being a primary endpoint at the end of the study.

8                            ACTING CHAIRMAN BORER:          Joann?

9                            DR. LIPICKY:      Tom, there weren't 100 other

10   endpoints, but there were 21 all told.

11                           DR. FLEMING: But as you would say when you

12   looked at, let's say, carbatylol and death was a secondary

13   measure, you might argue death isn't like every other

14   secondary issue.

15                           DR. LIPICKY:      Well, but that was not a good

16   decision.              So I wouldn't use that as an example.

17                           DR. FLEMING:       Not all secondary endpoints

18   are the same, and one has to ask whether specifically

19   death,           MI,    stroke    and   heart     failure     stand      out     as

20   particularly clinically relevant.

21                           DR.   KONSTAM:        You    know,    the     carbatyl

22   example, I think, is a great example, because there the

23   magnitude effect seemed enormous, and at least for what

24   it's worth, we know it's very disproportionate to every

25   other beta blocker study that's ever been done since then.

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1     I think that may be an example.

2                     DR. LIPICKY:     -- an endpoint contrived after

3    the first nonapproval letter.

4                     DR. KONSTAM:      Right.

5                     ACTING CHAIRMAN BORER:          Joann?

6                     DR. LINDENFELD:       I just want to take a little

7    bit more clinical view of this question.               I think that

8    you could make a case for the blood pressure being

9    important here.

10                    We know that the differences in heart failure

11   were early on.      The biggest differences in blood pressure

12   were early on, but later on with stroke. There's a lot

13   of information we don't have here.

14                    One is what was the incidence of atrial

15   fibrillation?       We know that one of the predisposing

16   factors to atrial fibrillation is hypertension.                       it's

17   quite conceivable in my mind that there could have been

18   more atrial fibrillation in the group with the slightly

19   higher blood pressure, which predisposes to stroke, and

20   that could explain this late sort of slow progression

21   in the increased incidence of stroke.

22                    So while I'm not sure about any of this, I

23   think one could make a plausible explanation here, and

24   we just -- Without knowing if there were differences in

25   atrial fibrillation, I think that's just where, again,

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1    we could use more data.

2                       ACTING CHAIRMAN BORER:          Steve?

3                       DR. NISSEN:      I think we shouldn't have any

4    illusions         here.     Three    millimeters         systolic      blood

5    pressure difference is a lot.                 I would point out to

6    everyone that that's the difference that was seen in the

7    HOPE      trial    between    placebo     and    ramapril.          It    was

8    associated with very strong differences in a whole variety

9    of endpoints, and many of us believe that that was the

10   exclusive explanation for the results of the HOPE trial.

11                      So I think that from that perspective, 3

12   millimeters is large.           But I also have some concerns here

13   about how blood pressure was measured.                   You know, this

14   was not chronic ambulatory blood pressure.                 We don't know

15   whether this was peak or trough.

16                      These drugs work by different mechanisms,

17   and they may have different peak and trough effects.

18   They may have different effects on ambulatory blood

19   pressure versus an office blood pressure.                     So there's

20   a lot of fuzziness here that I can't get my arms around,

21   because I don't have the data.               So I don't know what it

22   means in this context.

23                      ACTING CHAIRMAN BORER:          Bob?

24                      DR. FENICHEL:      It's hard to answer no to a

25   question that begins with "might."               But I guess I'll give

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1    sort of the same answer other people have given.                                     It's

2    pretty plausible for the stroke, notwithstanding the

3    delay.           But I find the delay plausible.                    It's certainly

4    clear enough that one shouldn't expect people to have

5    a stroke tomorrow if you take them off their medication

6    today, and so on.                   Things take time.

7                           Congestive          failure,      to       the    extent        you

8    believe          it    really          happened    and    was      not     simply        an

9    unmasking, as Ray has hypothesized -- that's a little

10   bit harder to pin on 3 millimeters, but I go along with

11   what Steve said.                  It's really hard to know on the basis

12   of the data we had what the real blood pressure differences

13   were, integrated over time view.

14                          ACTING CHAIRMAN BORER:                 Ralph?

15                          DR. D'AGOSTINO:              In the Framingham study

16   where I spend most of my life, we always think that

17   systolic          is       a     better     measure      than      diastolic,          and

18   especially as you get older.                       So I'm not upset that the

19   diastolic was similar and the systolic at a difference.

20                          I       think    that,     in   fact,       the     difference

21   observed is pretty important, and with the possibility

22   of racial effects here -- there's a lot of non-whites

23   in the study -- it may have more of an effect than some

24   of the meta-analysis would indicate.

25                          I do think that it's probably -- and here

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1    I'm sort of stepping out of analysis, because we don't

2    have it.         It's probably more with the stroke and the

3    congestive heart failure, but I think that with the stroke

4    you could probably say that not all of it but a good portion

5    is explained by the blood pressure, reasonably explained

6    by it.

7                      ACTING CHAIRMAN BORER:         Okay.   So, Ray, the

8    answer to this is resoundingly yes.               Any differences in

9    outcome might be attributable to the degree of systolic

10   blood pressure control.

11                     DR. TEMPLE:      Jeff?

12                     ACTING CHAIRMAN BORER:          Yes?

13                     DR. TEMPLE:     I guess I wanted to explore that

14   one little bit further.            Again, it's hard to know how

15   to cross studies, but the entire effect of the treatment

16   difference in SHEP, which is, as I recall it, about 6

17   or 7 millimeters of mercury, produced a 50 percent

18   reduction in this endpoint.

19                     Here you have to believe that a difference

20   -- Now I mean granting what Marv says about the instability

21   of the estimate, you sort of have to believe that 2 to

22   3 millimeters of mercury had an effect similar to the

23   entire effect of the treatment in SHEP, not for stroke

24   where I find it plausible, but in the heart failure.

25                     ACTING CHAIRMAN BORER:           No, I don't think

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1    that's what people have answered.           The issue is, is there

2    any impact of the blood pressure, not could all the heart

3    failure difference be explained by blood pressure.                    It

4    could be or couldn't be.         But I think the question here

5    is could the data have been confounded by this factor,

6    among others?

7                     I think everybody is saying yes, without

8    knowing the extent to which it could be confounded.

9                     DR. TEMPLE:      Okay.     I'm just reading the

10   question, Jeffrey.        It says "might any differences in

11   outcome" -- any --

12                    ACTING CHAIRMAN BORER:         Yes, any.

13                    DR. TEMPLE:     -- "be attributable," which I

14   would read as entirely, "to the degree of systolic blood

15   pressure control."       So you're saying, no, not all of it

16   but some of it?

17                    ACTING CHAIRMAN BORER:           No, no, I'm not

18   saying that.        I'm saying I interpret the question

19   differently, a little bit, and that what I'm understanding

20   people to say is, number one, it's hard to know what the

21   absolute magnitude of the difference really is, although

22   we have point estimates, and number two, it's hard to

23   know how to relate blood pressure changes to those

24   differences, but that, number three, it seems plausible

25   and reasonable from all the data we've ever seen that

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1    differences of this magnitude in blood pressure could

2    affect the outcomes that we saw, maybe not totally.                 Maybe

3    it doesn't account for all of it, but could have an

4    important impact.

5                      That may be one of a number of confounders.

6     I don't want to jump ahead in the questioning, but there

7    may be other confounders as well that might make us less

8    than fully comfortable in drawing very firm conclusions

9    from the data we've seen so far.

10                     DR. LIPICKY:       Jeff, you are interpreting

11   "any" as if it had been "some."

12                     ACTING CHAIRMAN BORER:         That's right.       More

13   than none.

14                     DR. TEMPLE:       Okay.     That's fine.        I just

15   want to be sure what you were telling us.

16                     ACTING CHAIRMAN BORER:            Number 1.4:        The

17   primary endpoint in ALLHAT was the combined incidence

18   of fatal coronary heart disease plus non-fatal myocardial

19   infarction.       The primary hypotheses were that the three

20   comparator arms would be superior to chlorthalidone; this

21   was not an equivalence study.

22                     1.4.1:    Did ALLHAT demonstrate a difference

23   between doxazosin and chlorthalidone for the primary

24   endpoint?        I don't think we need a discussion of that.

25    I think that the general consensus has been that it did

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1    not, although, as Tom pointed out, there was a small

2    difference, the importance of which can't be evaluated

3    from the data we have.

4                     1.4.2:   If not, how should one interpret any

5    secondary endpoint when the primary endpoint showed no

6    significant difference?

7                     We've heard some discussion of that, but I

8    think we need to hear just a bit more.                Tom, why don't

9    you begin, and then we'll go to Ralph, and we'll see if

10   anybody has anything to add?

11                    DR. FLEMING:      Yes.    Just to clarify.           You

12   had referred to my answer to 1.4.1.             Unequivocally, the

13   data do not establish superiority of doxazosin in the

14   primary endpoint.

15                    Usually, when we ask how to interpret a

16   secondary endpoint then, it's in the context of saying

17   you have not shown superiority in the primary, but at

18   least do you get superiority out of a secondary?                 So I'm

19   not exactly sure I understand the question, because if

20   we've said that the primary endpoint clearly didn't

21   establish superiority, the secondary endpoint goes in

22   the wrong direction.

23                    In what way did you wish us to comment about

24   this?

25                    ACTING CHAIRMAN BORER:         I think, if I'm not

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1    mistaken -- and, Ray, you can clarify this further.                                I

2    think       what    we've    often    heard     in    discussions         from

3    statisticians at these meetings is that, if the primary

4    endpoint isn't achieved -- that is, you don't show a

5    consistent difference between treatment A and treatment

6    B -- that it's very difficult to interpret a secondary

7    endpoint result.

8                        If you don't make it on the primary, you can't

9    look to the secondary.            Is that what you are asking, Ray?

10                       DR. LIPICKY:      That's at one extreme, and the

11   other extreme, I guess, is if it's important, you're

12   supposed to look at it.             So where does this sit in that

13   spectrum, in your estimation?

14                       Then the next question sort of gets at what

15   does that -- How should you interpret p-values?                          Where

16   do you get your strength of evidence?                     So I guess 1.4.2

17   and 1.5 are sort of tied together, with 1.4.2 being initial

18   thoughts before getting into the particulars of 1.5.

19                       Does it make sense or do you think it's a

20   ridiculous question to provide?               It could be a ridiculous

21   question.          It's all right.

22                       DR.   FLEMING:        Well,      if    one    needs       to

23   determine or one needs to interpret the significance level

24   of .001 or less than .001 and determine whether this is,

25   in fact, validly interpreted as conclusive statistical

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1    evidence of better results on heart failure with the

2    dialysis regimen or worse results on heart failure with

3    the alpha blocker regimen, I think we could get into a

4    major controversial issue here as to whether this -- on

5    a      secondary       measure,       whether       this       statistical

6    significance level is interpreted as being conclusive.

7                      My read of all of this is it's very relevant

8    to -- It's always relevant to consider secondary measures.

9     One of the reasons we go through an effort of identifying,

10    hopefully, a small number of secondary measures is to

11   be able to -- whereas, we don't give it the same attention

12   as the primary endpoint, to be able to make clear that

13   these aren't just data exploration endpoints that showed

14   up in a large myriad of different analyses that were done.

15                     So    there's      kind     of    a     middle     ground.

16   Clearly, the major focus is on the primary endpoint.

17   We would always say in a DSMB, though, any decision about

18   early        termination      must     take    into       account      global

19   consideration of all relevant information on efficacy

20   and safety where you look often first and foremost to

21   secondary efficacy measures and to safety measures as

22   well as to relevant external data.

23                     That's exactly what this committee did.

24                     DR. LIPICKY:        Well, that's okay.            It's not

25   with respect to what the committee did.                   It's with respect

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1    to how we should be taking inference from this.                         How

2    firmly do we know that this observation, whatever the

3    observation is, and in 1.5 is the congestive heart

4    failure, that that observation is pretty sound; because

5    we have this one thing of, you know, we hear this business

6    of, if you don't make the primary endpoint, don't bother

7    me with the secondary.

8                      DR. FLEMING:        All right.        Well, in that

9    context, my answer to 1.4 is -- and it's ordered in the

10   correct way.         1.4.1 is the most important question.

11   Clearly, these data do not establish superiority for the

12   alpha blocker.        In fact, if anything, they suggest that

13   the results are the same or a minuscule worse.                 Clearly,

14   they don't establish superiority.

15                     The secondary endpoint, the most important

16   one, as I see it, would be the heart failure and stroke

17   measures.        Those also trend in the wrong direction.                 My

18   interpretation is I view the strength of evidence from

19   heart failure to be fairly strong, but because it's in

20   the wrong direction, I don't know whether it's even

21   necessary to get into the rigors of saying is it

22   conclusively        negative.       I   don't     see   why   that's           a

23   necessary issue.

24                     DR. LIPICKY:      Well, we may get to that, but

25   okay.        So then what you're saying is you don't even need

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1    a nominal p-value.            That is, the p-values for the

2    secondary endpoints here have no particular relevance

3    to you.          It's that indeed the point estimate and

4    confidence limits are really very different, and whether

5    you calculated a p-value or not is irrelevant.

6                      DR. FLEMING:      Absolutely, if in fact you

7    hold to the 1.4.1 assumption that what one needs to do

8    first and foremost is establish superiority on the primary

9    endpoint.

10                     If we open a whole different issue here and

11   say, well, that's not true, the quality on the primary

12   endpoint is enough because SHEP has shown diuretics are

13   effective.        So if alpha blockers are the same, that's

14   -- Now it does matter more whether we think that the heart

15   failure evidence is conclusive.               But 1.4.1 is putting

16   us in the context of saying you have to show superiority

17   on the primary endpoint.

18                     Clearly, they didn't.        And having trends in

19   the wrong direction or significant effects in the wrong

20   direction on secondary measures isn't going to change

21   my impression.

22                     DR. LIPICKY:     But don't we have to interpret

23   the data the way the protocol was written?             Can't we take

24   the liberty here now of saying, well, we're going to treat

25   this like a nonsuperiority?

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1                      DR. FLEMING:         And that's the way your

2    questions are phrased, and that's the way I'm interpreting

3    them.

4                      DR. LIPICKY:      Okay, but that's legitimate,

5    you think?

6                      DR. FLEMING:      Yes.

7                      DR. LIPICKY:      Not illegitimate.

8                      DR. FLEMING;       If we follow the protocol,

9    this study -- and this is my belief for why the Data Safety

10   Monitoring Board and the Steering Committee made their

11   judgment.        Based on the intention to show superiority,

12   clearly that evidence made it clear that the probability

13   that you could achieve superiority was minimal.                           And

14   added to that, as they said, they were also persuaded

15   by the strong evidence for an unfavorable trend in heart

16   failure.

17                     One doesn't have to put a p-value on it to

18   justify that conclusion.

19                     DR. LIPICKY:      Okay, fine.         So that it isn't

20   the p-value.       It is the directionality and other kinds

21   of --

22                     DR. FLEMING:       And a general sense of the

23   strength of evidence, without getting into the technical

24   details.

25                     DR. LIPICKY:       -- and other kinds of warm

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1    tinglies or something?

2                       DR. FLEMING:      Ultimately, one has to blend

3    both statistical strength of evidence and clinical

4    judgment, particularly when one is looking at secondary

5    endpoints.

6                       DR. LIPICKY:      Okay, fine.

7                       ACTING CHAIRMAN BORER:          Ralph, do you have

8    any additional comments about this?

9                       DR. D'AGOSTINO:        Yes.    I think one of the

10   activities or one of the messages that we try to get out

11   to people putting studies together today is that maybe

12   you should save a little of your alpha for some of the

13   secondary endpoints like mortality or some of the big

14   ones, so that you aren't in the situation where, if your

15   primary values' endpoints don't work, that you therefore

16   end your analysis.

17                      If you look at this in a very rigorous way

18   in terms of the sort of statistical finesse brought to

19   it, they basically would have to stop in a formal way

20   after looking at the primary endpoint.                     It wasn't

21   significant.        It wasn't significant in the superiority

22   fashion.         So why are you splitting things out with the

23   secondary endpoints?

24                      I've mentioned a number of times, and I could

25   be all wet on it, but I think that, no matter what

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1    vocabulary we want to use, the DSMB was driven by safety

2    concerns, and I'm not sure that they were sitting around

3    saying, hey, we have a primary endpoint, we have an

4    analysis, now can we look at the secondary endpoints.

5                     I think they rushed to all the safety

6    concerns, and in this case safety is the -- One of the

7    safety components is the heart failure.

8                     To respond formally, 1.4.1 is no.                     After

9    1.4.2, how do you interpret the secondary endpoints?

10   You can't interpret them.            You shouldn't do it.              But I

11   think that, in fact, as I say, that they were driven by

12   different concerns, and I switch more to saying that,

13   well, I don't have a problem with understanding how stroke

14   turned out to be p of .04 with all the multiple testing,

15   with the blood pressure.

16                    I look at congestive heart failure, and I'm

17   not sure I know what they are talking about in terms of

18   heart failure in this case here.                So my response, and

19   maybe it's something that Tom was saying also, that you

20   start       mixing   the   clinical      interpretation         with      the

21   statistical interpretation.                      I      think   that      the

22   statistical interpretation of the p-values has run out

23   of steam, and that they are really being motivated by

24   considerations like the safety data and the importance

25   of stopping a drug if they think that there is a real

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1    problem with it.

2                         There they can pull p-values, and they can

3    be overwhelmed by them, but the straight interpretation,

4    which I'm -- I'm taking this in a formal sense as opposed

5    to how do you then put all the clinical -- that there's

6    no p-value really that makes sense in the 1.4.2.

7                         Even if it were mortality, you could say

8    that, well, what if it were mortality?                      You should be

9    overwhelmed by mortality.                 It's not the way the study

10   was designed, and you have a hard time attaching a p-value

11   post hoc to it.

12                        So I think that the p-values really are

13   almost           uninterpretable.         It's    really     a   different

14   consideration, that you saw something very upsetting,

15   and that you did your confidence interval.                       You did a

16   p-value, but it's not in the same fashion as the formal

17   noninferiority           or   superiority        primary,    then     versus

18   secondary.

19                        ACTING CHAIRMAN BORER:         Ileana and then Bob.

20                        DR. PINA:     Yes.    I want to bring this back

21   to the clinical reasons why this trial was ever done,

22   at least how I interpret it, to look                 at the use of drugs

23   that are commonly used now as first-line therapy for

24   hypertension and compare it to chlorthalidone, which has

25   been so nicely proven in the SHEP trial.

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1                        If I'm a clinician and I'm looking at the

2    two curves sitting on top of each other for the primary

3    endpoint, that may give me some sense of comfort.                       When

4    I see the heart failure, it gives me a big sense of

5    discomfort, and would not use the drug, because I don't

6    want to deal with the heart failure, even though the heart

7    failure          occurrence     did   not    alter       ultimately       the

8    mortality.

9                        I don't think that the clinicians will sit

10   down and say, well, this is a superiority or inferiority,

11   we're going to look at the p-value.                   I think we have to

12   take it back to what the original reason for the design

13   of this trial was, which was really to look at true

14   clinical practice.

15                       I think that people don't up-titrate to the

16   16 milligrams and they don't up-titrate every two weeks.

17    They probably up-titrate once a month when they see the

18   patient.         So I think it was set up to be reality.

19                       DR.   D'AGOSTINO:           The    difficulty       with

20   pushing that, though, is when you have a big enough study

21   and you have a large number of outcomes, you are bound

22   to see something that's going to upset you very much.

23                       DR. PINA:    I'm not one to approve of subgroup

24   analysis or any of these, but this was one of the grouping

25   of secondary endpoints in a group of cardiovascular events

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1    or     cardiovascular      effects.        So   I   think     it's      very

2    critical.         It's there.        It's there as a secondary

3    endpoint.        It just happens to be grouped together among

4    others.

5                      DR. D'AGOSTINO:          But it wasn't even a

6    separate endpoint, though, was it?

7                      DR. PINA:      No.     It was grouped together

8    among others.

9                      ACTING CHAIRMAN BORER:         Bob Temple and then

10   Bob Fenichel.

11                     DR. TEMPLE:       Yes.     I'm sort of having a

12   slightly "through the looking glass" feeling here.                               I

13   want to remind everybody that the published report of

14   the CAST study declared that the CAST trial was stopped

15   for futility.

16                     They   had    a    one-sided      hypothesis,           not

17   two-sided.        So they could not find an adverse effect.

18   Now fortunately, nobody paid any attention to that, and

19   everybody knows that CAST showed that those drugs were

20   harmful.

21                     Now why were they able to do that, even though

22   the study as designed didn't permit that conclusion?

23   It's because these rules are not absolute, and you got

24   to use your head.

25                     So having said that, and maybe this just

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1    proves I'm a closet Bayesian, it doesn't shock me that

2    on heart failure the alpha blockers don't do very well.

3     There are published reports.                There's V-HEFT-1.

4               It tells you it's not going to do very well on that;

5    whereas, in contrast, the other drug that it was compared

6    to is well known to have a very favorable effect on heart

7    failure, both from controlled trials and from the simple

8    logic of the fact that it's a diuretic.

9                      Having said all that, it's hard for me to

10   imagine that one doesn't take the finding at least pretty

11   seriously.       What the exact p-value is, I don't know how

12   to put that on it, but that it's strong.                   I mean, if you

13   assume there's 21 endpoints and multiply the p by 21,

14   it still comes out .002 or less than.                    And p-values may

15   not be precise figures, but they give you some idea of

16   how removed from chance this is likely to be.                       So they

17   are not irrelevant.

18                     The actuality of the finding, I must say,

19   seems        fairly     strong.       What    it    means,      what       the

20   implications of it are, that's a different question.

21   But the finding itself, even though it wasn't the primary

22   endpoint?        Not so strong.

23                     DR.    FENICHEL:        Bob,     you     mentioned       two

24   points, and I have to jump in on the first.                         You had

25   mentioned about CAST.             I argue most trials are one-sided

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1    intrinsically, and what one is looking at is strength

2    of evidence to determine either that there is benefit

3    ruling out no benefit or that there is lack of benefit

4    ruling out benefit.

5                     Just as you could in a noninferiority trial

6    have       enough   evidence      to     say    you     can      rule       out

7    noninferiority, if it is so positive, you can rule

8    equality and be superiority.             Similarly, in a trial --

9    In any one-sided trial where the opposite of proving

10   benefit is to rule out benefit, if it is so bad you actually

11   rule out equality, which is proving harm.

12                    I argue that is always the goal, is to be

13   able to do one or the other.           And if it's so bad it rules

14   out harm, of course, that's permissible within the

15   statistical procedures.

16                    Let me, though, emphasize -- In your second

17   point, I am bothered by a comment that would say heart

18   failure is one of a large array of endpoints, and we have

19   to interpret its strength of evidence as though it was

20   pulled out from one of a myriad of endpoints.

21                    I would rather look at the aggregate picture

22   here, and the aggregate picture here is pretty consistent.

23    The aggregate picture here is showing for all of these

24   prespecified        endpoints     that    are    secondary         measures

25   similar kinds of patterns, 19 percent higher stroke,

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1    doubling in CHF, 16 percent higher angina, coronary

2    revascularization           15    percent     higher.          Then       not

3    surprisingly,         the        combined      CHD       and     combined

4    cardiovascular disease endpoints that are driven by these

5    others are showing the same thing.

6                      I see a consistent pattern here, and there's

7    only a few elements that are driving all of this that

8    happen to be the most clinically relevant elements, I

9    would say.       In addition to cardiovascular related deaths

10   and MIs, you look at -- even before you look at angina.

11    If you go to angina, that's also in the wrong direction.

12                     You look at other measures such as stroke

13   and heart failure.               These are one of 23 different

14   measures.        If you choose to look at it that way, doing

15   a Bonferrani, dividing by 23 isn't the right thing to

16   do.       You look at the aggregation.                  If they are all

17   pointing in the same direction, that ought to give you

18   a composite sense here.

19                     DR. D'AGOSTINO:       I guess, Tom, the question,

20   though, is -- Maybe that's what I was trying to say, but

21   that's not what the question is that, I think, we are

22   sitting here with, is that it's not sort of inspiration

23   but what do the p-values mean.               There was nothing that

24   was driving the study.

25                     I mean, I think we're all saying the same

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1    thing, that how do you put the ensemble of information

2    together?        If you ask what do the p-values mean, I don't

3    think they mean at this point anything, but how do you

4    put this -- Interpretation, I think, is really the next

5    question.

6                      ACTING     CHAIRMAN        BORER:      I    think,        Bob

7    Fenichel, did you have a comment?                No?     Steve.

8                      DR. NISSEN:         Of course, we're always making

9    the assumption for statistical purposes that this was

10   heart failure.        I just want to point out to you that every

11   antihypertensive drug, most of the direct acting drugs

12   cause fluid retention and some peripheral edema.                          True

13   for amlodipine, true for doxazosin, true for a lot of

14   drugs, but not true for diuretics.

15                     It's almost like it's a circular definition

16   here, because if         you look at the criteria for what was

17   heart failure, edema was one of those major categories.

18    So, you know, we made all these assumptions based upon

19   the statistical analysis.

20                     This     was    not    a    centrally       adjudicated

21   endpoint.         We know that heart failure reporting by

22   investigators tends to be pretty unreliable, and I'm very

23   concerned that we are doing all these gymnastics with

24   the      statistics      when    we    really    don't       have    a    well

25   adjudicated endpoint, in the first place.

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1                     ACTING CHAIRMAN BORER:         That's a very cogent

2    point, because it brings us right to 1.6.1, and I just

3    want to, for the record, point out that we are always

4    -- we always welcome the comments of a closet Bayesian.

5                     1.6.1    follows      1.6,     which    is:           The

6    publications attribute the excess cardiovascular events

7    in the doxazosin arm largely to excess CHF.             This analysis

8    was retrospective.

9                     1.6.1 then is:      How was CHF diagnosed, which

10   is exactly what Steve is questioning here, and has made

11   a cogent comment about.

12                    Ileana, do you have anything else to add?

13                    DR. PINA:     I think that, you know, taking,

14   as was shown, two columns and taking a point from one

15   column and a point from the second column and making the

16   diagnosis can lead you to error if one of the columns

17   that you are choosing is simply peripheral edema and

18   that's what you are calling heart failure.               However, we

19   do have some data that a good number of the patients had

20   ejection fractions, in fact, below 35 percent.

21                    We also know well that this class of drugs

22   does retain fluid.        This has been well described in the

23   prazosin data.       It's been well described with elevated

24   renin levels.

25                    So I am not surprised.          I am not surprised

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1    at all,s but I do have some problems with how the

2    definition        was reached, even though              it's the same

3    definition as reached in SHEP.

4                      ACTING CHAIRMAN BORER:          Why don't you take

5    one step further, since actually you and Steve have both

6    answered the other elements of this question.                      Do you

7    think that there is -- I'm going to modify this --

8    important bias in the study outcome as a result of the

9    issues about diagnosis of CHF?

10                     DR. PINA:    I would have to say possibly, with

11   the choice of agent, very possibly and very possibly with

12   the other groups not seeing it, because you have an ACE

13   inhibitor in the group.

14                     ACTING CHAIRMAN BORER:         Marvin, what's your

15   thought about this?

16                     DR. KONSTAM:       I'm not super-worried about

17   the bias.        You know, I think it depends on what you mean

18   by bias, of course.           So it's up against the diuretics.

19    So there's no doubt that chlorthalidone is a diuretic

20   and, therefore, there will be more edema in the doxazosin

21   group.

22                     The question is, you know -- But that will

23   be a manifestation of heart failure.

24                     DR. LIPICKY:      That's what bias meant here.

25                     DR. KONSTAM:       Well, it's bias only in the

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1    sense that the patient actually doesn't have heart failure

2    but is being diagnosed as having heart failure, because

3    they have edema.

4                     DR. LIPICKY:     Or has heart failure and isn't

5    diagnosed, because they don't have edema.

6                     DR. HIRSCH:     It's a physiologic bias.

7                     DR. KONSTAM:     No, I don't think that -- Yes,

8    I don't think I would call that bias.            I think, you know,

9    something happened to these patients.                 They presented

10   with an event that was called heart failure, and the

11   question -- and so there are two different parts of that.

12                    One is what's going on physiologically.                     I

13   think that's what you are talking about.                But I'm not

14   super-concerned that these patients actually did not have

15   heart failure, although I don't know why.             I mean, I might

16   be concerned, but I'm not real concerned about that.

17

18                    I think the bigger question is, you know,

19   how important was that to their natural history, given

20   the fact that if somebody had preexisting ventricular

21   dysfunction, not being on a diuretic might have caused

22   that to manifest frank clinical heart failure.

23                    So I don't know if I've answered it.

24                    ACTING CHAIRMAN BORER:         Alan?

25                    DR. HIRSCH:     Just to reemphasize the same

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1    point, I mean, assuming this is a physiologic bias based

2    on known mechanisms of the drugs, one might have pre hoc

3    proposed what Ray is saying would have happened.

4                      On the other hand, I interpreted the question

5    differently.            You   have    a   blinded       study   with      two

6    customers, in a sense, the doctors and the patients.

7    The patients suffered some kind of fluid retention, raw

8    S3 edema which I doubt they wanted to have, and the

9    physician made a diagnosis based on those findings that

10   I doubt the physician wanted to see.

11                     So whereas it is perhaps a predictable effect

12   of the study design and may be unfortunate --

13                     DR. KONSTAM:        I think we're really             being

14   semantic.

15                     DR.    HIRSCH:     It is semantical.

16                     DR. KONSTAM:        I think when somebody with

17   ventricular dysfunction retains fluid, gee, I think we

18   might as well call that heart failure.                  I mean, why not?

19                     DR. HIRSCH:        That's my point.

20                     DR. KONSTAM:        The issue really then will

21   become, okay, how important is that?              Is that irreparable

22   harm?        Those are the important next questions.

23                     DR. LIPICKY:        So it may be better to not

24   discuss this too much unless you have --

25                     ACTING CHAIRMAN BORER:         Just one last point

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1    from Steve.

2                         DR. NISSEN:      Yes.      We don't know what the

3    breakdown was, how many has S3 gallops, how many had

4    peripheral edema.            We don't know any of that.              So, you

5    know, maybe all of this was driven by the edema issue.

6                         Now I every now and then practice medicine

7    for a living, and I can tell you that patients on direct

8    acting           vasodilators    come      in   my   clinic   every       week

9    complaining of peripheral edema.                 Is that heart failure?

10    Do I diagnose that as heart failure?

11                        Well, I think that I would have been much

12   more       comfortable       here     to     have    had    some     central

13   adjudication process and to have in front of us the data

14   on how many episodes were there of acute pulmonary edema.

15    I mean hard heart failure endpoints.                      These are soft

16   endpoints, and peripheral edema is a known endpoint of

17   vasodilator drugs that we all see every day.

18                        ACTING CHAIRMAN BORER:          Steve, do you draw

19   any inferences from the fact that the quality control

20   effort showed that a central adjudication found that 33

21   percent of the diagnoses were not what the committee would

22   have accepted?

23                        DR. NISSEN:     Well, again, I didn't -- I don't

24   know if that data has been published.

25                        ACTING CHAIRMAN BORER:          No, but we were told

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1    about it.

2                         DR. NISSEN:        So it's a little hard to

3    interpret it, you know, when it's not really in front

4    of us.           But again, you know, there are real problems with

5    heart failure as an endpoint in clinical trials.                    That's

6    why     it tends to be centrally adjudicated, because

7    particularly when a known side effect of the comparator

8    drugs here includes what is probably benign peripheral

9    edema.

10                        I'm concerned that a lot of this could have

11   been driven by the simple peripheral edema caused by

12   direct acting vasodilators.               I just don't know the answer

13   to that.

14                        ACTING CHAIRMAN BORER:         I guess, just before

15   you speak, Michael, I guess one of the questions that

16   I want to ask you, Ray, if this is one of the implications

17   of your question.           If you see that somebody has peripheral

18   edema, whatever the cause, are you more likely to go look

19   for and even find, whether it's there or not, other

20   physical signs or symptoms that would be consistent with

21   the diagnosis of congestive heart failure that you infer

22   is probably there because you see the peripheral edema?

23    And that may actually feed into the bias issue that you're

24   asking about.           Mike?

25                        DR. ARTMAN:      Along those lines, you got to

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1    check for having heart failure if you were an outpatient

2    with some edema or if you got hospitalized.                    Do you have

3    any information on that breakdown?                    How many patients

4    actually         were    hospitalized       with     heart    failure         or

5    worsening heart failure?

6                       DR. CUTLER:       Yes.    Those outcomes are in the

7    paper.

8                       DR. ARTMAN:        I didn't see the numbers.

9                       DR. CUTLER:       The numbers -- I don't know if

10   I have the numbers.

11                      DR. ARTMAN:        Because it would seem to me,

12   if the majority of those heart failure events were

13   outpatients complaining of some ankle edema --

14                      DR. CUTLER:        No.    I think it was the other

15   way      around.         I   think     it   was    the     majority       were

16   hospitalized.           I don't have the exact breakdown.

17                      DR. KONSTAM:         But you could fall into the

18   endpoint of heart failure without being hospitalized?

19                      DR. CUTLER:         As defined, yes.          Then it's

20   subset to hospitalized or fatal with the same results

21   in that subset, and the ejection fraction data you saw

22   was on the hospitalized subset.

23                      ACTING CHAIRMAN BORER:           Okay.     I think that

24   what we've heard here is that there's some                   concern about

25   the lack of precision perhaps in the diagnosis of CHF,

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1    not that the data are wrong but that we are a little

2    concerned about interpreting those data, and that it may

3    be that the choice of drug influenced -- without knowledge

4    of the choice of drug, but the specific drugs used may

5    have influenced the diagnosis of CHF because of the

6    presence of a symptom that may not have been due to CHF.

7     But we don't know that.         It's just sort of an amorphous

8    concern, because we don't have the data.

9                     So let's move on to 1.7:             ALLHAT is still

10   in progress.      The data from ALLHAT are not available for

11   FDA review.      Are there questions of interpretation that

12   can be addressed only by review of the complete data?

13                    I think we've heard yes, but Tom?

14                    DR. FLEMING:      Could I just go back, Jeff,

15   before we go to that question?          This may be what you were

16   looking for in the manuscript, the result for fatal and

17   non-fatal heart failure with hospitalization.                 Relative

18   risk was 1.83, was similar to that for all heart failure.

19    Is that what you were looking for?

20                    DR. CUTLER:    Yes, but the question was what

21   proportion of all cases fell into that subset.               The paper

22   doesn't have it.

23                    DR. FLEMING:      And I don't have that right

24   here, although it says basically, if you restrict yourself

25   to heart failure with hospitalization, you see the same

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1    rough relative risk.

2                           DR. HIRSCH:     Just to amplify that, as we look

3    at      other          clinical     trials      there's        avoidance         of

4    hospitalization.               That's not moot.

5                           ACTING CHAIRMAN BORER:           Okay.     So a cause

6    of concern but perhaps not overwhelming concern by itself.

7                           We've heard that there are questions of

8    interpretation that can be addressed only by review of

9    the complete data from all four arms of the completed

10   trial.           Do you want more of a statement than that, Ray?

11                          DR. LIPICKY:      No.    I think that's --

12                          ACTING CHAIRMAN BORER:          Bob.

13                          DR. FENICHEL:       I think this is really the

14   central question.              I mean, it seems to me, we've had other

15   meetings          of    this    Committee      that    center      upon      very

16   impressive published papers in major journals.                            We had

17   a viserinone meeting several years ago which essentially

18   followed by a few months a lead article in the New England

19   Journal in which very small p-values were described

20   showing how viserinone was the best thing for heart

21   failure that had ever come along.

22                          There    were   nine    voting        members    on     the

23   Committee, each of whom made a little statement after

24   having seen the data, which we've not seen today.                           After

25   having seen the data, the nine members each came up with

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1    a different and sufficient reason to turn it down.

2                     The sponsor came into the meeting saying that

3    it would be unethical to do another trial of the drug,

4    because it was so good.          They did another trial, and it

5    failed.

6                     I think that this is the central question.

7     Do we have the data?        Are we the only regulatory agency

8    in the world that looks at original data or do we just

9    read the journals?

10                    ACTING    CHAIRMAN      BORER:        I   think       that

11   everybody would agree with Bob, but the answer is still

12   yes.

13                    Which of the following can be taken today

14   as adequately -- Oh, I'm sorry.              Tom?

15                    DR. FLEMING:      Sorry to interrupt you again.

16    Bob has raised an important question, and I would be

17   interested in knowing from Ray and Bob, who brought this

18   before us knowing specifically that we would be in essence

19   relying on the published manuscripts, whether what Bob's

20   argument -- do you view Bob's argument to be compelling?

21    Are you asking us to come to judgment here in the absence

22   of having the formal full dataset?

23                    DR. TEMPLE:         We, obviously, are.                 Now

24   whether you are going to want to do that --

25                    DR. LIPICKY:      No, we're not

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1                       DR. TEMPLE:       Well, we're asking you for an

2    opinion about a bunch of things.

3                       DR. LIPICKY:       No, no. But go ahead with what

4    you were saying.

5                       DR. TEMPLE:       Well, we have a petition before

6    us that asks us to do various things.                     We're coming to

7    you for advice on how to resolve and respond to that

8    petition.

9                       So part of the conclusion you are going to

10   advise us on is whether we can reach any conclusions with

11   the absence of the complete data.

12                      I   do     want     to    make     an    observation.

13   Viserinone is certainly a good example where, with the

14   help of a committee, with a lot of help of the committee,

15   I have to emphasize, we concluded that the study should

16   not be taken as showing something.               But it wasn't because

17   with full review we blew any holes in that study.

18                      We looked at other data, other studies, and

19   the Committee and a lot of people found information that

20   was      not     compatible     with     that,    the      absence      of        a

21   pharmacologic effect and things like that.                     But I have

22   to tell you, I can't think of a case yet where a very,

23   very low p-value has been reversed by our review of the

24   data.

25                      That's not to say it couldn't happen, and

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1    the concerns about what heart failure actually means in

2    a particular case is certainly a fruitful area to look.

3     So I'm not dismissing the idea that it might be very

4    important, but it's not an everyday occurrence for very

5    extreme results to be shown incorrect.

6                     Marginal results where a couple of people

7    go the wrong way and it makes a difference?                Yes, that

8    happens all the time.          But part of what we are asking

9    you, I think, is whether we should reach a conclusion

10   in the absence of the detailed data.

11                    ACTING CHAIRMAN BORER:          Or at least in the

12   absence of more data than we have.

13                    DR. LIPICKY:       But I think the basic issue

14   is:      Is there enough here, with all of the questions that

15   are unresolved and the importance of the decision that

16   has to be made, to allow you to come to what you think

17   are definitive conclusions.           That's the question you are

18   being asked.

19                    DR. TEMPLE:      Yes, but a component of that

20   is whether you could ever do that if you didn't have the

21   data in your hands.         That's one part of the question.

22                    DR. LIPICKY:      Well, and I guess a subtitle

23   to that is that it's the first time you as a committee

24   have come to grips with not seeing an FDA review of the

25   data.        I guess part of the question is should we ever

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1    do that, and what do we do that for?                      We make everyone

2    else send in the data.

3                      ACTING CHAIRMAN BORER:            Although it wasn't

4    to the extent that we are doing it today, there was some

5    sense of the same thing in the review a few years ago

6    of calcium channel blockers, although some of the data

7    had been reviewed by the FDA; some were not.

8                      DR. LIPICKY:          Yes, but that was really

9    overview kind of stuff.              It's just -- You know, SHEP,

10   for example, as a trial has never been reviewed by us.

11    Chlorthalidone is not approved for that indication.

12                     We have the data sitting on a shelf in one

13   of the project manager's office.               We've never been asked

14   by anyone to approve the indication, and it still sits

15   on the shelf -- SHEP.

16                     So     SHEP,     which     is    isolated        systolic

17   hypertension, not the kind of hypertension here, a very

18   different        population, is a trial that we've never

19   analyzed, and we couldn't tell you any details with regard

20   to SHEP and have a publication to look at.

21                     You know, the question is how can you be

22   satisfied?        I can tell you, I feel very uncomfortable,

23   because I know that when you go into a dataset, you don't

24   start to figure out what the problems are until you start

25   analyzing it and look at it in different ways, and the

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1    kinds of questions that you've been asking sometimes lead

2    somewhere and sometimes they don't.

3                     I can't tell you the number of times that

4    a trial that was part of an NDA which looked very good

5    from the vantage point of the way in which it was analyzed,

6    in fact, kind of fell apart when you started looking at

7    it in detail.         You know, that's numbers of times that

8    that has happened.

9                     It has been very rare indeed -- this is, I

10   think, only the second time in 20 years in my experience

11   that a publication is given, and we're being asked to

12   say make an important decision on the basis of that

13   publication.

14                    I feel uncomfortable with that, but I don't

15   know whether I should, and that's one of the things that

16   you are supposed to answer.

17                    DR. TEMPLE:        Jeff, it's worth pointing out

18   also      that   in   hypertension,       unlike     a   lot   of     other

19   cardiovascular diseases, we've never been asked, and

20   never have, addressed the outcome components in labeling.

21    This has been to the Committee.                We've discussed it a

22   little bit.       It turns out to be very hard to do, because

23   every study is different and so on.                  But whatever the

24   excuses, we never have.

25                    So we've reviewed very few hypertension

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1    outcome studies, hardly any, maybe none.

2                     DR. NISSEN:    It's not just that we don't have

3    all the results of the trial.          It's that we have missing

4    data from the interim analysis that resulted in this

5    ending of the trial.      I mean, things that I would consider

6    to be very basic like what the mean doses were and that

7    sort of thing.      What were the kinds of events of heart

8    failure events?      What was the distribution of kinds of

9    heart failure events?        How many peripheral edemas?            How

10   many S3, etcetera?

11                    So it's really hard, because not only we

12   don't know about the other arms of the trial, we don't

13   know very much about this arm of the trial at this point.

14    We have one relatively express type publication, and

15   that's really all we have

16                    DR. LIPICKY:       Well, but for example, it

17   would be pretty important to know how things looked with

18   amlodipine.      If this business of heart failure goes on

19   and you just mask it with chlorthalidone is a farce, then

20   amlodipine wouldn't show any heart failure.

21                    So there's all kinds of stuff that would

22   really lend insight, because indeed if you believe this

23   secondary endpoint, striking, which looks like you ought

24   to pay attention to it -- If you believe that result,

25   if you think it's real and attributable to doxazosin as

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1    having done something, not that it was insufficiently

2    dosed but that it did something, well, then chlorthalidone

3    -- amlodipine should have had that same kind of effect

4    or at least in part, unless this was all hypertension

5    and it was dose.

6                     Without that kind of comparative look at the

7    results of the entire trial, it's very hard to put this

8    in a perspective, and I want to just emphasize that the

9    DSMB said don't stop the trial.              An independent board

10   said that.

11                    So, obviously, the people who were looking

12   at the results systematically, who were concerned, who

13   knew what was going on, had a difference of opinion with

14   respect to whether or not the trial should be continued,

15   and I still don't have a flavor for how that decision

16   got made or what the considerations were.

17                    Ordinarily, we get the minutes of the DSMB

18   and look at them and find out what it is that they were

19   talking about and what data did they have and what

20   direction were the point estimates going in, and how did

21   they get to or not get to the boundary conditions that

22   led to whatever claim they were making.

23                    All of that is missing, but it's possible

24   -- because, Tom, you seem convinced for a moment.                     So

25   it's possible that one can be convinced from the published

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1    data and that all of this other stuff is just stuff, and

2    you're being asked to make that decision.                    So that's

3    question 2 or 3 or 4 or whichever one it was.                      That's

4    what that was meant to elicit, whichever question that

5    was.

6                     ACTING CHAIRMAN BORER:         Tom, you wanted to

7    respond earlier?

8                     DR. FLEMING:        I'll try to be brief.                In

9    essence, to paraphrase what I'm hearing from Ray and Bob,

10   when I look at what the protocol team specified as their

11   prespecified rationale for early termination, they said,

12   quote, "Compelling evidence from this or another study

13   of an AE of a study treatment sufficient to override any

14   potential benefit on CHD and preclude its further use

15   in the target population."

16                    Now   they    obviously      struggled     with      this

17   criterion, and they came to a conclusion that this result

18   should be released as it related to the alpha blocker

19   and, in particular, though, the other regimens in the

20   study were to continue, which is what put them in the

21   difficult position of not releasing all the information

22   to us.

23                    What I hear you saying is, certainly, we

24   don't have to agree with their judgments.                      They may

25   terminate a trial.       We may not view that to be conclusive

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1    to act on.       But to answer -- To address Bob Fenichel's

2    point in my words, yes, it is important to be cautious,

3    not having the totality of information.                Nevertheless,

4    in a setting such as this the results may be viewed by

5    us to be so compelling on such clinically important

6    endpoints that it is important to take action before

7    waiting for the entire completion of the trial.

8                     DR. LIPICKY:        And that, in fact, is the

9    entire issue.

10                    ACTING CHAIRMAN BORER:          Now that the issue

11   perfectly well defined, which of the following can be

12   taken today as adequately established?

13                    2.1:   Doxazosin is less effective than other

14   treatments for the ALLHAT primary endpoint of prevention

15   of fatal coronary heart disease and nonfatal myocardial

16   infarction.

17                    I don't think we need to discuss that.            We've

18   already heard that we can't take that as adequately

19   established.

20                    2.2:   Doxazosin is less effective than other

21   treatments for the ALLHAT secondary endpoints of -- Maybe

22   we ought to modify that just a little bit, if you will

23   allow me to, to "doxazosin is less effective under the

24   regimen that was used in the study than other treatments

25   for the ALLHAT secondary endpoints of."

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1                     Is that a fair way for us to look at it for

2    you?

3                     DR. LIPICKY:     At the doses studied?

4                     ACTING    CHAIRMAN     BORER:        At     the      doses

5    studied, the whole regimen used.

6                     DR. LIPICKY:     Yes, right.

7                     DR. PINA:      Jeff, wouldn't that be then

8    chlorthalidone, since that's the only data that we have?

9     Is it really fair to say "than other treatments"?                         We

10   only have one.

11                    ACTING CHAIRMAN BORER:          Yes.

12                    DR. LIPICKY:      Well, you asked what other

13   treatment?

14                    ACTING CHAIRMAN BORER:         Yes.     I think that

15   comes down the list here, and the answer will be

16   chlorthalidone, if we have a yes.

17                    All cause mortality:         Does anybody on the

18   Committee think that we have shown that doxazosin is less

19   effective than other treatments for all cause mortality?

20    I see no hands going up.

21                    Combined    coronary       heart       disease        plus

22   revascularization procedures plus hospitalized angina?

23    Any takers on that one?

24                    Stroke?    Does anybody believe that, as of

25   today, we have adequately -- or it has been adequately

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1    established that doxazosin is less effective at the doses

2    studied than other treatments for the ALLHAT secondary

3    endpoint of stroke?

4                     DR. FLEMING:       I want to make sure I am

5    interpreting the question as you intend.              Do you mean

6    by this "less effective," do you mean do we believe that

7    there is adequate strength of evidence to conclusively

8    establish this?

9                     DR. LIPICKY:     Correct.

10                    DR. FLEMING:     As opposed to there are data

11   to suggest this?

12                    DR. LIPICKY:     No.    This is as if it were an

13   approval issue.

14                    DR. FLEMING:      Okay.     And we all recognize

15   that the world shouldn't be black and white, i.e., there

16   are middle ground, particularly if you are looking at

17   secondary supportive data.

18                    DR. LIPICKY:     I thought you saw everything

19   as black and white.

20                    DR. FLEMING:      Certainly not for secondary

21   supportive measures.

22                    DR. LIPICKY:     But it is -- For each of these

23   things, is the strength of evidence the equivalent of

24   two trails at p 05, to put it in those terms.          And I don't

25   -- I'll leave it there.

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1                     ACTING CHAIRMAN BORER:         We are going to get

2    beyond this just to general impressions.                          But I'm

3    inferring from the silence along the table here that

4    nobody believes that we have as yet adequately established

5    that doxazosin is less effective at the doses studied

6    than other treatments for stroke in the ALLHAT trial.

7                     Left ventricular hypertrophy by ECG?                    No?

8                     Renal disease by slope and reciprocal of

9    serum creatinine or by need for chronic dialysis or

10   transplant?      No.

11                    Health related quality of life?                No.

12                    Major costs of medical care?           No.

13                    Fatal or nonfatal cancer?            No.

14                    Gastrointestinal bleeding?           No.

15                    Combined coronary heart disease plus stroke

16   plus coronary revascularization procedures plus angina,

17   hospitalized or medically treated, plus CHF, hospitalized

18   or medically treated -- that's outpatient treated -- plus

19   peripheral arterial disease, hospitalized or outpatient

20   revascularization procedure?

21                    There is the key endpoint.            Do we believe

22   -- Does anyone believe that, as of today with the data

23   that we have, it is adequately established that doxazosin

24   is less effective at the doses studied than other

25   treatments for the ALLHAT secondary endpoint of this,

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1    2.2.1?           This is the endpoint that reached a p less than

2    .001, I believe.

3                         DR. LIPICKY:       Correct.       Does the silence

4    mean no?

5                         ACTING CHAIRMAN BORER:          I'm asking.

6                         DR. FLEMING:        This is an extremely hard

7    question for me to answer.              When you are looking at this

8    composite endpoint and you look at either heart failure

9    itself or the combined cardiovascular disease endpoint

10   that includes heart failure and these other elements,

11   there is in my words considerable evidence.

12              Whether it matches .025 squared on a primary

13   endpoint,           I'd be hard pressed to say yes, but that's

14   where I really struggle with everything else is irrelevant

15   then, which I don't know that you are saying.                   But a lot

16   of people might conclude that from this discussion, if

17   nobody says any of these event prove it, then everything

18   is fine.

19                        DR. LIPICKY;      Oh, no.      No, no, no.      That's

20   not the case.          This is how strong is it.           You can still

21   argue they didn't find anything, but you want something

22   in labeling, if you think that makes a logical argument.

23    So you how you answer this question is sort of important.

24                        ACTING CHAIRMAN BORER:          You could say that

25   you don't think that the standard of evidence of a p less

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1    than .05 times two is appropriate.

2                     DR. LIPICKY:     Yes.     So maybe the answer to

3    2.2.10 is "sort of."

4                     ACTING CHAIRMAN BORER:         Well, maybe, but I

5    think we need to hear some specific comments here.                Ralph,

6    why don't you start?

7                     DR.   D'AGOSTINO:        The   endpoint       or    this

8    combined endpoint when analyzed did come out to be

9    significant, but it is very much driven by the CHF.                           I

10   mean, to look at a composite endpoint and sort of indict

11   all these components is very hard for me to do.                 I mean,

12   it's a secondary endpoint, and there isn't necessarily

13   consistency in terms of if I see one endpoint being

14   significant, another one should be significant, another

15   one should be significant.

16                    So I don't really have a hard time saying

17   that I'd put a no to this, and then my difficulties would

18   come in with something like the stroke, which we've

19   addressed above, and then the CHF which we will address

20   below.

21                    DR. TEMPLE:      Jeff, can we be sure we're

22   getting the answer we need?              There isn't a separate

23   question on heart failure alone.             Right?

24                    ACTING CHAIRMAN BORER:               There is, 2.3.

25   Yes, there is.

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1                         DR. TEMPLE:      Okay, fine.

2                         ACTING CHAIRMAN BORER:          Bob Fenichel?          I'm

3    sorry.           Ralph, were you finished?

4                         DR. FENICHEL:         Yes.     Well, I think the

5    answer is no.           I think it is a harder call than any of

6    the other components of 2.2, but I think that I agree

7    with Tom that there are conditions under which, even in

8    the absence of looking at the data, one has to be carried

9    away with the force of an apparent result and to wonder,

10   gee, how could it possibly be undermined if we saw what

11   was really there.

12                        Well, if this were an unequivocal measure

13   of irreversible harm, I think one has to give more weight

14   to this sort of data-less finding, but as things are,

15   I would say no.

16                        ACTING CHAIRMAN BORER:          Steve?

17                        DR. NISSEN:     You know, it's very difficult,

18   because this is driven so much by the heart failure

19   endpoint, and I remain terribly troubled with the problem

20   of diagnosing heart failure for two classes of drugs,

21   one of which produces edema and one of which relieves

22   edema.

23                        So it's just such a soft endpoint in this

24   application that I have to tend to factor a lot of that

25   out, and I'm just very concerned that investigators saw

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1    some peripheral edema, looked for other things and found

2    them, and that that's driving all of this.

3                      So I would have to say no.

4                      ACTING CHAIRMAN BORER:          Joann?

5                      DR. LINDENFELD:       I would also say no, I don't

6    think this is conclusively established.

7                      ACTING CHAIRMAN BORER:          Tom?

8                      DR. FLEMING:      Is your thought the same, even

9    recognizing        that   when    you    say    heart      disease         with

10   hospitalization, you still have basically the same

11   relative         risk?      You    still       think      that's          soft,

12   hospitalization with heart failure?

13                     DR. NISSEN:     Yes, I do think it's soft, and

14   I'll tell you why it's soft.            That is that somebody comes

15   in the clinic with some symptoms perhaps and has edema.

16    They may be hospitalized for that.                     I mean, this is

17   enough -- There is enough that might suggest a bias in

18   choosing who you are going to put in the hospital that

19   would make me concerned.

20                     Is it a better endpoint?              Yes.     But I just

21   would have been much -- I would have felt much better

22   about this if the whole adjudication procedure and all

23   of that had been somehow cleaner, because of all of the

24   endpoints that we look at in medicine, those like heart

25   failure where it's a multifactorial combination of

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1    symptom and physical finding, it's a very subtle clinical

2    diagnosis.       That subtlety can get played out in lots of

3    ways.

4                      I think, you know, edema can drive a lot of

5    things, and I've actually -- I will tell you that there's

6    data from several generations of cardiologists to suggest

7    that an awful lot of people get put on digitalis for benign

8    postural edema.        We've known that for years.

9                      So I think we just have to be terribly careful

10   here.

11                     ACTING CHAIRMAN BORER:          Tom?    Tom Graboys?

12                     DR. GRABOYS:      Well, I feel in a query about

13   this.        I'm not sure how to answer it.

14                     ACTING CHAIRMAN BORER:          Alan?

15                     DR. HIRSCH:     I've expressed my concern about

16   the diagnosis of heart failure from the beginning.                        So

17   I think that it's hard to be definitive, and I guess I'd

18   say no, but I'm worried.            But no.

19                     ACTING CHAIRMAN BORER:          Ileana?

20                     DR. PINA:     That combined endpoint comes out

21   to be statistically significant, but again it's driven

22   by heart failure.         But it's also driven by angina, and

23   so I can't say that the entire combined endpoint is, but

24   it causes me great concern.

25                     ACTING CHAIRMAN BORER:         So do you think that

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1    this is adequately established or no?

2                     DR. PINA:       I think there's some heart

3    failure there.       I don't know that every single -- and

4    I'd love to see how the adjudication was made.               I don't

5    know that every single diagnosis of heart failure was

6    truly heart failure.

7                     I'd love to see the amlodipine data because

8    amlodipine causes a lot of peripheral edema, which is

9    not heart failure, and it would be very interesting to

10   see how many clinicians identified that as heart failure.

11    Of course, we're not going to have access to that data.

12                    DR. LIPICKY:     So are you refusing to answer

13   the question?

14                    DR. PINA:    No.

15                    DR. LIPICKY;        Is that the answer to the

16   question?

17                    DR. PINA:    Yes.

18                    DR. ARTMAN:      Now I'm really confused.                 A

19   simple no.

20                    ACTING CHAIRMAN BORER:         Marvin?

21                    DR. KONSTAM:     Well, I'm going to answer the

22   question by suggesting that, if the results were the

23   opposite and Pfizer was in here asking for an extension

24   of the indication, you would throw them out of the room.

25    So I guess the answer would have to be no.

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1                       ACTING CHAIRMAN BORER:            Okay.       And I also

2    believe that it hasn't been established.

3                       2.3: Doxazosin is less effective -- I'm going

4    to add again here "at the dose employed" or "with the

5    regimen employed" -- than other treatments for the ALLHAT

6    other        protocol     specified        outcome    measurements              or

7    endpoints of: Mortality from coronary heart disease?

8                       DR. FENICHEL;       Wait a second, Jeff.             Is this

9    question different from -- Why is this not just more of

10   2.2?       What's different here?

11                      DR. LIPICKY:       The difference is that in the

12   protocol there were primary and secondary endpoints

13   clearly indicated, but we are also interested in the

14   following.        So that these are the following.

15                      ACTING    CHAIRMAN       BORER:         Mortality        from

16   coronary heart disease?               Does anybody believe that a

17   difference has been established here?                     No.

18                      Mortality        from      other        cardiovascular

19   disease?         No.

20                      Mortality from neoplastic diseases?                     No.

21                      Mortality from other medical causes?                      No.

22                      Mortality from non-medical causes?                    No.

23                      Myocardial infarction?            No.

24                      Angina?     Tom?

25                      DR. FLEMING:       Well, I'll just jump ahead and

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1    say angina and CHF are the two elements that I can't give

2    a no answer to.     I cannot say it's a .025 squared primary

3    endpoint conclusive level of evidence, but there are,

4    in my view, strong data here indicating that -- in fact,

5    I would argue, stroke, heart failure and angina are more

6    frequently occurring in the alpha blocker regimen.

7                     ACTING CHAIRMAN BORER:        Okay.   Does anybody

8    else on the committee have a sense that there's adequate

9    information to establish doxazosin as less effective for

10   angina or for preventing angina from developing?                Steve?

11                    DR. NISSEN:      Can I make just a comment?

12   There's something that I'm troubled by here, and that

13   is    that 3 millimeter difference in systolic blood

14   pressure.

15                    I would have felt much better about that

16   conclusion if the drugs were given to equal blood pressure

17   effect, and we then saw a difference in the event rates.

18    So I can't attribute it to the choice of drug as opposed

19   to the way the drug was used.

20                    I think it's terribly important as the

21   committee that we have to understand what we've learned

22   and what we haven't learned here, and what we know is

23   that there was a blood pressure difference.            I can't tease

24   that out of the data.

25                    DR. FLEMING:       But, Jeff, I thought you

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1    clarified very carefully at the beginning that this

2    question is relating to the regimens as they were

3    delivered.

4                     ACTING CHAIRMAN BORER:         Right.

5                     DR. FLEMING:     So for the regimen as it was

6    delivered, and your point is well taken.              But that changes

7    the question.

8                     DR. LIPICKY:      It's strength of evidence.

9    It's an intent-to-treat, strength of evidence.                       It's

10   everything as done.

11                    ACTING    CHAIRMAN       BORER:          Integrating

12   everything that we know.

13                    DR. NISSEN:    I guess what I'm saying is I'm

14   concerned that doxazosin was not titrated to its optimal

15   dose, and so what we're doing is we are comparing a

16   suboptimal dose of one drug to an optimal dose of another.

17                    That means that weakens the strength of the

18   evidence tremendously, in my view, and makes that standard

19   that has to be demonstrated here much, much more rigorous

20   before I'm going to be convinced.

21                    DR. LIPICKY:     No.    No, it would be okay to

22   say that dose X of drug A is less effective than dose

23   Y of drug B.     Okay?    That's a perfectly acceptable thing.

24    It doesn't mean that the two drugs are different from

25   one another if they are used at equally effective doses,

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1    but at the doses studied, it's okay to say that one regimen

2    is less effective than the other.                 That implies nothing

3    with respect to the drugs and their potential to be

4    effective.           It just means those doses are different.

5                         ACTING CHAIRMAN BORER:           With that -- Yes,

6     Ralph?

7                         DR. D'AGOSTINO:        Let me give my two cents

8    on it.           I have a feeling that the CHF, no matter how you

9    beat the data, you're not going to lose that significance.

10    So I find it very hard to put a no there.                    I don't know

11   what the alternative is, though.                 I wouldn't want to put

12   a yes.

13                        DR. LIPICKY:       Well, that's fine.           I wrote

14   down "sort of."

15                        ACTING CHAIRMAN BORER:          Okay.     Well, there

16   we are.           Okay, I think to move ahead here, my sense is

17   that, although there are some concerns that Tom has voiced

18   here about angina, nobody else, including Tom, really

19   is ready to say that it is adequately established that

20   doxazosin is less effective at the dose employed, with

21   the      regimen       employed,      than     other       treatments       for

22   prevention of angina.

23                        Peripheral arterial disease?             No.

24                        Nonfatal accidents and attempted suicides?

25    No.

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1                      CHF?   That's where the rubber meets the road

2    here, and I think Ralph made one very important statement

3    here.        He can't say no, but it's very hard to know whether

4    you say -- He can't say that it is less effective, but

5    it's very hard to say no.

6                      Why don't we pick up from there?          Ralph, do

7    you want to add to that?

8                      DR. D'AGOSTINO:        Well, you know, this is

9    where, if we had the other arms, we could see how

10   consistent the CHF is.           I mean, is it going to turn out

11   to be the diuretic, so that it beats out everybody on

12   all the other treatments?            And then we don't -- Then we

13   suddenly say maybe there's something strange about the

14   diuretic arm and so forth.

15                     So I don't know what more you want me to say

16   on this, but I don't know how to really interpret the

17   results that we have except that from a statistics point

18   of view -- and we're stopping with two zeroes and a one.

19    What we were told earlier, the zeroes extend out even

20   beyond that.         So this is a highly significant result.

21   How you interpret it, I think, is the real problem for

22   me.

23                     ACTING CHAIRMAN BORER:           So this is a real

24   cause of concern here, and we haven't come to closure

25   yet on whether we can definitively say that doxazosin

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1    is less effective at the doses employed and the regimens

2    used than other treatments so far.

3                     Next, Bob Fenichel?

4                     DR. FENICHEL:         Well, I'm not sure -- I

5    thought we had already answered this.

6                     ACTING CHAIRMAN BORER:               Well, we didn't

7    answer the CHF part, I think, or maybe we did.

8                     DR. FENICHEL:      Oh.      Well, okay.         Well, I

9    would say no on the same grounds as before.

10                    ACTING CHAIRMAN BORER:         Okay.     Steve?

11                    DR. NISSEN:     No.

12                    DR. LINDENFELD;       No.

13                    ACTING CHAIRMAN BORER:         Tom?

14                    DR. FLEMING:     Yes.

15                    ACTING CHAIRMAN BORER:         Okay. Tom Graboys?

16                    DR. GRABOYS:       I continue to be troubled

17   about the CHF occurrence.           I think there is something

18   there that we are missing.           We are bending over to try

19   to come up with some rationalization which would allow

20   us to kind of cosmetically accept it, and I can't do it

21   at this point.

22                    ACTING CHAIRMAN BORER:          I don't know that

23   we have to cosmetically accept it.           I think this question

24   is have we definitively -- are the data sufficient at

25   this moment that we have seen -- Are they sufficient to

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1    adequately establish to our satisfaction, based on

2    whatever strength of evidence we choose to use as the

3    bar, that doxazosin is less effective at the doses used

4    in the regimen employed than other treatments in the

5    ALLHAT study for prevention of CHF?

6                      The answer can be no, it hasn't been adequate

7    established, but we may still at the end of the day feel

8    so unsettled by all this that there's a conclusion or

9    an action item that could follow.

10                     DR. GRABOYS:      Then, no.

11                     ACTING CHAIRMAN BORER:          Alan?

12                     DR. HIRSCH:     Boy, I'm troubled.         Very close

13   to yes, and the rationale, just to say one more time,

14   is that we have a different kind of study here than

15   normally we analyze.            I can take any study I've ever

16   looked at that we could design and, based on dose and

17   administration routes, find a way of criticizing a single

18   study, and never coming up with a definitive answer.

19                     It's very easy to look backwards and ask for

20   the      second   study,    the    different      p-value      that      are

21   justification of the point estimate.                    So you're going

22   to ask me what do I think.

23                     ACTING CHAIRMAN BORER:           Well, I think you

24   just said what you think.            Ileana?

25                     DR. PINA:     I mirror exactly what Alan says.

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1     I can't sit here and say definitively no, but I'm very

2    close to saying yes, because I think that even if we remove

3    some of the cases, there were enough hospitalizations,

4    that a hospitalization for heart failure is one of our

5    key diagnostic points for defining heart failure.

6                      ACTING CHAIRMAN BORER:          Mike?

7                      DR. ARTMAN:      No.

8                      ACTING CHAIRMAN BORER:          Marvin?

9                      DR.   KONSTAM:         At    the      risk   of     being

10   unhelpful, but maybe this will be helpful, maybe not,

11   I'm going to -- Can I offer a statement that I would say

12   yes to?

13                     ACTING CHAIRMAN BORER:          Please.

14                     DR. KONSTAM:       And maybe this articulates

15   some of the discomfort that people have, and this is as

16   far as I would go with it, that doxazosin in doses used

17   appears to be less effective than chlorthalidone for

18   prevention of the clinical manifestations of heart

19   failure without indication of any implication with regard

20   to irreparable harm.

21                     I think that there is something going on

22   here.        So just saying no -- and I think that's where a

23   lot of the discomfort is.            So I don't know whether it's

24   worthwhile or not, but it might be worthwhile crafting

25   what it is that we think is going on.                   And that's what

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1    I think is going on.

2                     DR. LIPICKY:          It is worthwhile, and it

3    probably should have been written that way, but basically

4    I think you're saying the same thing everyone else said.

5     I still take what everyone else said as "sort of."

6                     You had added the irreversible harm part,

7    and I think that's very important here, because if one

8    things that -- and that's a preamble to the next question.

9     If one thinks that doxazosin caused heart failure, then

10   this is applicable stuff to BPH also.                    It isn't not as

11   effective        in   hypertension        and     not     effective         in

12   hypertension causes the ventricular dysfunction.

13                    It is doxazosin causes something, and then

14   it's equally applicable to BPH, and we would have to

15   incorporate some language to say something about that.

16    So the irreversible harm is important.

17                    ACTING     CHAIRMAN      BORER:         Okay.       So     to

18   summarize the statements about 2.3.1.0, I think it would

19   be fair to say the sense of the Committee is that, no,

20   it is not adequately established that doxazosin is less

21   effective at the dose used in other treatments for the

22   prevention of congestive heart failure, but there's

23   enough information here so that everyone is concerned,

24   and that may lead to an action suggestion of some sort

25   -- I'm not sure what sort yet -- and that we have some

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1    other issues to deal with, and Marvin just began to deal

2    with them.

3                        Number three -- Tom?

4                        DR. FLEMING:       I actually hadn't done this

5    before.          I just did a quick chi square just to see what

6    the strength of evidence is, and I come up with a z-value

7    of 10.           I ran it quickly twice.         I'm not certain, but

8    I'm pretty certain that's right.

9                        So there is an enormous number of zeroes in

10   front of this one.          So if we're talking about statistical

11   strength of evidence -- I know that there are other issues.

12                       DR. LIPICKY:        Well, I thought you said

13   p-values don't count here.

14                       DR. FLEMING:       Well, everything is in the

15   context of -- I think what I said was -- weighing strength

16   of evidence with clinical judgment.                       And strength of

17   evidence is, in fact, a relevant factor.

18                       So I'm just throwing out the fact.                    This

19   isn't a p-value of .001.            You had raised the .025 squared

20   paradigm, and that's not enough here, because this is

21   a secondary endpoint, generally speaking.

22                       So I just wanted to, for the record, point

23   out that this is -- Unlike the other associations here,

24   this one has a very strong statistical                       association,

25   granted, though, it's a secondary endpoint.

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1                      ACTING CHAIRMAN BORER:            Okay.     Number 3

2    gets to the issue that Marvin just raised again.                 If you

3    answered in the affirmative for any part of question 2,

4    was doxazosin worse than placebo would have been?

5                      We heard some information from Tom about that

6    from a quick and dirty calculation, and I think that,

7    even though formally the answer to 2.3.10 may have been

8    no, I think we really do have to resolve this as a

9    committee, and perhaps also with regard to strokes and

10   maybe we'll ask for an opinion about angina.

11                     Was doxazosin worse than placebo would have

12   been?        In other words, does it cause harm?        Can we infer

13   that it causes harm of any kind, number one?                Number two,

14   does it cause irreversible damage, myocardial damage,

15   irreversible harm?

16                     Let's try and grapple with 3.1, and we'll

17   begin with Marvin.          Are we giving you information you

18   don't want?

19                     DR. LIPICKY:      Pardon me?

20                     ACTING CHAIRMAN BORER:         I say, are we giving

21   you advice you don't want?

22                     DR. LIPICKY:       Yes, you're doing good, but

23   I want to just sort of preamble, Marvin, just a little

24   bit from an interpretation point of view.

25                     The intent here is not to, from the data

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1    available, I think, calculate what the probabilities are

2    that it had beat placebo, had the placebo been present.

3     Although that's part of it, it's just that you don't

4    have the proper control group or the proper trial to

5    estimate size of the effect.                  So it would be very

6    difficult        to go through that calculation with                   any

7    precision.

8                      I think Tom's sort of thing of, well, you're

9    not going to be sure is probably right, even if you did

10   everything and so on and so forth.            So I don't think that's

11   the issue.        It isn't this noninferiority stuff or would

12   you, had placebo been present.               It is the business of

13   from the data can you conclude somehow or another from

14   something you've seen that this does harm and that there

15   is something intrinsic.          Then, in particular, is the harm

16   irreversible?

17                     Those are the things to struggle with, if

18   you can.

19                     ACTING CHAIRMAN BORER:          Bob?

20                     DR. TEMPLE:     Maybe my thought will be wrong,

21   but I didn't hear anybody suggest that the answer to that

22   was yes.         So maybe you could just find out if anybody

23   thinks that there is evidence of harm, as opposed to just

24   not working.

25                     ACTING CHAIRMAN BORER:          It's a good point.

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1     Does anybody believe that this drug caused bad things

2    to happen to the heart?

3                           DR. GRABOYS:     Irreparable?

4                           ACTING CHAIRMAN BORER:          As opposed to just

5    not working.             Well, let's have any, and irreversible,

6    or irreversible, both.               Answer the one and the other.

7                           Tom, do you have something?

8                           DR. TEMPLE:       But particularly, by doing

9    something bad as opposed to not being good.

10                          ACTING CHAIRMAN BORER:               Yes, an active

11   badness.          Well, in other words, did it cause myocardial

12   damage?          Did it cause the heart failure?

13                          DR. TEMPLE:    Should someone with BPH worry?

14                          DR. GRABOYS:     If we think it contributed or

15   caused the CHF, then the answer to that would be yes.

16                          ACTING CHAIRMAN BORER:          Do we think that it

17   did?             The    question      applies     to     someone      without

18   hypertension but with BPH.                  Would your expectation be

19   that that person would develop heart failure because of

20   being on the drug?             That would be an implication of it,

21   or is it just that it doesn't do the good thing that

22   chlorthalidone did, which could have a bad outcome.                            We

23   don't really know that.

24                          DR. KONSTAM:     Can I just make the statement

25   and see if anybody disagrees with it?                   You know, I don't

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1    think that you can conclude from the data, even with regard

2    to the clinical manifestations of heart failure, that

3    doxazosin causes it as opposed to some imputed placebo,

4    and I think there's a lot of reason to believe that, in

5    fact, it wouldn't.

6                     ACTING CHAIRMAN BORER:        But I want to be sure

7    that Tom Graboys is satisfied with this.

8                     DR.   GRABOYS:         Yes,    I     accept     Marv's

9    explanation.

10                    ACTING CHAIRMAN BORER:        Okay.    We're saying

11   we have no evidence that it causes harm, irreversible

12   or otherwise.      Tom?

13                    DR. FLEMING:     We might even be able to say

14   more than we have no evidence that it -- "We have no

15   evidence" would seem to suggest that we don't know

16   anything; whereas, we have evidence.              I would say there

17   is evidence that suggests on some of these measures, most

18   notably heart failure, that the rate is higher than it

19   is with diuretics.

20                    Also on other measures such as stroke and

21   angina, it appears to be somewhat higher as well.              However

22   -- However, if I can use information on diuretics, such

23   as SHEP, the evidence there suggests that the overall

24   level of benefit that diuretics provides exceeds the

25   amount that alpha blockers are worse than diuretics.

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1                     So when I put all this together, my sense

2    is that the best evidence I have would suggest that there

3    is maybe no effect of alpha blockers on heart failure,

4    i.e., if I had an imputed placebo, I would expect the

5    results are similar, but I'm having to make a leap of

6    faith about using SHEP and imputing that into ALLHAT.

7    And if I do the same thing on the primary endpoint or

8    on stroke, I actually see some evidence that alpha

9    blockers would be better than placebo.                   But again I'm

10   having to stretch, but not statistically significantly

11   better.

12                    ACTING CHAIRMAN BORER:                Okay.        I think

13   that's the -- Bob?

14                    DR. FENICHEL:        Well, one more thing in the

15   same vein:        Once again, looking across trials and

16   slightly looking across drugs, I think it's reassuring

17   if one looks at the V-HEFT-1 study, where prazosin, a

18   close cousin, was not any good for people with congestive

19   failure, but it certainly didn't do any harm.                  The results

20   were absolutely superimposable, placebo versus prazosin.

21                    So that also is somewhat reassuring that harm

22   is not being done.

23                    ACTING CHAIRMAN BORER:                Okay.        I think

24   we're all in agreement on that one.               Ileana?

25                    DR.   PINA:      I    disagree        with     that      last

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1    statement.        It showed that there was no difference in

2    mortality, but there was nothing in there about the

3    occurrence of heart failure with prazosin, and I don't

4    remember ever seeing that in the trial either.

5                      ACTING CHAIRMAN BORER:          Okay.    But I mean,

6    I think we've all agreed that we don't see any evidence

7    that doxazosin caused harm.

8                      In comparison with which other treatments

9    is doxazosin less effective?             Again, I would ask for a

10   response with regard to CHF predominantly, and if anybody

11   has any thoughts about stroke or angina, you can give

12   them.        But, Ileana, you raised this issue before.                  Why

13   don't you try to answer that for us?

14                     DR. PINA:     The only drug that I can say right

15   now is chlorthalidone, because we don't have any other

16   data available.        Maybe at the end of the trial we will.

17                     ACTING CHAIRMAN BORER:           Okay.      So is the

18   evidence sufficiently strong so that you can say that

19   doxazosin is less good than chlorthalidone for prevention

20   of CHF development?

21                     DR. PINA:     I'd have to say yes, with that

22   p-value.

23                     ACTING CHAIRMAN BORER:         Okay.     Any other --

24   Does everybody agree with that?               Does anybody have any

25   other comment?        Ralph?

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1                      DR. D'AGOSTINO:       Well, it's back to the CHF,

2    but we've not really sure that we're that comfortable

3    with CHF.        I would prefer not to leave this study in terms

4    of making the interpretations.             So I think that the data

5    does indicate that it might be less effective than other

6    drugs, in particular, the diuretic here.                 But again,

7    there's all sorts of caveats attached to that:                 What is

8    the CHF that we're really talking about?

9                      I would not extend it to stroke.             I think

10   the result for stroke was significant at a .04, and one

11   may argue that there's a right direction and so forth,

12   but I think that's really overreading -- that might get

13   us into overreading the data.             So I would stay with the

14   CHF.

15                     DR. TEMPLE:      Jeff, I read this question as

16   asking what the comparator, that the thing you thought

17   in 2.3 was is a guess, and since the only drug it compares

18   to is chlorthalidone, maybe just see if anybody thinks

19   there is any other drug this applies to.

20                     ACTING CHAIRMAN BORER:          Well, I was trying

21    to get at something more.                   It's clear that only

22   chlorthalidone was involved, but rather do we believe

23   that there is a clear superiority of chlorthalidone?

24                     DR. TEMPLE:       Right.      But isn't that what

25   2.3.10 was?          I mean, I admit, the results are not

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1    equivocally obvious, but it's the same question.

2                      DR.   FENICHEL:        No,    it's    not   the     same

3    question.        One might believe that, inasmuch as the other

4    arms of the ALLHAT study have not been stopped, the other

5    comparators to chlorthalidone can't possibly be as bad,

6    and therefore, from that one might believe that doxazosin

7    is a little bit worse, at least, than those others.

8                      I think that's a terrific stretch, but I

9    think that may be the intent of the question.

10                     DR. TEMPLE:     You're right, Bob, but I think

11   I was wondering whether Jeff could ask whether anybody

12   believes that, so you don't have to spend a lot of time

13   on it.

14                     ACTING CHAIRMAN BORER:          I'm going to ask if

15   anybody believes that.           No.    Okay, let's move on then.

16                     Do the findings generalize to other drugs

17   with predominant alpha-adrenergic antagonist activity?

18    Does anybody believe that we should draw that inference,

19   extrapolate that way?           I'll take that as a no.

20                     With alpha-adrenergic antagonist activity,

21   in part?

22                     DR. PINA:     Jeff, let me ask a question of

23   Ray.       Ray, do you know if in the label of prazosin, is

24   there any statement about volume retention?               I mean, it's

25   been a long time, but do you recall?

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1                        DR. LIPICKY:     I guess my best answer would

2    be what's prazosin?           Does that answer your question?

3                        DR. PINA:     I guess that answers it.

4                        DR. TEMPLE:    Jeff, I know what prazosin is.

5     I think the answer is yes, because there was a lot of

6    agony we spent about the fall in hematocrit and certain

7    other       blood    borne    things    with    prazosin          which       was

8    attributed to fluid volume expansion.                     I'd bet a lot,

9    without looking, that there's some discussion of it in

10   there.

11                       How much edema and stuff like that, I don't

12   remember, but I know there was concern with fall of

13   hematocrit and sodium and stuff like that, and it was

14   attributed to volume expansion.                So I know that much.

15                       DR. LIPICKY:     You're right.

16                       ACTING CHAIRMAN BORER:           Again, do we want

17   to extrapolate from the results of these data to other

18   alpha-adrenergic         agonists      or    drugs       that     have      some

19   alpha-adrenergic agonist activity, if they also have

20   other properties?            I'm not hearing a groundswell.

21                       DR. LIPICKY:     If you take 3.3.1 as no, the

22   rest of the questions aren't worth asking.

23                       ACTING CHAIRMAN BORER:        Okay.         We won't ask

24   them.

25                       Number 4 -- since you are the one who is

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1    asking for the advice:            Should an antihypertensive agent

2    be considered as "second line" if it is less safe than

3    another agent?          Less effective at reducing systolic or

4    diastolic        pressure?          Less     effective     in    reducing

5    cardiovascular         events?          If   so,   which   ones?        Less

6    effective in reducing mortality?

7                      I think that we would all say that it is true

8    that, if it was less safe, less effective at reducing

9    cardiovascular events, and we can name some, and less

10   effective in reducing mortality, that one would not want

11   to consider it first line.              But then we come back to 4.2,

12   less       effective     at    reducing      systolic      or   diastolic

13   pressure?

14                     I    assume     you    mean      going   to   maximally

15   tolerated dose and determining that there is such a

16   difference.       Is that what you are asking us?

17                     DR. LIPICKY:       Well, yes, I guess.        Well, let

18   me sort of see if I can make an assertion, and then someone

19   on the committee can disagree.

20                     I think what this question was trying to get

21   at through multiple questions, and we only have an hour

22   left, was how does one get to be second line?                        Right?

23    And is it the way in which Tom was reasoning earlier

24   today or is it on some specific reason like you know it's

25   less safe or you know it doesn't reduce blood pressure

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1    as much or you know it has some event problem -- you know,

2    it doesn't reduce some event rates enough -- or it doesn't

3    reduce mortality?

4                     So I think what this question was meant to

5    do was to say, if you really knew that the drug did

6    something, and we've talked about all of the things that

7    you know and don't know, which one of those things would

8    be sufficient in your mind to make it second line?

9                     ACTING CHAIRMAN BORER:          Can I just begin by

10   asking for clarification.           I mean, I spoke very quickly

11   when I was reading the question.               But 4.1, "less safe

12   than another agent" -- We don't think about approvability

13   or utility of a drug in terms of safety.                We think of

14   it in terms of safety for the intended use, and we relate

15   the safety to the efficacy.

16                    So you know, one would have to look at this

17   question in totality.          We would have to know something

18   about the efficacy for what, not just blood pressure but

19   for event lowering, if we wanted to make a statement,

20   and then relate safety to that.

21                    You know, it's hard to answer 4.1 in a vacuum.

22    Similarly, with regard to all of these issues.

23                    DR. LIPICKY:     Well, I'll tell you what.           Let

24   us retract that question, because it's too theoretical,

25   and there is no real setting to answer it by, and you

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1    will be answering some of that question in the next

2    question.

3                     ACTING CHAIRMAN BORER:           Ah, we've just saved

4    some time.       Steve?

5                     DR. LIPICKY:       Right.     So skip 4.

6                     DR. NISSEN:      Not to want to waste any time,

7    I want to make a point here about all of this, and it

8    relates to this whole discussion today.                 That is, what

9    does "first line" mean, and what does "second line" mean?

10                    Well, I think thoughtful practitioners who

11   treat hypertension choose drugs on the basis of a lot

12   of factors, including the concomitant conditions.                        So

13   if I see somebody that has hypertension and angina, I

14   may      favor   a   beta   blocker.         In   somebody     who     has

15   hypertension and congestive heart failure, I may favor

16   an ACE inhibitor.

17                    So in one setting, a drug could be first line,

18   and in another it could be second line.                 So one of the

19   complicating factors here is that we use these drugs in

20   a context of multiple other factors.               So I think it would

21   be a disservice to label drugs first line, second line

22   or anything like that, because we don't know the context.

23                    DR. LIPICKY:       You're 100 percent right, and

24   this is sort of oriented toward stupid FDA, in a way,

25   in that when a new antihypertensive is approved, it's

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1    just approved.           You get to make whatever choices you want,

2    but the labeling doesn't say use me first, use me second,

3    use me third or use me in certain circumstances.                         Okay?

4                       Sometimes for safety reasons that are even

5    less than we have seen in ALLHAT, drugs don't get approved

6    for hypertension, and sometimes they will definitely be

7    approved as second line because we know they work, but

8    for safety reasons we say it shouldn't be used before

9    you know you have to use it.

10                      In those circumstances we usually require

11   that there be evidence that it lowers blood pressure in

12   circumstances where other drugs are used and they do not

13   lower blood pressure.

14                      ACTING CHAIRMAN BORER:           A primary example

15   is captopril when it was first approved.

16                      DR. LIPICKY:        Yes.

17                      DR.     TEMPLE:       Jeffrey.        Or     minoxidil.

18   Minoxidil, if you were basing it on blood pressure

19   lowering effect, would be the number one drug for

20   everybody.         But we know it isn't.

21                      It's    also     important     to     appreciate         the

22   possible         nuances    of    various     recommendations.              The

23   insertion of a word like "generally" allows people to

24   think about other things, if they want to, doesn't lock

25   them in, and you can do that.             But just as a proposition,

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1    if you really believe -- if -- that if the first line

2    therapy doesn't have some ability to treat developing

3    heart failure, some people might reach the conclusion

4    that      the     first        drug    you    use   in    the    treatment         of

5    hypertension ought to be a drug that has that capability.

6                           I'm not asserting that as a truth, but one

7    could give that advice.                   I mean, advice to doctors is

8    going to include things like that.                        Other people feel

9    free to make those generalizations.                            The question is

10   whether labeling might want to do that, too, and it doesn't

11   have to be absolute, and it doesn't have to threaten

12   disbarment if you don't do it.

13                          It could say as a general idea, it's a                  good

14   idea to have a drug that treats heart failure, because

15   a lot of people with high blood pressure get that.                                 So

16   there's a lot of possibilities, and you don't want to

17   think of only one.

18                          Okay.     I'm sorry, Bob?

19                          DR. FENICHEL:          I find the whole idea of

20   second line therapy for a class of drugs which is approved

21   on the basis of a surrogate to be very difficult.                          I think

22   this is a systemic problem.

23                          I mean suppose -- Let's take something that

24   no     one       has    a     commercial      interest         anymore.        Take

25   reserpine.             Let us suppose for the sake of argument that

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1    reserpine is just awful, that it causes lots and lots

2    of suicidal depression, you know, much more than with

3    any other antihypertensive.

4                     Well, suppose that's all true.             It still

5    might be true if one showed that in fact mortality --

6    even counting all those suicides, mortality at the end

7    of the day or the end of the year was less on reserpine,

8    and all your patients who are now on ACE inhibitors or

9    doxazosin or whatever, chlorthalidone, would be better

10   off -- more of them would be alive and happy -- even

11   counting all the reserpine stuff, and happy at the end

12   of a year, well, then it doesn't matter that reserpine

13   is less safe.

14                    What does that mean, it's less safe?                The

15   whole business of -- or even suppose you had something

16   which didn't reduce the blood pressure as much.                   Well,

17   if there are more people standing at the end of the year,

18   that's all that matters.

19                    The business of trying to make second line,

20   first line calls in an area of surrogate endpoints is,

21   I think, fraught with paradox.             I think it's probably

22   to be avoided.

23                    ACTING CHAIRMAN BORER:         Bob?

24                    DR. TEMPLE:    There's a partial truth in that

25   and a partial non-truth.          This is the largest and best

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1    attempt to compare outcomes we are ever going to see,

2    and it found something that has a p-value as long as your

3    arm, and people are still extremely doubtful about whether

4    it has shown anything at all.

5                     All the rest of the comparisons are going

6    to be, I presume, less impressive since they haven't

7    stopped the trial yet.            It's very hard to detect a

8    difference when the bulk of the effect of the therapies

9    is due to lowering blood pressure, which based on all

10   the data we have for a wide variety of drugs simply must

11   be true.

12                    The differences are likely to be very small.

13    I think in an area like this you have to look at possible

14   other advantages.       You may or may not decide to have one

15   thing be second line or another, but it isn't ridiculous

16   to do that, based on the assumption that, other things

17   being equal, blood pressure tells us what to do and that

18   you can find differences that you think will be meaningful

19   even though you have no guaranty.             I don't think that's

20   crazy.

21                    DR. FLEMING:     Bob, I agree.       Bob Fenichel,

22   I understand your point in the world of surrogates, how

23   difficult it is really to order and sort things through.

24    It's the reason that I find the ALLHAT trial so remarkably

25   important.

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1                     Here we have a major study that involved

2    randomization of 24,000 people followed at this point

3    in time of our analysis 3.3 years and eventually six years

4    as it presents its final data where we are looking at

5    hard clinical endpoints.

6                     We are looking at fatal CHD and nonfatal MIs.

7     We have 1,000 events.           We have 600 strokes.         We have

8    nearly 1,000 heart failures.            I know that there is some

9    ambiguity in some of these, but to my way of thinking,

10   I'm not persuaded that we cannot view hospitalization

11   with heart failure as a very relevant point, and I am

12   persuaded by the strength of evidence here.

13                    I believe it's real, and I believe that's

14   what, in essence, the team was telling us as well, is

15   they had to make an ethical judgment as to whether it

16   was acceptable to continue this regimen in this study.

17                    We have two facts on important clinical

18   endpoints.       Heart failure is much more frequent on alpha

19   blockers, point on.        Point two, evidence on 1,000 events

20   suggests similar outcomes on fatal CHD and nonfatal MIs

21   with enough evidence to rule out that, if this study had

22   gone all the way to its bitter end, there would have been

23   much chance at all that that would have been altered

24   meaningfully.

25                    To my way of thinking, this is an incredibly

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1    important insight that should guide our thinking, and

2    I don't see all of these being equal.                   Specifically, I

3    don't see the diuretic's profile to be the same as the

4    alpha blocker's profile.

5                      DR. LIPICKY:      Well, it's doxazosin profile,

6    because you already said you can't generalize to alpha

7    blockers.        Okay?   But I do think -- I don't disagree with

8    a word you said, Tom, with the exception being that I

9    don't know how to incorporate that information into the

10   context of what we know about doxazosin and how you are

11   supposed to use it.

12                     ACTING CHAIRMAN BORER:          We're about to tell

13   you.

14                     DR.    LIPICKY:      All    I   know    is that you

15   shouldn't use it as ALLHAT did.               That's all I know.

16                     ACTING CHAIRMAN BORER:          Steve?

17                     DR. NISSEN:       There's another problem here,

18   and it's one that really has bothered me all along with

19   this whole discussion.            That is that we're looking at

20   these agents as if they are used alone, and the number

21   of patients that I see that are on monotherapy or

22   hypertension is pretty small.

23                     So now we have the complex issues of what

24   happens to patients -- I mean, many patients are going

25   to be on doxazosin, you know, in clinical practice and

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1    a diuretic or on           doxazosin and an ACE inhibitor.

2                      So    there     are    so   many     combinations         and

3    permutations, and the fact is we rarely treat patients

4    with hypertension with monotherapy, and I don't know how

5    to factor any of that into our thinking about what to

6    recommend here.

7                      DR. HIRSCH:       But, Steve, don't you basically

8    have the data here?            This is the practice group sort of

9    like you're asking for, and we're going to be more and

10   more looking at data like this.                 So at the end of the

11   day you have to look at the global data to have the answer.

12                     ACTING CHAIRMAN BORER:              Okay.   that's what

13   we're going to try and do now.            I mean, I think the general

14   consensus here is that, with a greater or lesser degree

15   of assurance, depending upon where at the table you sit,

16   everybody believes that, as Tom said, heart failure is

17   more frequent among the patients who took doxazosin                       than

18   the patients who didn't take doxazosin                    in this trial.

19                     There are a lot of confounds, etcetera,

20   etcetera,        but    that     seems     to    be    reasonably         well

21   established.       Now it's the interpretation of it on which

22   we differ or on which we can't draw a conclusion, and

23   we are being asked at the end of the day to provide a

24   suggestion for action by the FDA, which is really the

25   ultimate goal of this exercise.

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1                     So    what     action       is   now    indicated         for

2    doxazosin?       We'll do this, rather than by free comment,

3    just by a vote and, if you have a cogent comment to make

4    about why, make it.            But let's try and keep it short,

5    because we are going to have to discuss --f we find

6    something that needs to be done, we're going to have to

7    be pretty precise about our recommendations.

8                     Withdraw marketing approval?                 Yes or no.

9    Start down with Tom -- I'm sorry, with Marvin.

10                    DR. KONSTAM:        No.

11                    ACTING CHAIRMAN BORER:            Mike?

12                    DR. ARTMAN:        No.

13                    DR. PINA:       No.

14                    DR. GRABOYS:        No.

15                    DR. FLEMING:        No.

16                    DR. LINDENFELD:          No.

17                    DR. NISSEN:        No.

18                    DR. FENICHEL:         No.

19                    DR. D'AGOSTINO:          No.

20                    ACTING CHAIRMAN BORER:              Okay.      Nobody is

21   suggesting withdrawing marketing approval.

22                    Change the label to remove the indication

23   for essential hypertension?               Let's start with Ralph.

24                    DR. D'AGOSTINO:          No.

25                    DR. FENICHEL:         No.

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1                     DR. NISSEN;      No.

2                     DR. LINDENFELD:        No.

3                     DR. FLEMING:      No.

4                     DR. GRABOYS:      No.

5                     DR. HIRSCH: No.

6                     DR. PINA:     No.

7                     DR. ARTMAN:      No.

8                     DR. KONSTAM:      No.

9                     ACTING CHAIRMAN BORER:           So it's unanimous

10    that nobody wants to remove the indication for essential

11   hypertension.

12                    Indicate      for       second        line    use        in

13   hypertension?       This is the issue we've just been going

14   over.        If you just want to vote, that's fine.                If you

15   have a succinct and cogent comment, make it.                   Marvin?

16                    DR. KONSTAM:        Well, I'll just comment.                  I

17   would say no at the present time.              You know, I do think

18   that more data needs to come in from this trial.                I think,

19   in particular, I think that we need to understand the

20   relationship between the events and the blood pressure

21   effect before we could do anything, and it is possible

22   after that's clarified that there might be other changes

23   that make sense.        But without even understanding that,

24   anyway I would vote no at this point.

25                    DR. FENICHEL:       Jeff.

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1                     ACTING CHAIRMAN BORER:         Yes, Bob Fenichel.

2                     DR. FENICHEL:       Yes.     Actually, one could

3    believe the worst of doxazosin now.             Suppose we had all

4    the data, and everything was as it appears to be, and

5    we all agree that it is worse than chlorthalidone.

6               It would not then be appropriate to offer second

7    line status.      Second line status is given to drugs which

8    are shown to be effective when other things are not, which

9    might not be true of doxazosin. It might be that by the

10   time people have flunked other therapy, they are going

11   to flunk doxazosin, too.         I don't know that, but I think

12   that's a separate question.

13                    DR. TEMPLE:     Jeffrey, the term has an odd

14   use in this case.        What Bob says is what second line

15   usually means, don't use unless you failed on something

16   else.

17                    In this case, it's the distinction between

18   initial therapy and add-on therapy, and what I think

19   people might be talking about is whether this should be

20   the first drug you use, which has one implication, or

21   whether you would reserve it for adding on to gain control

22   when the other therapies you tried hadn't worked yet.

23                    DR. FENICHEL:        But isn't that the same

24   thing, Bob?      Do we know that it works as add-on?

25                    DR. TEMPLE:    Sure, we do.          We have data that

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1    shows these drugs work when you add them to a diuretic.

2

3                       ACTING CHAIRMAN BORER:                Well, that they

4    lower blood pressure.

5                       DR. TEMPLE:      And in that case, presumably

6    the diuretic takes care of the heart failure, since as

7    based on a previous vote, nobody thinks this causes heart

8    failure.         They think it just fails to treat it.

9                       ACTING CHAIRMAN BORER:                Okay.      Marvin,

10   would you change your vote at all, given those comments?

11                      DR. KONSTAM:      You know, not at this point.

12                      ACTING CHAIRMAN BORER:          Okay.     Mike?

13                      DR. ARTMAN:      I don't think we have enough

14   information and, if the drug were used as labeled for

15   hypertension, it may be just fine.                 So I would say no.

16                      ACTING CHAIRMAN BORER:          Ileana?

17                      DR. PINA:     I think that's going to be up to

18   JNC-7, whenever it happens, to define the first line and

19   the second line.         So I don't think we should do anything

20   about it.

21                      DR. HIRSCH:     Agreed.      I think that's not our

22   role.        That's the JNC role.        No.

23                      DR. GRABOYS:      No.

24                      ACTING CHAIRMAN BORER:          Tom?

25                      DR. FLEMING:        Well, I'm struggling with

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1    this, because in essence the data, as I -- Well, two

2    points.          First, ultimately this issue needs to be

3    reassessed when we have access to full data from ALLHAT.

4

5                      I'm uncomfortable with the results at this

6    point being viewed as doxazosin is an equally appropriate

7    first line choice with diuretics, and I don't know how

8    specifically to convey that that isn't an appropriate

9    perspective.        I don't know what our options are here in

10   order to convey the sense that the overall evidence that

11   we have here -- I'm in spirit very much in understanding

12   what the data monitoring committee and what the Steering

13   Committee judged and what they decided when I look at

14   the totality of this evidence.

15                     So how does one convey from these data that

16   there is evidence to suggest benefit to risk profiles

17   favor diuretics?

18                     DR.   KONSTAM:         Well,     can    I   just       say

19   something.        You know, we're going to get to the last item

20   here where there is going to be an opportunity to try

21   to come to some clarity, and that might be a lot more

22   effective than just saying second line therapy.

23                     DR. FLEMING:       All right.         That being the

24   case, then I'll abstain.

25                     ACTING CHAIRMAN BORER:          Joann?

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1                     DR. LINDENFELD:       I would say not.          Not yet,

2    I wouldn't.       I think there might be a more effective way

3    to do this.

4                     ACTING CHAIRMAN BORER:          Steve?

5                     DR. NISSEN:      Not yet.

6                     ACTING CHAIRMAN BORER:          Bob?

7                     DR. FENICHEL:       No.

8                     DR. D'AGOSTINO:       No.

9                     ACTING CHAIRMAN BORER:           And I'll add a no

10   also.

11                    Add a black box warning?              I would say that

12   if you want to answer that one yes, tell what the black

13   box warning is.       Ralph?

14                    DR. FLEMING:       I don't know.           For me, it

15   would be helpful.       Could we give a good regulatory review

16   of the factors that really draw the line in your mind

17   between whether we give a black box warning or not, and

18   whether we give a bolded warning or not?

19                    DR. TEMPLE:     Well, there's a lot of judgment

20   in it, and I think -- I'm sure you should hear what Ray

21   says, too.       There are no fixed rules yet.            We don't even

22   have clear internal guidance yet.

23   However, the black box usually refers to something

24   terrible that's going to happen and that you're quite

25   sure of, and you use dark print if you're a little less

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1    sure and it's a little less terrible.

2                       What you're talking about here is a somewhat

3    unusual case, which is you don't think the drug actually

4    does anything.        You think it fails -- At most, you think

5    it fails to provide a benefit that some other class does.

6                       Those things have appeared in dark print

7    sentences added to the indication section or to warnings

8    in a variety of other places.                But I think the bottom

9    line is you have complete discretion.                    Remember that a

10   box is louder.        It prevents certain kind of advertising

11   such as reminder advertising.                 it has to be featured

12   prominently in all promotion, as do all of these things,

13   but it makes a bigger splash.

14                      I think you have a lot of discretion, as we

15   think we do.

16                      DR. FLEMING:       So the description you just

17   gave, Bob, of the dark print for an intervention that

18   maybe       doesn't   do    something      important       that    another

19   intervention does -- that would correspond to the bolded

20   warning.         Is that what that is?

21                      DR. TEMPLE:      That would be the more usual

22   thing you would do, if that's what you wanted to do.

23                      DR. LIPICKY:         And I would add that in

24   thinking about that it should be done, you need to say

25   something about what that should say to people with BPH,

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1    because it doesn't seem right to say, geez, you people

2    with hypertension ought to worry, but you guys with BPH

3    are perfectly okay, or do we know that?

4                      DR. PINA:     One more point.         Is the bolded

5    warning -- Does the bolded warning have to appear on

6    advertisement?

7                      DR. TEMPLE:        We would generally say that,

8    if an advertisement didn't have a bolded warning, it would

9    be misleading.       So it does.       It's not as obvious, because

10   the box sort of stands out.

11                     DR. PINA:     So both of them have to appear

12   in some form?

13                     DR. TEMPLE:      Yes.      We would say that.

14              DR.   FLEMING:      And    then    the   last   option        was

15   describing       the clinical findings, which is a less

16   significant step.           Is that correct?

17                     DR. LIPICKY:        That's correct.           It would

18   just go into the clinical pharmacology section, but then

19   if you chose that option, I would ask you to say -- You

20   know, it's easy enough to write down the demographics

21   and who was randomized and what the results are.                         But

22   you have about two sentences to say what they mean, and

23   it's going to be hard for me to see how to write that

24   when we have spent the day trying to figure it out.

25                     DR. FLEMING:        One of the issues that was

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1    apparent in the presentation to us in the citizens'

2    petition was some research that they had done that

3    suggested that a large number of clinicians were unaware

4    of ALLHAT, and we were challenged to consider whether

5    at a minimum we should take steps to ensure that people

6    are informed.

7                     Now that could be accomplished by either the

8    bolded warning or describing the clinical findings?

9                     DR. LIPICKY:       No.    No, that could only be

10   accomplished by doing the talk papers, by doing "Dear

11   Doctor" letters, by getting press releases, and by having

12   a Med Alert kind of thing; because if you just put a black

13   box on the label, it will go into the PDR edition after

14   next, and no one will ever know it.

15                    DR. TEMPLE:      No.     It goes into promotion,

16   too.       But the petitioners made a fairly strong case for

17   arguing that, if you don't do something more than change

18   the labeling, oftentimes people don't know about it.

19   That's why they suggested it, and Sid suggested a Med

20   Guide.

21                    DR. LIPICKY:       Well, but I think there are

22   a couple of distinctions to make here from the vantage

23   point of what we're being asked to do, and I guess we

24   should have paid more attention to it in the questions.

25                    There's a certain amount of professional

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1    information that is needed, presumably.                    Presumably,

2    that is up to FDA to supply, because medical schools don't,

3    and the societies don't, and journals don't and stuff

4    like that. So only FDA can educate physicians through

5    labeling.        But I'll drop that.

6                      So    there     is    the    element    of   educating

7    physicians.       That's what Pfizer's poll was about.                Okay?

8     The other component of what we have been asked to do

9    by the citizens' petition is to get to the patients, each

10   individual        patient,      because       this   is   obviously        an

11   emergency to the patient who is receiving doxazosin, and

12   that patient must absolutely know and make a decision

13   as to whether or not their lives are at risk because they

14   are on doxazosin, and they should go see their doctor

15   and get off it.

16                     DR. FLEMING;         So the suggested FDA approved

17   mandatory Med Guide which we were hearing this morning

18   as a suggestion actually is not on your list here.

19                     DR. LIPICKY:          That's correct.          It's an

20   inadvertent omission.

21                     DR. FLEMING:         And if you were to insert it

22   based on a level of concern that would generate the need

23   for such information, where does it get inserted in terms

24   of severity relative to these other five?

25                     DR. LIPICKY:           Well, it would be other

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1    actions, I guess, and then what you're asking someone

2    to do is to put into plain English for people who don't

3    know what congestive heart failure is what it is that

4    we haven't been able to figure out here today.

5                       DR. TEMPLE:      Tom, there are three reasons

6    for having the Med Guide that are listed in our regulation.

7     One is to warn people about something that they can

8    prevent.         That's why you engage the patient in this.

9                       The other is to let them know that there's

10   some terrible risk that they want to think about before

11   they go on this.          The third -- never used so far -- is

12   that there's important information to them about how to

13   use the drug.         This might be conceivably one of those.

14    That is, maybe you should be on something else first.

15    So it --

16                      DR. LIPICKY:      But I don't think that's the

17   message.         I think the message is, if you are not on 16

18   milligrams, go see another doctor.

19                      DR.   TEMPLE:       Well,     there   are   possibly

20   multiple messages, but in any event, they are all in that

21   third category of how do use either this therapy or how

22   to use general therapy.             Those are the conditions for

23   a Med Guide, particularly.

24                      I just want to say one other thing.               Don't

25   think of any of these categories as limiting.                           For

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1    example, you could describe the study, but it sort of

2    screams for you to say something about what it means.

3    So maybe that goes in the indication section.

4                     You can think broadly.           There's a lot of

5    possibilities, if you think they are worth it and right.

6                     ACTING CHAIRMAN BORER:         Tom?

7                     DR. GRABOYS:      You know, at the end of the

8    day and a lot of discussion, you have to take a step back

9    and ask the question, am I going to prescribe this drug

10   for my patients, number one?              Number two, if I have

11   patients on the drug, am I going to withdraw the drug?

12                    There's enough ambiguity, enough concern for

13   me personally to indicate that I won't prescribe the drug

14   at this point, and I will pull patients off of that drug,

15   because we don't know.        There's a lot of "we don't know."

16                    ACTING CHAIRMAN BORER:          I want to ask you

17   to add a little bit to that comment, Tom.              What have we

18   heard that says that, if somebody is on a medical regiment,

19   whatever that medical regiment is -- you know, I won't

20   pick one yet -- and part of it is doxazosin, that that

21   person is going to be harmed by it?

22                    We concluded that there was no evidence that

23   the drug caused harm.

24                    DR. GRABOYS:      We concluded with a lot of

25   angst, with a lot of discussion about the data, is it

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1    hard, is it soft.

2                      DR. FLEMING:        Basically, is the only thing

3    that we have to be sure we inform patients about is if

4    something is harmful?              When you have -- Whether this

5    applies or not, let me just state a general circumstance.

6                      When you have highly effective standard

7    therapy and now you come along with an experimental

8    therapy that maybe is the same in certain parameters and

9    clearly worse in others but not worse than placebo, does

10   that mean patients aren't needing to be fully informed?

11    Does that mean that it's not perfectly clear that the

12   standard in this case would be preferred?

13                     DR. HIRSCH;        Just to amplify that, that's

14   exactly right.          It's not about harm.              I have no worry

15   that this drug is causing harm, but I know where he's

16   coming from.       Tom is saying that the patient has a right,

17   as the petitioner said, to additional information.

18                     ACTING CHAIRMAN BORER:             Okay.    I think we

19   have several separate issues here, and I think we are

20   going to have dissect them out and deal with them

21   separately.

22                     It may be that it's important to inform

23   patients better than we do, not only with regard to

24   doxazosin        but    with     regard     to    everything        in     the

25   pharmacopeia.          That may be a very important note.

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1                     DR.   KONSTAM:        I'd    just     say   there       is

2    information that will be -- that should be available that

3    will have enormous impact on any way we want to answer

4    this question.         You know, that is the blood pressure

5    related effects of the endpoints and the doses that were

6    actually used.

7                     How do we know what it is we are talking about

8    and whether this is worthy of some kind of letter without

9    knowing what that letter is going to say, and how do we

10   know what that letter is going to say if we don't even

11   know whether we are talking about the fact that patients'

12   blood pressure should be better treated or this drug isn't

13   as effective even in equivalent blood pressure doses?

14                    How do we even approach the answer to this

15   question?

16                    DR. PINA:      Well, I disagree with you.                    I

17   think that we do have enough information that you can

18   say something, whether it gets modified later on whenever

19   this particular manuscript that you've said is somewhere

20   in press and has more information.              But I think we have

21   enough --

22                    DR. LIPICKY:      What can you say?

23                    DR. PINA:     -- to say something.

24                    DR. LIPICKY:      What?

25                    DR. PINA:     I wrote something down, but I'm

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1    waiting for you to --

2                     DR. LIPICKY:      Go ahead.

3                     ACTING CHAIRMAN BORER:               Okay, go ahead,

4    please.

5                     DR. PINA:     Here's what I wrote:         In a blood

6    pressure trial of 24,335 patients with hypertension and

7    at least one other cardiovascular risk factor, doxazosin

8    was associated with a significant increased risk of heart

9    failure compared to chlorthalidone.              The doxazosin arm

10   of the trial was terminated early.           The dose of doxazosin

11   was --

12                    DR. LIPICKY:       Yes, and what are patients

13   supposed to do with that?           Now this is true confession

14   time, and you feel good.          What are patients supposed to

15   do with that?      And you said that --

16                    ACTING CHAIRMAN BORER:         The implication, I

17   think, of Ray's comment, if I can interpret because he's

18   asked you a question, is where is the information there

19   about the dose that was used?           Where is the information

20   about the regimen?       Where is the information about the

21   specifics?

22                    As Marvin says we don't have a lot of that.

23    But that's something to think about.                  I'm not saying

24   it's wrong.

25                    DR. KONSTAM:     You have to resolve -- I don't

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1    think you can get away from resolving the basic core issue.

2     That is, if you think there's something wrong here, then

3    is it that their blood pressure was not adequately

4    affected or is it that at equivalent blood pressure

5    effects, there still were adverse effects?

6                     Without knowing that answer, what are you

7    going to say?        What's the message?

8                     ACTING CHAIRMAN BORER:           Steve?

9                     DR. NISSEN:      Okay.     Do we really want to put

10   a black box warning, a bolded warning or describe clinical

11   trial findings for a trial that's incomplete where we

12   don't even have the data that's known?                   We don't even

13   know what the doses were that were used in these two drugs.

14                    I mean, to me, it really is a terrible reach.

15    Now I'm prepared to make such a conclusion, but not until

16   we have an adequate amount of data on which to base such

17   a decision.

18                    I   think     that     I'm     not     rejecting        the

19   possibility, but I'm saying there's just too much that

20   we don't know here, and I still to this day don't even

21   know what the mean dose of doxazosin that was administered

22   to these patients were.           So how can you write something

23   about the clinical trial when you don't even know what

24   the mean dose was?         It makes no sense to me.

25                    ACTING CHAIRMAN BORER:           Bob Fenichel?

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1                        DR. FENICHEL:     Yes.    Can we have a black box

2    that uses some of that neutroceutical language that says

3    these results have not been reviewed by FDA?

4               ACTING    CHAIRMAN     BORER:       Okay.       Rather       than

5    focusing on what we would say yet, let's firs conclude

6    that we want to say something, and perhaps now that there's

7    been a clarification of the options for saying things,

8    which, if any, of them we want to suggest to the FDA that

9    it mandate or use.

10                       We were on black box warning.           Let me just

11   ask, is there anyone here -- Just raise your hands.                         Is

12   there anyone who votes for a black box warning?                           No.

13   A bolded warning?            We have one "hard to know" and any

14   yeses?

15                       DR. TEMPLE:     Can we include the idea of                   a

16   bolded something? I mean, not everything you say                        is a

17   warning.

18                       ACTING   CHAIRMAN      BORER:        Okay.       Bolded

19   anything.        Okay, let's go down from the end. Marvin, do

20   you want anything in bold put into the label?                     Just yes

21   or no.

22                       DR. KONSTAM:     Well, I'm not sure yet.              I'd

23   rather deal with the last part of this and see if there

24   is consensus reached, and then say, okay, is that worth

25   bolding.

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1                        ACTING CHAIRMAN BORER:           Okay.     We can.       You

2    mean describe clinical trial findings?

3                        DR. KONSTAM:        Right.

4                        ACTING CHAIRMAN BORER:             Okay.     Let's hear

5    about that.          Why don't you start commenting, Marvin?

6                        DR. KONSTAM:       Well, you know, I do think that

7    there is something going on here,and I think that we've

8    heard loud and clear that there is an impetus that this

9    ought to be communicated -- that the results of the trial

10   ought to be communicated.                 I do believe the results of

11   the trial ought to be communicated.

12                       I think that, you know, just with regard to

13   the heart failure endpoint, I proposed some language a

14   little bit earlier which I think reflects what the trial

15   showed,          which   is    at   the    doses     used,     compared        to

16   chlorthalidone, there was -- doxazosin appeared less

17   effective at preventing the clinical manifestations of

18   heart failure, although this did not show evidence of

19   irreparable harm.

20                       Something to that effect at this point, I

21   would be comfortable with and, I think, ought to be

22   communicated.

23                       I think that beyond that, again, I think that

24   we really need to know -- and I want to say it in a positive

25   way, not just say, well, we shouldn't do anything until

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1    we know more.         I think that we should know more with all

2    due haste, and we should find out, and the FDA should

3    find out more about the blood pressure relationship with

4    the events, what doses were patients on, in order to fine

5    tune this message and see if there is something more

6    definitive that can be said.

7                       I think those sorts of pieces of information,

8    I think, ought to be in the label.

9                       ACTING CHAIRMAN BORER:          Marvin, can I just

10   ask you.         I mean, I think that's a well crafted statement,

11   but I wonder if it's missing one piece of information

12   that you might want to add, which is that there was a

13   difference in the level of blood pressure lowering with

14   the two regimens.

15                      DR. KONSTAM:      Right.

16                      ACTING CHAIRMAN BORER:           Because there's a

17   message to people as patients.

18                      DR. KONSTAM:      That's right.       So then to say

19   that -- Well, what you are saying is then these differences

20   may have been, at least in part, a reflection of clearcut

21   differences in the degree and rapidity with which blood

22   pressure lowering was achieved -- pressure control was

23   achieved.

24                      DR. LIPICKY:      For me to get a feel of what

25   you mean, in addition to what you said and what Jeff said,

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1    I added a sentence that said "Do not use doxazosin like

2    it was used in ALLHAT.       Follow the instructions for use."

3

4                     Would that be objectionable to you, and had

5    that in bold and the rest of it in lower case?              What are

6    we trying to communicate is what I'm asking.

7                     DR. TEMPLE:     Well, it's worth noticing --

8    what to do about is not so clear -- that our impression

9    of the average dose that's used is that it's not 16

10   milligrams.       It's some lower dose.          Now to the extent

11   that is true -- and I'm sure that's discoverable -- when

12   it's used as initial therapy, there people are in fact

13   using it just this way, and as Ray suggested, maybe that's

14   not such a good thing.

15                    DR. LIPICKY;      But I don't see that that's

16   relevant.

17                    DR. TEMPLE:     You do think or don't think?

18                    DR. LIPICKY:     I don't.       How it is used, I

19   don't know.      I don't know how you know.

20                    DR. TEMPLE:      No.    I'm just saying that's

21   discoverable, because someone has done the --

22                    DR. LIPICKY:      But we don't know.           So we

23   shouldn't be deciding what to write when we don't know

24   what to write.

25                    DR. TEMPLE:    Well, you can find out certain

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1    things.          You can find out the dose that was used, for

2    example.

3                       DR. LIPICKY:         We can find out whether

4    doxazosin is really bad.             We can get the whole results

5    of the trial.         We can look at all four arms.        We can see

6    if amlodipine suffered the same problems.                  We can get

7    all kinds of -- There's no question that a lot of the

8    indecision that exists here, we can resolve.                    We just

9    can't resolve it today.

10                      DR. TEMPLE:         Ray, this is a different

11   question.         It is knowable in very short order what the

12   average dose of this drug is, and you can find it out

13   for any of its indications.              That is discoverable.

14                      DR. LIPICKY;       I agree 100 percent, but it

15   depends on whether you think you have an emergency here.

16

17                      DR. TEMPLE:      No, that's got nothing to do

18   with further analysis of the trial.

19                      DR. LIPICKY:      Well, it does to how rapidly

20   you can come up with the data.

21                      DR. TEMPLE:      That's not hard data to get,

22   and I'm sure Pfizer knows it already.

23                      DR. LIPICKY:      Well, but that's not relevant

24   if it doesn't matter.

25                      ACTING CHAIRMAN BORER:         Is it reasonable for

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1    us to suggest that the FDA should consider adding to the

2    label some kind of description?                I'm going to suggest

3    one in a minute -- suggest that you consider, and that

4    that decision be modifiable with the acquisition of new

5    data in short order about dose and other things that may

6    come out of the study that we heard is almost ready for

7    submission for publication.

8                     Let me just put this forward and see if it

9    flies and, if it doesn't, it doesn't.

10                    When used as initial therapy at doses lower

11   than those for which it is labeled -- maximally labeled

12   or     something   --     in    patients    with     --    describe        the

13   descriptors, the population -- for whom blood pressure

14   often was not reduced to the target range, there was more

15   congestive heart failure among patients treated with

16   doxazosin        than      among       patients           treated        with

17   chlorthalidone.

18                    That's not directive, but I think it's an

19   accurate description of what we know.

20                    DR. KONSTAM:          I would say the greater

21   clinical manifestations of heart failure.

22                    ACTING        CHAIRMAN    BORER:          Okay.         More

23   clinical manifestations.

24                    DR.    NISSEN:           Jeffrey,    I      wrote       some

25   alternative language for you to consider.

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1                     ACTING CHAIRMAN BORER:         Okay.

2                     DR. NISSEN:    In an incomplete clinical trial

3    of     antihypertensive     therapy,      an   uncertain       dose      of

4    doxazosin was associated with a higher incidence of

5    investigator reported congestive heart failure compared

6    to an uncertain dose of chlorthalidone.

7                     ACTING CHAIRMAN BORER:          Let me ask.         I'll

8    champion that.

9                     DR. LIPICKY:    That is informative, and these

10   findings were not reviewed by FDA, and we do not know

11   what they mean, but we think we must communicate them.

12                    DR. KONSTAM:     And then put it in bold.

13                    DR. TEMPLE:    I suggest that this is getting

14   inappropriate and should stop.

15                    ACTING CHAIRMAN BORER:           Let's just get a

16   sense from the committee, just by a yes or no vote.                      Do

17   we agree -- Do we believe that some information needs

18   to be communicated by the FDA, either in labeling or in

19   some medication guide for patients or in both or some

20   combination thereof?        Just a yes or no.         Ralph?

21                    DR. D'AGOSTINO:      You said just a yes or no,

22   but you are including other means beyond the label?

23                    ACTING CHAIRMAN BORER:        Yes.     I'm including

24   other means beyond the label, but that the FDA must mandate

25   it.

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1                     DR. D'AGOSTINO:      Yes.

2                     ACTING CHAIRMAN BORER:         Bob?

3                     DR. FENICHEL:      No.

4                     DR. NISSEN:     I want to wait for more data.

5                     ACTING CHAIRMAN BORER:         Okay.    So that's a

6    no.

7                     DR. LINDENFELD:        Yes.     I think something

8    should be communicated.

9                     ACTING CHAIRMAN BORER:         Tom?

10                    DR. FLEMING:      Yes, definitely.

11                    ACTING CHAIRMAN BORER:         Tom Graboys.

12                    DR. GRABOYS:      Yes.

13                    ACTING CHAIRMAN BORER:         Alan?

14                    DR. HIRSCH:     Yes, to be revisited again when

15   we have more data.

16                    DR. PINA:    Yes, not only to patients but also

17   to physicians.

18                    ACTING CHAIRMAN BORER:         I'm sorry.

19                    DR. ARTMAN:     Yes.

20                    ACTING CHAIRMAN BORER:         Yes.    Mike?

21                    DR. KONSTAM:       I'm sorry.        Are we talking

22   including a change in labeling or are we saying --

23                    ACTING CHAIRMAN BORER:          Anything.        We are

24   saying do we want the FDA to cause communication of

25   something?

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1                     DR. KONSTAM:     Something which could simply

2    include a change in labeling and nothing more?

3                     ACTING CHAIRMAN BORER:         It could.

4                     DR. KONSTAM:      Well, I'd say the answer is

5    yes, and I think something should be done, and I think

6    that that message needs to be refined based on additional

7    data that needs to be gathered.

8                     ACTING CHAIRMAN BORER:        Okay.   so the sense

9    of the committee is that something needs to be or should

10   be communicated in some form.            That might include some

11   addition to the label, might include something beyond

12   that, might not include something in the label.                   Bob?

13                    DR. TEMPLE:    The two pieces of data that have

14   come up a few times -- One is finding out what the actual

15   doses were.      I'm sure we can actually get that from them.

16    But Marv has referred to something else, and I wonder

17   whether we are going to have that, which is some attempt

18   to relate the outcome in terms of frequency of heart

19   failure to the degree of control.             That, obviously, is

20   not a randomized observation, but it doesn't mean it's

21   entirely silly either.

22                    Is that something that you guys can actually

23   do?      And strokes, too, I guess.

24                    DR. CUTLER:     We have largely done it, not

25   entirely to my satisfaction at this point, but --

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1                     DR. TEMPLE:     Okay.     So we will be getting

2    that not too far from now?

3                     DR. LIPICKY:        You'll be getting it as a

4    publication.

5                     ACTING CHAIRMAN BORER:          Well, okay, but--

6                     DR. LIPICKY:     We're back to the same place.

7                     ACTING CHAIRMAN BORER:           All right.          That

8    leads us to two ancillary questions.                  The sense of the

9    committee is that something needs to be communicated.

10   Let me break it down further.

11                    Should the something be communicated at

12   least in part in the label?            Marvin?

13                    DR. KONSTAM:     Yes, in the label.

14                    ACTING CHAIRMAN BORER:          Mike?

15                    DR. ARTMAN:     Yes, I would agree with that.

16                    DR. PINA:    Yes.

17                    ACTING CHAIRMAN BORER:          Alan?

18                    DR. HIRSCH:     Yes.

19                    ACTING CHAIRMAN BORER:          Tom?

20                    DR. GRABOYS:     Yes.

21                    ACTING CHAIRMAN BORER:          Tom?

22                    DR. FLEMING:     Yes.

23                    DR. LINDENFELD:       Yes.

24                    DR. NISSEN:     No.

25                    DR. FENICHEL:      No.

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1                      DR. D'AGOSTINO:       No.

2                      ACTING CHAIRMAN BORER:           Okay.    So we have

3    a split vote here, but there is a sense of the Committee.

4     The majority think that something should be put in the

5    label.

6                      Now should the something be put in now or

7    should we wait until we have some of the additional data

8    that we've been talking about, specifically the average

9    dose or, on top of the average dose, the result of the

10   analysis that Dr. Cutler is now reviewing and may be done

11   sometime in the next few months?                Ralph?

12                     DR. D'AGOSTINO:       I voted that I don't think

13   anything should be put in the label, and you're asking

14   me now -- Should I?

15                     ACTING CHAIRMAN BORER:                Oh, I'm sorry.

16   That's right.        No, you're right.           You voted no.           Bob

17   voted no.        Steve voted no.       Joann?

18                     DR. LINDENFELD:       I think something could be

19   added now.       It would just be average doses.           I don't know

20   that we need the whole additional analysis.

21                     ACTING CHAIRMAN BORER:           Okay.    So we have

22   to have at least --

23                     DR. LINDENFELD:        Once we have the average

24   doses --

25                     DR. LIPICKY:      So just average doses or --

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1                        DR. LINDENFELD:       I think so.        I don't think

2    we need --

3                        DR. LIPICKY:      -- range of doses or what more

4    information do we need before --

5                        DR. LINDENFELD:        Well, we know the range.

6     Right?          Because we know -- So we know the range.

7                        DR.   LIPICKY:          No,     we      don't.          The

8    distribution of doses actually used.

9                        DR. LINDENFELD:       We know the range, because

10   it was fixed.

11                       DR. LIPICKY:        From zero to eight.               Yes,

12   right.

13                       DR. LINDENFELD:       Right.

14                       DR.   LIPICKY;        But     we      don't   know      the

15   distribution.

16                       DR. CUTLER:       The distribution is in the

17   paper.

18                       ACTING CHAIRMAN BORER:         So that vote is that

19   nothing should be put in the label until we have some

20   additional information, but then something should be put

21   in.

22                       DR. LIPICKY:      But I want to be sure.                Now

23   means now.          If you mean get more data, then what --

24                       ACTING   CHAIRMAN      BORER:          That's    what          I

25   understand this vote to be that Joann --

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1                     DR. LIPICKY:      She said now means after we

2    get something, and mentioned one.

3                     DR. LINDENFELD:      Once we know the mean doses

4    of the --

5                     DR. LIPICKY:     Well, we can calculate that,

6    if the distributions are in the paper.

7                     DR. LINDENFELD:         Okay.        I think that's

8    enough.

9                     DR. FLEMING:     We interrupted Marv.            He was

10   in the process of constructing a recommended statement,

11   and in general I would like to pursue more what he --

12   where he was leading us with his suggested statement.

13   My sense of the matter is, when I have a clearer sense

14   of what that is, it will be easier to answer whether or

15   not there are elements that we need to know more

16   information about.

17                    I am assuming that, if there are more

18   specific elements that this Committee would like to have

19   before this study reaches its planned termination point

20   in March of 2002 -- and I assume there will be some lag

21   after that before everything is released, which by the

22   way, isn't that far away.        But if there was more immediate

23   need, I would assume we could request specific information

24   from the protocol team that would not put in jeopardy

25   the continued blinding of the comparative arms that

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1    continue in the trial.

2                      So my sense is I would prefer to see something

3    in as soon as possible.           I would like to go further and

4    hear more exactly where Marv was headed with that

5    statement and, if there are elements that we would need

6    that aren't already apparent to us, I would suggest we

7    might be able to communicate with the ALLHAT team, and

8    the FDA may be able to get that information.

9                      DR. D'AGOSTINO:        Can I make a comment?                  I

10   guess I thought one of the outcomes of this meeting would

11   be to go back to the ALLHAT team and say, you know, you

12   don't seem to have great reliability on the CHF, why don't

13   you do something to see how you can improve on that

14   retrospectively, realizing it's retrospectively.                         But

15   there are lots of questions raised by our deliberations,

16   can you do something with them?

17                     I feel very uncomfortable suggesting a label

18   change when we have so many uncertainties that have been

19   raised today.        Maybe I'm missing something.

20                     ACTING CHAIRMAN BORER:          Steve?

21                     DR. NISSEN:        Yes.       I guess I need to

22   understand from Ray how much precedent there is for

23   altering a label based upon data that the FDA has not

24   reviewed.        Do we commonly do this, and how important --

25   I mean, I just need to get a sense for this from a

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1    historical point of view.          Is this unprecedented or has

2    it been done before?

3                     DR. LIPICKY:     I think Bob Temple will have

4    a better recollection than I.            There is once, and that

5    was with CAST.      There, I think it was a very different

6    circumstance.      I wasn't a single trial and one adverse

7    effect and that sort of stuff.         It was that a whole belief

8    structure got damaged.

9                     It's not clear to me that a whole belief

10   structure got damaged by ALLHAT, primarily because one

11   doesn't know why it was less effective.               I don't think

12   anyone would conclude that it was not less effective or

13   didn't have data that would make it look like it was not

14   less effective, but basically there are a lot of questions

15   that remain unanswered, and certainly one doesn't have

16   the answer even for doxazosin, let alone the class of

17   alpha blockers.

18                    So it isn't the same, but there is once in

19   50 years, if that answers your question.

20                    ACTING CHAIRMAN BORER:         Tom, you suggested

21   that we should hear a statement and then see if elements

22   are missing.       But I would ask you to prospectively to

23   determine whether from what you've heard you have enough

24   information to write anything that would be useful for

25   people to know, that would be directive, that would

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1    actually inform them in a useful way.

2                         If the answer is yes, fine.          But if it's no,

3    then we don't really need to hear that draft at this point

4    to make a decision.

5                         DR. FLEMING:      Well, I had thought we had

6    already come to the conclusion, not by unanimous vote

7    but     by,      I   think,   with    two   dissenting      votes,       that

8    information needed to be communicated.

9                         Then when we asked if it was in the label,

10   I think we had a majority but with three dissenting votes.

11    So my impression is, whereas it's not unanimity, there

12   was strong sense in the Committee that we needed to

13   communicate.

14                        Now what we're really getting at is what is

15   the right way to do it, and what is the substance of what

16   we communicate?          In general terms, what we're confronting

17   here we may actually confront in the future more often

18   than we've confronted in the past.                        Specifically,

19   what's given rise to this circumstance is that we have

20   a major trial that's dealing with a number of important

21   scientific questions, one of which, the team viewed, was

22   conclusively          established,      that    required     release         of

23   information so that the public could be aware of what

24   was evidence that no longer was within what they thought

25   was equipoise.

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1                      They released that information, and yet to

2    preserve the integrity of the remaining objectives of

3    the      trial,   the    rest    of     the    information         was     kept

4    confidential.         This circumstance isn't unique.

5                      I'm chairing a data monitoring committee for

6    a breast cancer trial that, in fact, was in a similar

7    circumstance last December, and the FDA was asked to

8    approve the agent based on progression with our proposal

9    that we be allowed to keep survival data confidential,

10   not entirely unlike this type of circumstance; and it

11   may happen again in the future.

12                     I   respect     the    FDA    and      the     scientific

13   community for allowing this randomized trial to continue

14   in a blinded fashion, even though we have need for having

15   a better understanding of certain elements of the data.

16                     To say, however, that because we're not fully

17   informed, we as an FDA aren't going to take any action

18   or ensure that people are aware of what the results are

19   seems to be inconsistent.

20                     DR. LIPICKY:        Well, but, Tom, I don't know

21   who people are.

22                     ACTING CHAIRMAN BORER:              One second, Ray.

23   Tom has gone through the process that we have, just

24   resummarized it.          But what I was actually asking was,

25   okay, we all decided -- or not we all, but the majority

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1    believed that something should be communicated.

2                     My next question was when, and the answer

3    to that is based on do we have all the elements of

4    information that we want to put into that warning to make

5    it useful.       If we are leaving out elements and we're just

6    giving a sort of a general warning to people, then they

7    are going to be generally afraid, but I don't know what

8    they are going to be afraid of, and they may take

9    inappropriate action.

10                    If we are comfortable that we have all the

11   elements that we can put in to give a reasonable person

12   a reasonable warning, well, fine.              If we don't, then we

13   ought to wait until we have them.            Some of those elements

14   may be available right away.            Some may be available in

15   a few months.        Some may be available later than that.

16   I don't know.

17                    So that was really the thrust of my question.

18    Ileana?

19                    DR. PINA:     Yes.    I want to go back to that

20   same point that you just made.             I think that we do have

21   enough information now to say something, based on the

22   facts. There is a published article.            It's a peer reviewed

23   journal article, and we're here being asked by consumers

24   to allow physicians and patients to know, because of the

25   lack of knowledge out there of the preliminary findings

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1    of this trial and of the stopping of the arm.

2                     I mean, that's why we're here.          We're being

3    asked -- This is a consumer group asking us to allow

4    physicians to know and telling us how few physicians

5    really do know what's going on, what has gone on with

6    the trial, and that the arm has been stopped, even though

7    I know it was in the news, and how few patients know about

8    this, and then how many patients were actually on the

9    drug.

10                    I mean, this is a drug that's being used

11   extensively for BPH.         I have a problem with Marvin's

12   initial writing, not that I like mine any better.                     But

13   you implied that chlorthalidone prevented the heart

14   failure risk rather than doxazosin caused it, and I don't

15   think we know that.

16                    DR. KONSTAM:      Well, we voted on that.              We

17   voted on that.      We asked do we think there's any evidence

18   that doxazosin caused harm, and the answer was no.

19                    DR. PINA:    I agree.

20                    DR. KONSTAM:      And I thought the sentiment

21   of the panel was it probably didn't.

22                    DR. PINA:     I agree, but did we vote that

23   chlorthalidone prevented it, which is different?

24                    DR. LIPICKY:      Well, look.        To put this in

25   some perspective -- and I know this is not the sequence

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1    of the questions, but the next question asks: If you think

2    it's important to tell physicians and patients that

3    there's something they need to know about doxazosin, don't

4    you think on the same basis, the same data, we must put

5    this in chlorthalidone?

6                          Obviously,       people      should       know        that

7    chlorthalidone is the thing to take, and we ought to issue

8    press releases that say that.                    Why should we wait for

9    JNC?             I   mean,   where   are    we    here?       What     are      we

10   communicating?               What are we saying?            What do we want

11   people to know?

12                         ACTING CHAIRMAN BORER:          Steve?

13                         DR. NISSEN:     I want to get to a core point.

14    First of all, I understand and I'm very sympathetic to

15   those on the Committee that want to do something, but

16   I think it's very important that we dissociate regulatory

17   action from the setting of standards for medical practice.

18                         You know, we have large organizations like

19   the American College of Cardiology and the American Heart

20   Association and all of their subcommittees that establish

21   standards, and in those standards we make many statements

22   about how we think patients ought to be treated.

23                         It seems to me -- and the reason I feel like

24   with incomplete data it would not make good sense to act

25   is that I believe that this area is much better addressed

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1    by our colleagues who will come together and make these

2    kinds of recommendations about what the optimal treatment

3    of hypertension is, and all these issues of first line

4    versus second line.

5                      It's just too fuzzy to create regulatory

6    language.        I also wanted to address the issue that Tom

7    raised, which is I agree with Tom completely that it's

8    noble to continue the trial.             But it is also important

9    for us to keep in mind that, without undermining the trial

10   and its blinding, there is a lot more data we could be

11   provided with.

12                     I don't like us to make a decision on the

13   basis of data that is really quite obviously incomplete

14   and that may lead us to make a mistake.                   I think what

15   we are talking about here fundamentally is a medical

16   standards decision, not a regulatory decision, and I think

17   we are off base to try to make it a regulatory decision.

18                     DR. KONSTAM:      Can I respond to that?

19                     ACTING CHAIRMAN BORER:          Marv?

20                     DR. KONSTAM:      Steve, I agree with what you

21   said up to a point.           Where I really disagree with you

22   is I do believe that the FDA has every right and obligation

23   to influence treatment in every way to the extent that

24   it can.

25                     I think where the difference is -- and I think

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1    you are hitting on it -- is that they have a different

2    standard of evidence that they draw upon in order to make

3    those judgments than we do when we generate clinical

4    practice guidelines or JNC guidelines.

5                      So the FDA leaves big holes in practice

6    recommendations, because it doesn't have data that it

7    considers a high enough standard to act on, and that's

8    where guideline people take over.                  That's my way of

9    looking at it.

10                     You know, I think that there is a study that

11   was done here.        It was probably the best study of its

12   kind that's ever going to be done.             There are things that

13   came out.        There's a lot of difference of opinion, but

14   there's a lot of sentiment that something ought to be

15   communicated.

16                     Where I agree with you is that I think that

17   the level of evidence is problematic, and that's what

18   we have all struggled with all day long.                How certain

19   are we about what conclusion?            That's where I really hold

20   back on saying we ought to go out and communicate something

21   for the public and send letters and say this ought to

22   be second line therapy.

23                     I definitely would not do that, because I

24   don't think the level of evidence reaches that point.

25                     ACTING CHAIRMAN BORER:          Yes, Ralph?

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1                     DR.   D'AGOSTINO:          But    doesn't      putting

2    something in the label have that spirit to it, that we're

3    saying something profound, that we have established

4    something?       Label change isn't a trivial matter, to me,

5    that you go back next week and say, well, we've got a

6    little more data now, we're going to straighten it out.

7                     DR. LINDENFELD:       It's not a trivial matter,

8    but again I just have to emphasize, this is a very large,

9    well conducted trial with lots and lots and lots of

10   endpoints, and it does appear --

11                    DR. D'AGOSTINO:        But there are all these

12   questions.       I mean, we spent the whole day raising

13   questions, and we don't even have the data.                  Nobody in

14   the FDA, and myself as a statistician, consultant to the

15   panel, has sort of sat down and actually marched through

16   the data.

17                    All I'm doing is reading an article, and I've

18   been on this committee in terms of consulting and on other

19   committees where I have New England Journal Medical

20   articles, JAMA articles and so forth, and we end up saying

21   quite completely different things.

22                    I don't think that's going to happen here,

23   but we haven't even gone through that type of activity.

24                    ACTING CHAIRMAN BORER:           Ray?

25                    DR. LIPICKY:       Well, I guess I am less in

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1    favor of communicating.               I'm an isolationist.            But I

2    understand the need to communicate, and certainly FDA

3    wants to communicate more, and it has these Med Alerts

4    and Med Watches and watches for this and that and the

5    other, and everything else, and it's important, and there

6    are media and electronics and communication is the name

7    of the game.

8                       How    can    I    say    that     one   should        not

9    communicate?          The average patient who is receiving a

10   medicine for their blood pressure has absolutely no idea

11   what the basis of their receiving it is.                    So that now

12   we go and contact all of the patients that are taking

13   doxazosin and say something like the results of ALLHAT?

14                      I mean, I think that's misrepresentation.

15    I think it's totally garbage.              I think it will be totally

16   misinterpreted, and so --

17                      DR. TEMPLE:          That's a straw man, Ray.

18   Nobody insisted on a Med Guide and --

19                      DR. LIPICKY:         That's fine.        No, no, no.

20   Hold it.         It may be a straw man, but now who are we talking

21   about communicating with?

22                      DR. TEMPLE:       Well, most people are talking

23   about the physicians, I think.

24                      DR. LIPICKY:        So that's clear.          That is,

25   nobody is talking about talking to patients.

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1                     DR. TEMPLE:        No.      Like everything else

2    today, it's not entirely clear.

3                     DR. LIPICKY:          Okay.       Well, that isn't

4    clear.

5                     ACTING CHAIRMAN BORER:           That's a good point.

6                     DR. LIPICKY:      Wasn't clear to me.              Fine.

7                     ACTING CHAIRMAN BORER:           One second.        Can we

8    have a statement from the Committee about that.                   Is there

9    anyone on the panel here who is in favor of mandating

10   the FDA to cause a communication to be sent to all patients

11   who are taking this drug?          Any yeses?       No.     So we've now

12   eliminated that as an alternative, and we are talking

13   only about communicating something to physicians --

14                    DR. LIPICKY:      Through labeling.

15                    ACTING CHAIRMAN BORER:           -- and there hasn't

16   been a consensus on what would be communicated, although

17   the      majority      thinks   that      there     ought      to     be         a

18   communication.

19                    DR.    LIPICKY:       Right,      and    I     would       be

20   embarrassed if I had to try to write something that didn't

21   say something, and I still don't know what to say.                         The

22   only thing I know to say is, if you use doxazosin, use

23   it according to directions, and I don't know -- Otherwise,

24   you're liable to encounter this.             I don't know what else

25   to say.

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1                     DR. TEMPLE:    Actually, Ray, you already have

2    said more, if you believe it, if you describe the

3    consequence of using it the wrong way.

4                     DR.   LIPICKY:        Yes.           But    that's         an

5    encouragement to use doxazosin and at higher doses.

6                     DR. TEMPLE:     No, it says --

7                     DR. LIPICKY:     Is that what we should do?

8                     DR. TEMPLE:     It says, if you are going to

9    use it, you need to use it right.               Even that might be

10   an important message, not that you know --

11                    DR. LIPICKY:     Well, but we don't --

12                    DR. TEMPLE:     Wait a minute.             Not that you

13   know what the results of using it right are either.

14                    DR. LIPICKY:     But we don't know that that's

15   right.

16                    DR. TEMPLE:     But what you do know is that

17   using it wrong, which is probably the way most people

18   use it, doesn't work very well.

19                    DR. LIPICKY:     Well, I'll grant you that.

20                    DR. TEMPLE:     That's not irrelevant.

21                    DR. LIPICKY:        Okay, but that's a very

22   different message from this is a warning about this

23   chemical compound and its effects in man.

24                    DR. TEMPLE:    Ray, I don't think that anybody

25   has gotten far enough to say how loud, how shrill, how

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1    scary this should be.          People are grappling --

2                     DR. LIPICKY:      Well, bold is pretty loud.

3                     DR. TEMPLE:      What?

4                     DR. LIPICKY:      Bold is pretty loud.

5                     ACTING CHAIRMAN BORER:                But we haven't

6    gotten to bold yet, and we haven't said what we are going

7    to say.

8                     DR. TEMPLE:       Right.      It depends what you

9    bold.        Can I just make an observation, Jeffrey, about

10   before?

11                    It's relatively unusual for us to rely on

12   controlled data that we don't see.              And as Ray said, in

13   the case of CAST we did it.         But one shouldn't exaggerate

14   that as a precedent.         That was a body count.

15                    Whatever you believe about the NIH and their

16   competence, I believe they can count death.                          Okay?

17   That's not a long stretch.          Here -- and you know, as you

18   can probably figure out, I'm somewhat on the side of saying

19   something.

20                    The concern is that the observation of heart

21   failure may be not valid.           That's the very sort of case

22   where you do probe and you do look.            So this is a somewhat

23   longer stretch than CAST.            That's in no way saying it

24   shouldn't be the stretch you make, since the local

25   diagnosis may be the best you are going to do anyway.

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1    But I just want to make sure that that precedent isn't

2    overstated.           A body count is easy, easier than something

3    more subtle.

4                          ACTING CHAIRMAN BORER:           Mike, you had a

5    comment?

6                          DR. ARTMAN:    Well, I think we all agreed that

7    there was some red flags raised by this study, and now

8    we're just trying to decide how high to raise the flag

9    and how to wave it around.

10                         I'm not sure I have the answer either, but

11   Ray keeps asking what are we trying to say.                     I think we're

12   trying to say something like:                In doses of 8 milligrams

13   per day or less, which may be insufficient for optimal

14   control of blood pressure, doxazosin may unmask or promote

15   symptoms         of    heart    failure     in    patients        with      mild

16   hypertension and cardiovascular risk factors.

17                         I mean, that's basically what came out of

18   this, I think.

19                         ACTING   CHAIRMAN     BORER:         We    didn't       say

20   promote.

21                         DR. ARTMAN:     Well, scratch the "promote."

22    May unmask or allow symptoms of -- something like that,

23   less effective than a diuretic.

24                         ACTING CHAIRMAN BORER:        Alan, why don't you

25   make your comment, and then I want to make a point.

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1                       DR. HIRSCH:         I think I'm hearing sort of

2    consensus        toward      a    two-track      approach,       which     I'm

3    proposing to the rest of the panel members.                      One is that

4    we can fine tune language, because there's a clear

5    consensus        that     something      be   communicated        regarding

6    relative protective benefit.

7                       The second thing I'm hearing from Ray and

8    from Bob is that we would be wise to take a clear, deeper

9    look at the data, if it could be provided to us, and revisit

10   this      again,    and      make    sure     that   we    are    accurate,

11   appropriate, and don't set wrong precedents.

12                      ACTING CHAIRMAN BORER:            Okay.   I'd like to

13   suggest a modification to what Alan says, because I think

14   there is sort of a general sense that something needs

15   to happen as a result of all this.                   But I'm concerned,

16   and I'm concerned that we don't know, as Ray has really

17   said in several different ways -- we don't know exactly

18   what to say.

19                      I don't think that promoting concern is

20   appropriate unless you have a specific basis for the

21   concern reasonably well defined, and then we have to

22   determine what reasonably is.                 I think reasonably will

23   be when we have information (a) about the dose that was

24   used and (b) about the relation of the results to blood

25   pressure achieved.

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1                      That make take several months to get those

2    data, and at the end of that time the resulting analysis

3    may     show that it's not appropriate to communicate

4    something.        But the reason I think that it's appropriate

5    to wait at this point and not send out something right

6    now is that I don't think we have an emergency situation

7    here.

8                      I haven't seen any evidence that the drug

9    causes harm.       I think that a lot of people will be affected

10   by     premature     dissemination        of        information      that's

11   incomplete and that there is no great public health

12   problem that is going to be caused by not disseminating

13   that information until it's somewhat more complete.

14                     I'm not suggesting waiting until the end of

15   the ALLHAT trial.         I'm suggesting that we wait until we

16   have      just   those   two    elements       of    data   that     Marvin

17   suggested.        If at that time the data, when they are

18   reviewed, are sufficiently clear so that they warrant

19   a well defined statement about what happened with these

20   doses in these patients defined in this way, then that

21   statement ought to be made, and it ought to be added to

22   the label somehow.

23                     Marvin?

24                     DR. KONSTAM;      Jeff, I agree with everything

25   you said.        With regard to Michael's language, you know,

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1    I really -- and I guess this is why I'm more comfortable

2    advocating           saying   something        when       there    is     more

3    information, is because I would fall away from drawing

4    a conclusion.

5                        Your statement is drawing a conclusion.                   My

6    thought is to be much more descriptive.                       Describe the

7    results in a way, and then based on the data as it comes

8    in, sort of build as close a circle around what it means

9    as we can based on what we know, but mostly just describe

10   the results.

11                       ACTING CHAIRMAN BORER:            Okay.       So I think

12   that the issue that remains here is how do we properly

13   describe the results.            We have some information, but the

14   information is not as complete as we like, and do we have

15   enough information to describe the results in a reasonable

16   way without misstatements that will be more harmful than

17   helpful.

18                       DR. ARTMAN:       I just want to clarify one

19   thing.           I was in no way, shape or form trying to draw

20   any conclusion, because I don't think we can draw

21   conclusions.          I was merely trying to describe the data.

22                       ACTING CHAIRMAN BORER:            You know, I don't

23   think we are -- Ray, if you will allow me -- Ray, are

24   you here?           Ray, you asked for the advice.                I want to

25   suggest something to you.

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1                     You've     heard     the     discussion      of      the

2    Committee.       You've heard that several people are not in

3    favor of making any labeling change at this time.                     The

4    majority, by a little bit, are in favor of doing something,

5    but among those there's some disagreement about when and

6    what, with some believing we could put out some sort of

7    general statement, or suggest to you that you put out

8    some general statement to doctors, presumably in the label

9    -- I don't know how else we do it -- at this time, and

10   some suggesting you need more information before you can

11   do that, and at that time you can say something, although,

12   of course, the new information may suggest that you don't

13   have to.

14                    I don't know how much further --

15                    DR. LIPICKY:       So you're asking me do we have

16   enough information from you?

17                    ACTING CHAIRMAN BORER:          Yes.

18                    DR. LIPICKY:        Yes, I think so.          But the

19   question is does Dr. Temple; because I know what to do.

20    The question is does Dr. Temple know what to do or will

21   we argue with one another?

22                    DR. TEMPLE:      Well, we'll surely argue, but

23   that's okay.       I think we've heard enough.            I actually

24   don't think you can actually get closer, and having a

25   vote with another six to seven or something isn't going

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1    to help much more.        But let's be sure I understand the

2    areas of uncertainty.

3                     I'm positive we can find out what the

4    approximate dose was, either in the form of a distribution

5    or the average, and I actually don't see how that makes

6    too much difference, because we know it was well below

7    the 16 that you can go to.

8                     I gather there is an analysis closer to being

9    born -- whether we can get more details of it remains

10   to be seen -- that we'll look at whether, just to put

11   it in a simple minded way, the people who did have adequate

12   control also showed a increased rate of heart failure

13   in which case you would not really attribute it to not

14   using the drug properly, I think.

15                    In other words, you would match up groups

16   for the degree of control and see if there was still a

17   difference.       That's not a hard thing to do, and if I

18   understand Jeff's facial expressions, that's what they

19   have sort of done.

20                    That seems to me to be the area that people

21   are most nervous about, because it makes you ask whether

22   the entire thing is due to the blood pressure.                  If you

23   saw it in all levels of blood pressure control, you would

24   no longer believe that.

25                    So I think there's a fair sentiment that

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1    people would like us to get that information before we

2    did much.

3                        ACTING CHAIRMAN BORER:                I think that's

4    right, and I would add only that I heard several people

5    suggest that it would be nice if there were some effort

6    to firm up the diagnosis of CHF so we                     could know the

7    magnitude of the problem that exists.                             DR.

8    TEMPLE:          Jeff, the only thing about that is that is the

9    work of a very long time.

10                       DR. LIPICKY:      Right.     We will --

11                       DR. TEMPLE:      The other two things are much

12   easier.

13                       DR. LIPICKY:       We will argue some, because

14   what I heard some people saying in the reservations were,

15   you know, they wanted to get a lot more information than

16   just the average dose.              Give me three minutes in the

17   publication, and I'll give it to you.                 No, Tom will give

18   it to you, because I don't know how to take distributions

19   and get a mean.

20                       There are serious things that would require

21   getting some data, and I'm a firm believer in the fact

22   that you don't know what's there until you look, and that

23   when people have taken a lot of time looking, they point

24   you in the directions that are generally important, but

25   that, as we have learned time and time again, sometimes

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1    they overlook things, not purposefully, that in fact give

2    you better insights.

3                     I must admit that I don't have a better of

4    way of putting it, because I can't demonstrate that we

5    have ever contributed anything by analyzing data.                       But

6    I would feel violated by having to make an important

7    decision in the absence of having the data and looking

8    at it and doing some kind of an analysis.

9                     I just absolutely think -- I as an individual

10   think that dealing from the literature is almost absurd,

11   and I feel sorry for people who have to do that.

12                    DR. TEMPLE:     For what it's worth, I believe

13   my credentials as someone who believes in looking at the

14   data are adequate, and I believe I own one of the two

15   or three publications at FDA that actually ever showed

16   how the analysis makes a difference with the Anturin

17   reinfarction trials.

18                    So I'm a believer in that.            Those cases, it

19   should be noted, were cases in which the statistical

20   values were marginal, entirely based on a subset or

21   something like that.         They are not cases that are like

22   this.

23                    That said, I don't disagree.            We prefer to

24   have all the data, and there's usually a good reason.

25                    DR. LIPICKY:      No, but, you see, I wouldn't

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1    ever dream of calculating a p-value.                      The question is

2    what's related to what, and how are things related, and

3    how are correlations, and what goes where and, in

4    particular, how do the other arms -- how does amlodipine

5    look compared to chlorthalidone?

6                        If I didn't see a trend toward more heart

7    failure reports with amlodipine, I would buy in in a

8    moment.          Okay, I'd say, geez, this is real.           But without

9    seeing that, I'm saying to myself maybe that's not true.

10

11                       DR. TEMPLE:        No, you don't have enough

12   information about amlodipine to tell.

13                       DR. LIPICKY:      Well, that's what I'm telling

14   you.

15                       DR. TEMPLE:       No, but you won't with this

16   trial either.

17                       DR. LIPICKY:       No.    We will when the trial

18   is -- when we look at all of the results, but if we just

19   look at chlorthalidone and doxazosin, we will not be able

20   to -- you will not be able to give me the reassurance

21   I need to buy, like Tom does, the strength of evidence

22   here.

23                       I will be always short on that strength of

24   evidence.          But if the amlodipine arm really sort of look

25   like the same thing but not quite as bad, I'd buy Tom's

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1    argument in an instant.

2                      So I'm really -- I guess all I'm saying is

3    I don't think it's the mean dose.                 That isn't the thing

4    that is of importance.             We will argue about that some.

5                      ACTING CHAIRMAN BORER:              Well, okay.             The

6    sense of the Committee is that you need some additional

7    data before it's appropriate to provide information to

8    doctors.         That information should be available within

9    the foreseeable future, not years but months.                          I don't

10   know.

11                     At that time, it's necessary to review what

12   the data show and determine whether they still show the

13   strong suggestion of something that's not being done by

14   one drug that is being done by the other that doctors

15   probably ought to know about.

16                     At    that    time,     if    the       FDA   would       like

17   additional comments from this Committee, this Committee

18   will be happy to provide them.

19                     DR. LIPICKY:        Well, when you put it in the

20   context of months, you are clearly saying we do not have

21   to analyze the data.

22                     ACTING CHAIRMAN BORER:            That's right.             You

23   may not need to analyze the data.

24                     DR. LIPICKY:         No, no, no.         You are saying

25   you do not have to.

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1                     ACTING CHAIRMAN BORER:              No, no, I'm not

2    saying that.

3                     DR. LIPICKY:        Because we can't even get it

4    in a couple of months.

5                     ACTING CHAIRMAN BORER:             Right, but let me

6    tell you what I'm actually saying.                I'm actually saying

7    that you may see information that is so compelling that

8    you will choose to say something without demanding to

9    analyze the primary data.             You may, however, find that

10   the data are less compelling, and then we would be happy

11   to provide an additional opinion, or you may choose to

12   say I can't possibly do this without the primary data,

13   now that I've seen this.

14                    DR. GRABOYS:        Jeff, so at the end of the day

15   we are all leaving here saying that we feel comfortable

16   continuing our patients on the drug and prescribing it?

17                    ACTING CHAIRMAN BORER:             I feel comfortable

18   continuing my patients, of whom there are very few taking

19   doxazosin,       as    it   happens,      but   I    feel   comfortable

20   continuing my patients on doxazosin.

21                    I can tell you that not one of them -- Not

22   one of them is being treated with that drug as monotherapy

23   -- not one -- and that there may be patients who I am

24   seeing who are taking that drug for benign prostatic

25   hypertrophy.          If they are and I am seeing them -- and

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1    I'm a cardiologist, and I only see patients who have

2    cardiac problems.

3                      Those people probably are taking some other

4    cardio-active drug for some purpose, and I don't feel

5    uncomfortable in leaving them on their doxazosin for

6    benign prostatic hypertrophy, because I don't see any

7    evidence that this drug is causing harm.

8                      It may not be providing the benefit.               It may

9    or may not be.        It may not be.          I think the data show

10   that it doesn't seem to be providing some benefit that

11   another drug may be providing in the doses used according

12   to the regimen that was given.               But causing harm?            No.

13                     So, therefore, the answer to your question,

14   Tom, is yes, I do feel comfortable.

15                     DR. TEMPLE:     Jeff, I think you've done what

16   you can do, and we need to go back, think about it a little

17   more.        We may write to you for further suggestions.

18                     If anybody overnight thinks of an important

19   new way of writing this that's absolutely definitive and

20   perfect and no one would object to, send it to us.

21                     DR. LIPICKY:      Send it to Dr. Temple.

22                     DR. TEMPLE:     We both need to get it.            Right.

23                     ACTING CHAIRMAN BORER:            Okay.      Are there

24   any other issues that we need to deal with, any final

25   comments?          Does    anyone      feel     terribly       upset        or

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1   unfulfilled?      I don't see any yeses here.

2                    Meeting adjourned.

3                    (Whereupon, the foregoing matter went off

4   the record at 5:07 p.m.)

5




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